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Ligand-gated ion channels as operators

Ligand-gated ion channels as operators


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Isn't there a perfect analogy between ligand-gated and voltage-gated ion channels considered (mathematically) as (non-linear) operators, mapping one function (of time) to another one? Voltage-gated channels respond to voltage signals (= functions of time at a given location, not just a voltage), ligand-gated channels respond to neurotransmitter signals (not just neurotransmitters). Both yield a conductance profile (as a function of time, not just a conductance).

Both ligand- and voltage-gated ion channels display some form of hysteresis, i.e. the dependence of the state of a system on its history. Hysteresis can not be modelled by simple mathematical functions (by which dependencies normally are modelled), but maybe better by some non-linear operators.

With respect to the Hodgkin-Huxley model (that AliceD mentions in her answer): In this model (that is also used by Rall) the resistances (= ion channels) are just switched on and off instantaneously. But this may be oversimplified: it takes some time, and it cannot be done with arbitrary frequency. That's why we possibly need operators to describe them.

My question is: Are there references where ligand-gated channels are modelled mathematically as (non-linear) operators?


Short answer
Generally, Hodgkin & Huxley-derived models are used to describe the gating characteristics of ion channels and ligand operated receptors.

Background
Ligand-gated and voltage-operated ion channels do not really perform a memory task. Instead, they channel ions across the cell memnrane and by doing so they can convey information from out the cell (neurotransmitter release / voltage changes) into the cell. Their role is physiological and the way they are modeled is typically based on Hodgkin & Huxley kinetics (Sig, 2014) (Fig. 1).


Fig. 1. Hodgkin & Huxley model of membrane kinetics. source: Neuronal Dynamics

The Hodgkin-Huxley model models the semi-permeable cell membrane as a capacitor that separates the interior of the cell from the extracellular fluid. If an input current is injected into the cell, it may add further charge on the capacitor, or leak through the channels in the cell membrane. Each channel type is modeled by a resistor (conductor of current). The unspecific channel has a leak resistance R, the sodium channel a resistance RNa and the potassium channel a resistance RK. The diagonal arrow across the diagram of the resistor indicates that the value of the resistance is not fixed, but changes depending on whether the ion channel is open or closed. Because of active ion transport through the cell membrane, the ion concentration inside the cell is different from that in the extracellular liquid. The Nernst potential generated by the difference in ion concentration is represented by a battery. The Nernst potential depends on the ion and hence there are separate batteries for sodium, potassium, and the unspecific third channel, with battery voltages ENa, EK and EL (source: Neuronal Dynamics).

Now to your edited question: you say

[Ion channels] are just switched on and off instantaneously. But this may be oversimplified: it takes some time…

It goes further than that; voltage-operated ion channels like the Na+ channel are actively activated and inactivated with well-defined time constants that, among other things, govern the process of absolute and relative refractoriness of nerve cells (Fig. 2). The temporal gating characteristics in terms of activation and inactivation are expressed as time constants, which can be described in for example a Markov model (Wang et al., 2004). For example,

dm/dt = 1/τm(V) * (m∞(V)−m), where

m∞(V) = α(V) / [α(V)+β(V)] (9) τm(V) = 1 / [α(V)+β(V)]

Here, m∞ is the steady-state activation and τm is the activation time constant of the Na+ current (n∞ and τn represent the same quantities for the K+ current). In the case of h, h∞ and τh are called steady-state inactivation and inactivation time constant, respectively (source: Destexhe & Huguenard, 2007).

Similar formulas apply to the association and dissociation constants in ligand-operated channels, where timing of activation and inactivation are affected by the ligand's affinity for the receptor.


Fig. 2. Ion channel gating. source: Lehmann-Horne & Jurkatt-Rott (1999)

References
- Lehmann-Horne & Jurkatt-Rott, Physiol Rev (1999); 79(4): 1317-72
- Sig, J Gen Physiol (2014); 144(1) 7-26
- Wang et al., J Physiol (2004); 557(3): 705-17


Contents

Types Edit

This system [1] IPSPs can be temporally summed with subthreshold or suprathreshold EPSPs to reduce the amplitude of the resultant postsynaptic potential. Equivalent EPSPs (positive) and IPSPs (negative) can cancel each other out when summed. The balance between EPSPs and IPSPs is very important in the integration of electrical information produced by inhibitory and excitatory synapses.

Factors Edit

The size of the neuron can also affect the inhibitory postsynaptic potential. Simple temporal summation of postsynaptic potentials occurs in smaller neurons, whereas in larger neurons larger numbers of synapses and ionotropic receptors as well as a longer distance from the synapse to the soma enables the prolongation of interactions between neurons.

GABA is a very common neurotransmitter used in IPSPs in the adult mammalian brain and retina. [1] [6] GABA receptors are pentamers most commonly composed of three different subunits (α, β, γ), although several other subunits (δ,ε, θ, π, ρ) and conformations exist. The open channels are selectively permeable to chloride or potassium ions (depending on the type of receptor) and allow these ions to pass through the membrane. If the electrochemical potential of the ion is more negative than that of the action potential threshold then the resultant conductance change that occurs due to the binding of GABA to its receptors keeps the postsynaptic potential more negative than the threshold and decreases the probability of the postsynaptic neuron completing an action potential. Glycine molecules and receptors work much in the same way in the spinal cord, brain, and retina.

There are two types of inhibitory receptors:

Ionotropic receptors Edit

Ionotropic receptors (also known as ligand-gated ion channels) play an important role in inhibitory postsynaptic potentials. [1] A neurotransmitter binds to the extracellular site and opens the ion channel that is made up of a membrane-spanning domain that allows ions to flow across the membrane inside the postsynaptic cell. This type of receptor produces very fast postsynaptic actions within a couple of milliseconds of the presynaptic terminal receiving an action potential. These channels influence the amplitude and time-course of postsynaptic potentials as a whole. Ionotropic GABA receptors are used in binding for various drugs such as barbiturates (Phenobarbital, pentobarbital), steroids, and picrotoxin. Benzodiazepines (Valium) bind to the α and γ subunits of GABA receptors to improve GABAergic signaling. Alcohol also modulates ionotropic GABA receptors.

Metabotropic receptors Edit

Metabotropic receptors, often G-protein-coupled receptors, do not use ion channels in their structure they, instead, consist of an extracellular domain that binds to a neurotransmitter and an intracellular domain that binds to G-protein. [1] This begins the activation of the G-protein, which then releases itself from the receptor and interacts with ion channels and other proteins to open or close ion channels through intracellular messengers. They produce slow postsynaptic responses (from milliseconds to minutes) and can be activated in conjunction with ionotropic receptors to create both fast and slow postsynaptic potentials at one particular synapse. Metabotropic GABA receptors, heterodimers of R1 and R2 subunits, use potassium channels instead of chloride. They can also block calcium ion channels to hyperpolarize postsynaptic cells.

There are many applications of inhibitory postsynaptic potentials to the real world. Drugs that affect the actions of the neurotransmitter can treat neurological and psychological disorders through different combinations of types of receptors, G-proteins, and ion channels in postsynaptic neurons.

For example, studies researching opioid receptor-mediated receptor desensitizing and trafficking in the locus cereleus of the brain are being performed. When a high concentration of agonist is applied for an extended amount of time (fifteen minutes or more), hyperpolarization peaks and then decreases. This is significant because it is a prelude to tolerance the more opioids one needs for pain the greater the tolerance of the patient. These studies are important because it helps us to learn more about how we deal with pain and our responses to various substances that help treat pain. By studying our tolerance to pain, we can develop more efficient medications for pain treatment. [7]

In addition, research is being performed in the field of dopamine neurons in the ventral tegmental area, which deals with reward, and the substantia nigra, which is involved with movement and motivation. Metabotropic responses occur in dopamine neurons through the regulation of the excitability of cells. Opioids inhibit GABA release this decreases the amount of inhibition and allows them to fire spontaneously. Morphine and opioids relate to inhibitory postsynaptic potentials because they induce disinhibition in dopamine neurons. [7]

IPSPs can also be used to study the input-output characteristics of an inhibitory forebrain synapse used to further study learned behavior—for example in a study of song learning in birds at the University of Washington. [8] Poisson trains of unitary IPSPs were induced at a high frequency to reproduce postsynaptic spiking in the medial portion of the dorsalateral thalamic nucleus without any extra excitatory inputs. This shows an excess of thalamic GABAergic activation. This is important because spiking timing is needed for proper sound localization in the ascending auditory pathways. Songbirds use GABAergic calyceal synaptic terminals and a calcyx-like synapse such that each cell in the dorsalateral thalamic nucleus receives at most two axon terminals from the basal ganglia to create large postsynaptic currents.

Inhibitory postsynaptic potentials are also used to study the basal ganglia of amphibians to see how motor function is modulated through its inhibitory outputs from the striatum to the tectum and tegmentum. [9] Visually guided behaviors may be regulated through the inhibitory striato-tegmental pathway found in amphibians in a study performed at the Baylor College of Medicine and the Chinese Academy of Sciences. The basal ganglia in amphibians is very important in receiving visual, auditory, olfactory, and mechansensory inputs the disinhibitory striato-protecto-tectal pathway is important in prey-catching behaviors of amphibians. When the ipsilateral striatum of an adult toad was electrically stimulated, inhibitory postsynaptic potentials were induced in binocular tegmental neurons, which affects the visual system of the toad.

Inhibitory postsynaptic potentials can be inhibited themselves through a signaling process called "depolarized-induced suppression of inhibition (DSI)" in CA1 pyramidal cells and cerebellar Purkinje cells. [10] [11] In a laboratory setting step depolarizations the soma have been used to create DSIs, but it can also be achieved through synaptically induced depolarization of the dendrites. DSIs can be blocked by ionotropic receptor calcium ion channel antagonists on the somata and proximal apical dendrites of CA1 pyramidal cells. Dendritic inhibitory postsynaptic potentials can be severely reduced by DSIs through direct depolarization.

Along these lines, inhibitory postsynaptic potentials are useful in the signaling of the olfactory bulb to the olfactory cortex. [12] EPSPs are amplified by persistent sodium ion conductance in external tufted cells. Low-voltage activated calcium ion conductance enhances even larger EPSPs. The hyperpolarization activated nonselective cation conductance decreases EPSP summation and duration and they also change inhibitory inputs into postsynaptic excitation. IPSPs come into the picture when the tufted cells membranes are depolarized and IPSPs then cause inhibition. At resting threshold IPSPs induce action potentials. GABA is responsible for much of the work of the IPSPs in the external tufted cells.

Another interesting study of inhibitory postsynaptic potentials looks at neuronal theta rhythm oscillations that can be used to represent electrophysiological phenomena and various behaviors. [13] [14] Theta rhythms are found in the hippocampus and GABAergic synaptic inhibition helps to modulate them. They are dependent on IPSPs and started in either CA3 by muscarinic acetylcholine receptors and within C1 by the activation of group I metabotropic glutamate receptors. When interneurons are activated by metabotropic acetylcholine receptors in the CA1 region of rat hippocampal slices, a theta pattern of IPSPs in pyramidal cells occurs independent of the input. This research also studies DSIs, showing that DSIs interrupt metabotropic acetylcholine-initiated rhythm through the release of endocannabinoids. An endocannabinoid-dependent mechanism can disrupt theta IPSPs through action potentials delivered as a burst pattern or brief train. In addition, the activation of metabotropic glutamate receptors removes any theta IPSP activity through a G-protein, calcium ion–independent pathway.

Inhibitory postsynaptic potentials have also been studied in the Purkinje cell through dendritic amplification. The study focused in on the propagation of IPSPs along dendrites and its dependency of ionotropic receptors by measuring the amplitude and time-course of the inhibitory postsynaptic potential. The results showed that both compound and unitary inhibitory postsynaptic potentials are amplified by dendritic calcium ion channels. The width of a somatic IPSP is independent of the distance between the soma and the synapse whereas the rise time increases with this distance. These IPSPs also regulate theta rhythms in pyramidal cells. On the other hand, inhibitory postsynaptic potentials are depolarizing and sometimes excitatory in immature mammalian spinal neurons because of high concentrations of intracellular chloride through ionotropic GABA or glycine chloride ion channels. [15] These depolarizations activate voltage-dependent calcium channels. They later become hyperpolarizing as the mammal matures. To be specific, in rats, this maturation occurs during the perinatal period when brain stem projects reach the lumbar enlargement. Descending modulatory inputs are necessary for the developmental shift from depolarizing to hyperpolarizing inhibitory postsynaptic potentials. This was studied through complete spinal cord transections at birth of rats and recording IPSPs from lumbar motoneurons at the end of the first week after birth.

Glutamate, an excitatory neurotransmitter, is usually associated with excitatory postsynaptic potentials in synaptic transmission. However, a study completed at the Vollum Institute at the Oregon Health Sciences University demonstrates that glutamate can also be used to induce inhibitory postsynaptic potentials in neurons. [16] This study explains that metabotropic glutamate receptors feature activated G proteins in dopamine neurons that induce phosphoinositide hydrolysis. The resultant products bind to inositol triphosphate (IP3) receptors through calcium ion channels. The calcium comes from stores and activate potassium conductance, which causes a pure inhibition in the dopamine cells. The changing levels of synaptically released glutamate creates an excitation through the activation of ionotropic receptors, followed by the inhibition of metabotropic glutamate receptors.


Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders

Changes of voltage-gated ion channels and ligand-gated receptor channels caused by mutation or autoimmune attack are the cause of so-called channelopathies in the central and peripheral nervous system. We present the pathophysiology of channelopathies of the neuromuscular junction in terms of loss-of-function and gain-of-function principles. Autoantibodies generally have reduced access to the central nervous system, but in some cases this is enough to cause disease. A review is provided of recent findings implicating autoantibodies against ligand-activated receptor channels and potassium channels in psychiatric and neurological disorders, including schizophrenia and limbic encephalitis. The emergence of channelopathy-related neuropsychiatric disorders has implications for research and practice.

Keywords: AMPA receptor Caspr2 GABA receptor Lgi1 NMDA receptor acetylcholine receptor glycine receptor potassium channel.


Contents

Neuropharmacology did not appear in the scientific field until, in the early part of the 20th century, scientists were able to figure out a basic understanding of the nervous system and how nerves communicate between one another. Before this discovery, there were drugs that had been found that demonstrated some type of influence on the nervous system. In the 1930s, French scientists began working with a compound called phenothiazine in the hope of synthesizing a drug that would be able to combat malaria. Though this drug showed very little hope in the use against malaria-infected individuals, it was found to have sedative effects along with what appeared to be beneficial effects toward patients with Parkinson's disease. This black box method, wherein an investigator would administer a drug and examine the response without knowing how to relate drug action to patient response, was the main approach to this field, until, in the late 1940s and early 1950s, scientists were able to identify specific neurotransmitters, such as norepinephrine (involved in the constriction of blood vessels and the increase in heart rate and blood pressure), dopamine (the chemical whose shortage is involved in Parkinson's disease), and serotonin (soon to be recognized as deeply connected to depression [ citation needed ] ). In the 1950s, scientists also became better able to measure levels of specific neurochemicals in the body and thus correlate these levels with behavior. [3] The invention of the voltage clamp in 1949 allowed for the study of ion channels and the nerve action potential. These two major historical events in neuropharmacology allowed scientists not only to study how information is transferred from one neuron to another but also to study how a neuron processes this information within itself.

Neuropharmacology is a very broad region of science that encompasses many aspects of the nervous system from single neuron manipulation to entire areas of the brain, spinal cord, and peripheral nerves. To better understand the basis behind drug development, one must first understand how neurons communicate with one another.

To understand the potential advances in medicine that neuropharmacology can bring, it is important to understand how human behavior and thought processes are transferred from neuron to neuron and how medications can alter the chemical foundations of these processes.

Neurons are known as excitable cells because on its surface membrane there are an abundance of proteins known as ion-channels that allow small charged particles to pass in and out of the cell. The structure of the neuron allows chemical information to be received by its dendrites, propagated through the perikaryon (cell body) and down its axon, and eventually passing on to other neurons through its axon terminal. These voltage-gated ion channels allow for rapid depolarization throughout the cell. This depolarization, if it reaches a certain threshold, will cause an action potential. Once the action potential reaches the axon terminal, it will cause an influx of calcium ions into the cell. The calcium ions will then cause vesicles, small packets filled with neurotransmitters, to bind to the cell membrane and release its contents into the synapse. This cell is known as the pre-synaptic neuron, and the cell that interacts with the neurotransmitters released is known as the post-synaptic neuron. Once the neurotransmitter is released into the synapse, it can either bind to receptors on the post-synaptic cell, the pre-synaptic cell can re-uptake it and save it for later transmission, or it can be broken down by enzymes in the synapse specific to that certain neurotransmitter. These three different actions are major areas where drug action can affect communication between neurons. [3]

There are two types of receptors that neurotransmitters interact with on a post-synaptic neuron. The first types of receptors are ligand-gated ion channels or LGICs. LGIC receptors are the fastest types of transduction from chemical signal to electrical signal. Once the neurotransmitter binds to the receptor, it will cause a conformational change that will allow ions to directly flow into the cell. The second types are known as G-protein-coupled receptors or GPCRs. These are much slower than LGICs due to an increase in the amount of biochemical reactions that must take place intracellularly. Once the neurotransmitter binds to the GPCR protein, it causes a cascade of intracellular interactions that can lead to many different types of changes in cellular biochemistry, physiology, and gene expression. Neurotransmitter/receptor interactions in the field of neuropharmacology are extremely important because many drugs that are developed today have to do with disrupting this binding process. [4]

Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, and receptors on neurons, with the goal of developing new drugs that will treat neurological disorders such as pain, neurodegenerative diseases, and psychological disorders (also known in this case as neuropsychopharmacology). There are a few technical words that must be defined when relating neurotransmission to receptor action:

  1. Agonist – a molecule that binds to a receptor protein and activates that receptor
  2. Competitive antagonist – a molecule that binds to the same site on the receptor protein as the agonist, preventing activation of the receptor
  3. Non-competitive antagonist – a molecule that binds to a receptor protein on a different site than that of the agonist, but causes a conformational change in the protein that does not allow activation.

The following neurotransmitter/receptor interactions can be affected by synthetic compounds that act as one of the three above. Sodium/potassium ion channels can also be manipulated throughout a neuron to induce inhibitory effects of action potentials.

GABA Edit

The GABA neurotransmitter mediates the fast synaptic inhibition in the central nervous system. When GABA is released from its pre-synaptic cell, it will bind to a receptor (most likely the GABAA receptor) that causes the post-synaptic cell to hyperpolarize (stay below its action potential threshold). This will counteract the effect of any excitatory manipulation from other neurotransmitter/receptor interactions.

This GABAA receptor contains many binding sites that allow conformational changes and are the primary target for drug development. The most common of these binding sites, benzodiazepine, allows for both agonist and antagonist effects on the receptor. A common drug, diazepam, acts as an allosteric enhancer at this binding site. [5] Another receptor for GABA, known as GABAB, can be enhanced by a molecule called baclofen. This molecule acts as an agonist, therefore activating the receptor, and is known to help control and decrease spastic movement.

Dopamine Edit

The dopamine neurotransmitter mediates synaptic transmission by binding to five specific GPCRs. These five receptor proteins are separated into two classes due to whether the response elicits an excitatory or inhibitory response on the post-synaptic cell. There are many types of drugs, legal and illegal, that effect dopamine and its interactions in the brain. With Parkinson's disease, a disease that decreases the amount of dopamine in the brain, the dopamine precursor Levodopa is given to the patient due to the fact that dopamine cannot cross the blood–brain barrier and L-dopa can. Some dopamine agonists are also given to Parkinson's patients that have a disorder known as restless leg syndrome or RLS. Some examples of these are ropinirole and pramipexole. [6]

Psychological disorders like that of attention deficit hyperactivity disorder (ADHD) can be treated with drugs like methylphenidate (also known as Ritalin), which block the re-uptake of dopamine by the pre-synaptic cell, thereby providing an increase of dopamine left in the synaptic gap. This increase in synaptic dopamine will increase binding to receptors of the post-synaptic cell. This same mechanism is also used by other illegal and more potent stimulant drugs such as cocaine.

Serotonin Edit

The neurotransmitter serotonin has the ability to mediate synaptic transmission through either GPCR's or LGIC receptors. The excitatory or inhibitory post-synaptic effects of serotonin are determined by the type of receptor expressed in a given brain region. The most popular and widely used drugs for the regulation of serotonin during depression are known as SSRIs or selective serotonin reuptake inhibitors. These drugs inhibit the transport of serotonin back into the pre-synaptic neuron, leaving more serotonin in the synaptic gap.

Before the discovery of SSRIs, there were also drugs that inhibited the enzyme that breaks down serotonin. MAOIs or monoamine oxidase inhibitors increased the amount of serotonin in the synapse, but had many side-effects including intense migraines and high blood pressure. This was eventually linked to the drugs interacting with a common chemical known as tyramine found in many types of food. [7]

Ion channels Edit

Ion channels located on the surface membrane of the neuron allows for an influx of sodium ions and outward movement of potassium ions during an action potential. Selectively blocking these ion channels will decrease the likelihood of an action potential to occur. The drug riluzole is a neuroprotective drug that blocks sodium ion channels. Since these channels cannot activate, there is no action potential, and the neuron does not perform any transduction of chemical signals into electrical signals and the signal does not move on. This drug is used as an anesthetic as well as a sedative. [8]

One form of behavioral neuropharmacology focuses on the study of drug dependence and how drug addiction affects the human mind. Most research has shown that the major part of the brain that reinforces addiction through neurochemical reward is the nucleus accumbens. The image to the right shows how dopamine is projected into this area. Long-term excessive alcohol use can cause dependence and addiction. How this addiction occurs is described below.

Ethanol Edit

Alcohol's rewarding and reinforcing (i.e., addictive) properties are mediated through its effects on dopamine neurons in the mesolimbic reward pathway, which connects the ventral tegmental area to the nucleus accumbens (NAcc). [9] [10] One of alcohol's primary effects is the allosteric inhibition of NMDA receptors and facilitation of GABAA receptors (e.g., enhanced GABAA receptor-mediated chloride flux through allosteric regulation of the receptor). [11] At high doses, ethanol inhibits most ligand gated ion channels and voltage gated ion channels in neurons as well. [11] Alcohol inhibits sodium-potassium pumps in the cerebellum and this is likely how it impairs cerebellar computation and body co-ordination. [12] [13]

With acute alcohol consumption, dopamine is released in the synapses of the mesolimbic pathway, in turn heightening activation of postsynaptic D1 receptors. [9] [10] The activation of these receptors triggers postsynaptic internal signaling events through protein kinase A which ultimately phosphorylate cAMP response element binding protein (CREB), inducing CREB-mediated changes in gene expression. [9] [10]

With chronic alcohol intake, consumption of ethanol similarly induces CREB phosphorylation through the D1 receptor pathway, but it also alters NMDA receptor function through phosphorylation mechanisms [9] [10] an adaptive downregulation of the D1 receptor pathway and CREB function occurs as well. [9] [10] Chronic consumption is also associated with an effect on CREB phosphorylation and function via postsynaptic NMDA receptor signaling cascades through a MAPK/ERK pathway and CAMK-mediated pathway. [10] These modifications to CREB function in the mesolimbic pathway induce expression (i.e., increase gene expression) of ΔFosB in the NAcc , [10] where ΔFosB is the "master control protein" that, when overexpressed in the NAcc, is necessary and sufficient for the development and maintenance of an addictive state (i.e., its overexpression in the nucleus accumbens produces and then directly modulates compulsive alcohol consumption). [10] [14] [15] [16]

Parkinson's disease Edit

Parkinson's disease is a neurodegenerative disease described by the selective loss of dopaminergic neurons located in the substantia nigra. Today, the most commonly used drug to combat this disease is levodopa or L-DOPA. This precursor to dopamine can penetrate through the blood–brain barrier, whereas the neurotransmitter dopamine cannot. There has been extensive research to determine whether L-dopa is a better treatment for Parkinson's disease rather than other dopamine agonists. Some believe that the long-term use of L-dopa will compromise neuroprotection and, thus, eventually lead to dopaminergic cell death. Though there has been no proof, in-vivo or in-vitro, some still believe that the long-term use of dopamine agonists is better for the patient. [17]

Alzheimer's disease Edit

While there are a variety of hypotheses that have been proposed for the cause of Alzheimer's disease, the knowledge of this disease is far from complete to explain, making it difficult to develop methods for treatment. In the brain of Alzheimer's patients, both neuronal nicotinic acetylcholine (nACh) receptors and NMDA receptors are known to be down-regulated. Thus, four anticholinesterases have been developed and approved by the U.S. Food and Drug Administration (FDA) for the treatment in the U.S.A. However, these are not ideal drugs, considering their side-effects and limited effectiveness. One promising drug, nefiracetam, is being developed for the treatment of Alzheimer's and other patients with dementia, and has unique actions in potentiating the activity of both nACh receptors and NMDA receptors. [18]

Future Edit

With advances in technology and our understanding of the nervous system, the development of drugs will continue with increasing drug sensitivity and specificity. Structure–activity relationships are a major area of research within neuropharmacology an attempt to modify the effect or the potency (i.e., activity) of bioactive chemical compounds by modifying their chemical structures. [8]

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    ΔFosB as a therapeutic biomarker
    The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. .


Ligand-gated ion channels as operators - Psychology

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Feature Papers represent the most advanced research with significant potential for high impact in the field. Feature Papers are submitted upon individual invitation or recommendation by the scientific editors and undergo peer review prior to publication.

The Feature Paper can be either an original research article, a substantial novel research study that often involves several techniques or approaches, or a comprehensive review paper with concise and precise updates on the latest progress in the field that systematically reviews the most exciting advances in scientific literature. This type of paper provides an outlook on future directions of research or possible applications.

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to authors, or important in this field. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.


Matlab for Neuroscientists

MATLAB for Neuroscientists: An Introduction to Scientific Computing in MATLAB is the first comprehensive teaching resource and textbook for the teaching of MATLAB in the Neurosciences and in Psychology. MATLAB is unique in that it can be used to learn the entire empirical and experimental process, including stimulus generation, experimental control, data collection, data analysis and modeling. Thus a wide variety of computational problems can be addressed in a single programming environment. The idea is to empower advanced undergraduates and beginning graduate students by allowing them to design and implement their own analytical tools. As students advance in their research careers, they will have achieved the fluency required to understand and adapt more specialized tools as opposed to treating them as "black boxes".

Virtually all computational approaches in the book are covered by using genuine experimental data that are either collected as part of the lab project or were collected in the labs of the authors, providing the casual student with the look and feel of real data. In some cases, published data from classical papers are used to illustrate important concepts, giving students a computational understanding of critically important research.

MATLAB for Neuroscientists: An Introduction to Scientific Computing in MATLAB is the first comprehensive teaching resource and textbook for the teaching of MATLAB in the Neurosciences and in Psychology. MATLAB is unique in that it can be used to learn the entire empirical and experimental process, including stimulus generation, experimental control, data collection, data analysis and modeling. Thus a wide variety of computational problems can be addressed in a single programming environment. The idea is to empower advanced undergraduates and beginning graduate students by allowing them to design and implement their own analytical tools. As students advance in their research careers, they will have achieved the fluency required to understand and adapt more specialized tools as opposed to treating them as "black boxes".

Virtually all computational approaches in the book are covered by using genuine experimental data that are either collected as part of the lab project or were collected in the labs of the authors, providing the casual student with the look and feel of real data. In some cases, published data from classical papers are used to illustrate important concepts, giving students a computational understanding of critically important research.


Contents

Neuropharmacology did not appear in the scientific field until, in the early part of the 20th century, scientists were able to figure out a basic understanding of the nervous system and how nerves communicate between one another. Before this discovery, there were drugs that had been found that demonstrated some type of influence on the nervous system. In the 1930s, French scientists began working with a compound called phenothiazine in the hope of synthesizing a drug that would be able to combat malaria. Though this drug showed very little hope in the use against malaria-infected individuals, it was found to have sedative effects along with what appeared to be beneficial effects toward patients with Parkinson's disease. This black box method, wherein an investigator would administer a drug and examine the response without knowing how to relate drug action to patient response, was the main approach to this field, until, in the late 1940s and early 1950s, scientists were able to identify specific neurotransmitters, such as norepinephrine (involved in the constriction of blood vessels and the increase in heart rate and blood pressure), dopamine (the chemical whose shortage is involved in Parkinson's disease), and serotonin (soon to be recognized as deeply connected to depression [ citation needed ] ). In the 1950s, scientists also became better able to measure levels of specific neurochemicals in the body and thus correlate these levels with behavior. [3] The invention of the voltage clamp in 1949 allowed for the study of ion channels and the nerve action potential. These two major historical events in neuropharmacology allowed scientists not only to study how information is transferred from one neuron to another but also to study how a neuron processes this information within itself.

Neuropharmacology is a very broad region of science that encompasses many aspects of the nervous system from single neuron manipulation to entire areas of the brain, spinal cord, and peripheral nerves. To better understand the basis behind drug development, one must first understand how neurons communicate with one another.

To understand the potential advances in medicine that neuropharmacology can bring, it is important to understand how human behavior and thought processes are transferred from neuron to neuron and how medications can alter the chemical foundations of these processes.

Neurons are known as excitable cells because on its surface membrane there are an abundance of proteins known as ion-channels that allow small charged particles to pass in and out of the cell. The structure of the neuron allows chemical information to be received by its dendrites, propagated through the perikaryon (cell body) and down its axon, and eventually passing on to other neurons through its axon terminal. These voltage-gated ion channels allow for rapid depolarization throughout the cell. This depolarization, if it reaches a certain threshold, will cause an action potential. Once the action potential reaches the axon terminal, it will cause an influx of calcium ions into the cell. The calcium ions will then cause vesicles, small packets filled with neurotransmitters, to bind to the cell membrane and release its contents into the synapse. This cell is known as the pre-synaptic neuron, and the cell that interacts with the neurotransmitters released is known as the post-synaptic neuron. Once the neurotransmitter is released into the synapse, it can either bind to receptors on the post-synaptic cell, the pre-synaptic cell can re-uptake it and save it for later transmission, or it can be broken down by enzymes in the synapse specific to that certain neurotransmitter. These three different actions are major areas where drug action can affect communication between neurons. [3]

There are two types of receptors that neurotransmitters interact with on a post-synaptic neuron. The first types of receptors are ligand-gated ion channels or LGICs. LGIC receptors are the fastest types of transduction from chemical signal to electrical signal. Once the neurotransmitter binds to the receptor, it will cause a conformational change that will allow ions to directly flow into the cell. The second types are known as G-protein-coupled receptors or GPCRs. These are much slower than LGICs due to an increase in the amount of biochemical reactions that must take place intracellularly. Once the neurotransmitter binds to the GPCR protein, it causes a cascade of intracellular interactions that can lead to many different types of changes in cellular biochemistry, physiology, and gene expression. Neurotransmitter/receptor interactions in the field of neuropharmacology are extremely important because many drugs that are developed today have to do with disrupting this binding process. [4]

Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, and receptors on neurons, with the goal of developing new drugs that will treat neurological disorders such as pain, neurodegenerative diseases, and psychological disorders (also known in this case as neuropsychopharmacology). There are a few technical words that must be defined when relating neurotransmission to receptor action:

  1. Agonist – a molecule that binds to a receptor protein and activates that receptor
  2. Competitive antagonist – a molecule that binds to the same site on the receptor protein as the agonist, preventing activation of the receptor
  3. Non-competitive antagonist – a molecule that binds to a receptor protein on a different site than that of the agonist, but causes a conformational change in the protein that does not allow activation.

The following neurotransmitter/receptor interactions can be affected by synthetic compounds that act as one of the three above. Sodium/potassium ion channels can also be manipulated throughout a neuron to induce inhibitory effects of action potentials.

GABA Edit

The GABA neurotransmitter mediates the fast synaptic inhibition in the central nervous system. When GABA is released from its pre-synaptic cell, it will bind to a receptor (most likely the GABAA receptor) that causes the post-synaptic cell to hyperpolarize (stay below its action potential threshold). This will counteract the effect of any excitatory manipulation from other neurotransmitter/receptor interactions.

This GABAA receptor contains many binding sites that allow conformational changes and are the primary target for drug development. The most common of these binding sites, benzodiazepine, allows for both agonist and antagonist effects on the receptor. A common drug, diazepam, acts as an allosteric enhancer at this binding site. [5] Another receptor for GABA, known as GABAB, can be enhanced by a molecule called baclofen. This molecule acts as an agonist, therefore activating the receptor, and is known to help control and decrease spastic movement.

Dopamine Edit

The dopamine neurotransmitter mediates synaptic transmission by binding to five specific GPCRs. These five receptor proteins are separated into two classes due to whether the response elicits an excitatory or inhibitory response on the post-synaptic cell. There are many types of drugs, legal and illegal, that effect dopamine and its interactions in the brain. With Parkinson's disease, a disease that decreases the amount of dopamine in the brain, the dopamine precursor Levodopa is given to the patient due to the fact that dopamine cannot cross the blood–brain barrier and L-dopa can. Some dopamine agonists are also given to Parkinson's patients that have a disorder known as restless leg syndrome or RLS. Some examples of these are ropinirole and pramipexole. [6]

Psychological disorders like that of attention deficit hyperactivity disorder (ADHD) can be treated with drugs like methylphenidate (also known as Ritalin), which block the re-uptake of dopamine by the pre-synaptic cell, thereby providing an increase of dopamine left in the synaptic gap. This increase in synaptic dopamine will increase binding to receptors of the post-synaptic cell. This same mechanism is also used by other illegal and more potent stimulant drugs such as cocaine.

Serotonin Edit

The neurotransmitter serotonin has the ability to mediate synaptic transmission through either GPCR's or LGIC receptors. The excitatory or inhibitory post-synaptic effects of serotonin are determined by the type of receptor expressed in a given brain region. The most popular and widely used drugs for the regulation of serotonin during depression are known as SSRIs or selective serotonin reuptake inhibitors. These drugs inhibit the transport of serotonin back into the pre-synaptic neuron, leaving more serotonin in the synaptic gap.

Before the discovery of SSRIs, there were also drugs that inhibited the enzyme that breaks down serotonin. MAOIs or monoamine oxidase inhibitors increased the amount of serotonin in the synapse, but had many side-effects including intense migraines and high blood pressure. This was eventually linked to the drugs interacting with a common chemical known as tyramine found in many types of food. [7]

Ion channels Edit

Ion channels located on the surface membrane of the neuron allows for an influx of sodium ions and outward movement of potassium ions during an action potential. Selectively blocking these ion channels will decrease the likelihood of an action potential to occur. The drug riluzole is a neuroprotective drug that blocks sodium ion channels. Since these channels cannot activate, there is no action potential, and the neuron does not perform any transduction of chemical signals into electrical signals and the signal does not move on. This drug is used as an anesthetic as well as a sedative. [8]

One form of behavioral neuropharmacology focuses on the study of drug dependence and how drug addiction affects the human mind. Most research has shown that the major part of the brain that reinforces addiction through neurochemical reward is the nucleus accumbens. The image to the right shows how dopamine is projected into this area. Long-term excessive alcohol use can cause dependence and addiction. How this addiction occurs is described below.

Ethanol Edit

Alcohol's rewarding and reinforcing (i.e., addictive) properties are mediated through its effects on dopamine neurons in the mesolimbic reward pathway, which connects the ventral tegmental area to the nucleus accumbens (NAcc). [9] [10] One of alcohol's primary effects is the allosteric inhibition of NMDA receptors and facilitation of GABAA receptors (e.g., enhanced GABAA receptor-mediated chloride flux through allosteric regulation of the receptor). [11] At high doses, ethanol inhibits most ligand gated ion channels and voltage gated ion channels in neurons as well. [11] Alcohol inhibits sodium-potassium pumps in the cerebellum and this is likely how it impairs cerebellar computation and body co-ordination. [12] [13]

With acute alcohol consumption, dopamine is released in the synapses of the mesolimbic pathway, in turn heightening activation of postsynaptic D1 receptors. [9] [10] The activation of these receptors triggers postsynaptic internal signaling events through protein kinase A which ultimately phosphorylate cAMP response element binding protein (CREB), inducing CREB-mediated changes in gene expression. [9] [10]

With chronic alcohol intake, consumption of ethanol similarly induces CREB phosphorylation through the D1 receptor pathway, but it also alters NMDA receptor function through phosphorylation mechanisms [9] [10] an adaptive downregulation of the D1 receptor pathway and CREB function occurs as well. [9] [10] Chronic consumption is also associated with an effect on CREB phosphorylation and function via postsynaptic NMDA receptor signaling cascades through a MAPK/ERK pathway and CAMK-mediated pathway. [10] These modifications to CREB function in the mesolimbic pathway induce expression (i.e., increase gene expression) of ΔFosB in the NAcc , [10] where ΔFosB is the "master control protein" that, when overexpressed in the NAcc, is necessary and sufficient for the development and maintenance of an addictive state (i.e., its overexpression in the nucleus accumbens produces and then directly modulates compulsive alcohol consumption). [10] [14] [15] [16]

Parkinson's disease Edit

Parkinson's disease is a neurodegenerative disease described by the selective loss of dopaminergic neurons located in the substantia nigra. Today, the most commonly used drug to combat this disease is levodopa or L-DOPA. This precursor to dopamine can penetrate through the blood–brain barrier, whereas the neurotransmitter dopamine cannot. There has been extensive research to determine whether L-dopa is a better treatment for Parkinson's disease rather than other dopamine agonists. Some believe that the long-term use of L-dopa will compromise neuroprotection and, thus, eventually lead to dopaminergic cell death. Though there has been no proof, in-vivo or in-vitro, some still believe that the long-term use of dopamine agonists is better for the patient. [17]

Alzheimer's disease Edit

While there are a variety of hypotheses that have been proposed for the cause of Alzheimer's disease, the knowledge of this disease is far from complete to explain, making it difficult to develop methods for treatment. In the brain of Alzheimer's patients, both neuronal nicotinic acetylcholine (nACh) receptors and NMDA receptors are known to be down-regulated. Thus, four anticholinesterases have been developed and approved by the U.S. Food and Drug Administration (FDA) for the treatment in the U.S.A. However, these are not ideal drugs, considering their side-effects and limited effectiveness. One promising drug, nefiracetam, is being developed for the treatment of Alzheimer's and other patients with dementia, and has unique actions in potentiating the activity of both nACh receptors and NMDA receptors. [18]

Future Edit

With advances in technology and our understanding of the nervous system, the development of drugs will continue with increasing drug sensitivity and specificity. Structure–activity relationships are a major area of research within neuropharmacology an attempt to modify the effect or the potency (i.e., activity) of bioactive chemical compounds by modifying their chemical structures. [8]

  1. ^ Yeung AWK, Tzvetkov NT, Atanasov AG. When Neuroscience Meets Pharmacology: A Neuropharmacology Literature Analysis. Front Neurosci. 2018 Nov 1612:852. doi: 10.3389/fnins.2018.00852.
  2. ^Everitt, B. J. Robbins, T. W. (2005). "Neural systems of reinforcement for drug addiction: from actions to habits to compulsion". Nature Neuroscience. 8 (11): 1481–1489. doi:10.1038/nn1579. PMID16251991.
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  4. Wrobel, S. (2007). "Science, serotonin, and sadness: the biology of antidepressants: A series for the public". The FASEB Journal. 21 (13): 3404–17. doi:10.1096/fj.07-1102ufm. PMID17967927.
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  6. Lovinger, D. M. (2008). "Communication Networks in the Brain Neurons, Receptors, Neurotransmitters, and Alcohol. [Review]". Alcohol Research & Health. 31 (3): 196–214.
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  8. Sigel, E (2002). "Mapping of the benzodiazepine recognition site on GABA(A) receptors". Current Topics in Medicinal Chemistry. 2 (8): 833–9. doi:10.2174/1568026023393444. PMID12171574.
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  10. Winkelman, JW Allen, RP Tenzer, P Hening, W (2007). "Restless legs syndrome: nonpharmacologic and pharmacologic treatments". Geriatrics. 62 (10): 13–6. PMID17922563.
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  12. López-Muñoz, F. Alamo, C. (2009). "Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today". Current Pharmaceutical Design. 15 (14): 1563–1586. doi:10.2174/138161209788168001. PMID19442174.
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  16. "Alcoholism – Homo sapiens (human) Database entry". KEGG Pathway. 29 October 2014 . Retrieved 9 February 2015 . As one of the primary mediators of the rewarding effects of alcohol, dopaminergic ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) have been identified. Acute exposure to alcohol stimulates dopamine release into the NAc, which activates D1 receptors, stimulating PKA signaling and subsequent CREB-mediated gene expression, whereas chronic alcohol exposure leads to an adaptive downregulation of this pathway, in particular of CREB function. The decreased CREB function in the NAc may promote the intake of drugs of abuse to achieve an increase in reward and thus may be involved in the regulation of positive affective states of addiction. PKA signaling also affects NMDA receptor activity and may play an important role in neuroadaptation in response to chronic alcohol exposure.
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  18. Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway . Retrieved 31 October 2014 .
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  20. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 372. ISBN9780071481274 . Despite the high concentrations required for its psychoactive effects, ethanol exerts specific actions on the brain. The initial effects of ethanol result primarily from facilitation of GABAA receptors and inhibition of NMDA glutamate receptors. At higher doses, ethanol also inhibits the functioning of most ligand- and voltage-gated ion channels. It is not known whether ethanol selectively affects these channels via direct low affinity binding or via nonspecific disruption of plasma membranes which then selectively influences these highly complex, multimeric, transmembrane proteins. Ethanol allosterically regulates the GABAA receptor to enhance GABA-activated Cl− flux. The anxiolytic and sedative effects of ethanol, as well as those of barbiturates and benzodiazepines, result from enhancement of GABAergic function. Facilitation of GABAA receptor function is also believed to contribute to the reinforcing effects of these drugs. Not all GABAA receptors are ethanol sensitive. . Ethanol also acts as an NMDA antagonist by allosterically inhibiting the passage of glutamate-activated Na+ and Ca2+ currents through the NMDA receptor. . The reinforcing effects of ethanol are partly explained by its ability to activate mesolimbic dopamine circuitry, although it is not known whether this effect is mediated at the level of the VTA or NAc. It also is not known whether this activation of dopamine systems is caused primarily by facilitation of GABAA receptors or inhibition of NMDA receptors, or both. Ethanol reinforcement also is mediated in part by ethanol-induced release of endogenous opioid peptides within the mesolimbic dopamine system, although whether the VTA or NAc is the predominant site of such action is not yet known. Accordingly, the opioid receptor antagonist naltrexone reduces ethanol self-administration in animals and is used with modest effect to treat alcoholism in humans.
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  22. Forrest MD (April 2015). "Simulation of alcohol action upon a detailed Purkinje neuron model and a simpler surrogate model that runs >400 times faster". BMC Neuroscience. 16 (27): 27. doi:10.1186/s12868-015-0162-6. PMC4417229 . PMID25928094.
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  24. Forrest, Michael (April 2015). "The neuroscience reason we fall over when drunk". Science 2.0 . Retrieved January 2, 2019 .
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  26. Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am J Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID25083822.
    ΔFosB as a therapeutic biomarker
    The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. .


Matlab for Neuroscientists

MATLAB for Neuroscientists: An Introduction to Scientific Computing in MATLAB is the first comprehensive teaching resource and textbook for the teaching of MATLAB in the Neurosciences and in Psychology. MATLAB is unique in that it can be used to learn the entire empirical and experimental process, including stimulus generation, experimental control, data collection, data analysis and modeling. Thus a wide variety of computational problems can be addressed in a single programming environment. The idea is to empower advanced undergraduates and beginning graduate students by allowing them to design and implement their own analytical tools. As students advance in their research careers, they will have achieved the fluency required to understand and adapt more specialized tools as opposed to treating them as "black boxes".

Virtually all computational approaches in the book are covered by using genuine experimental data that are either collected as part of the lab project or were collected in the labs of the authors, providing the casual student with the look and feel of real data. In some cases, published data from classical papers are used to illustrate important concepts, giving students a computational understanding of critically important research.

MATLAB for Neuroscientists: An Introduction to Scientific Computing in MATLAB is the first comprehensive teaching resource and textbook for the teaching of MATLAB in the Neurosciences and in Psychology. MATLAB is unique in that it can be used to learn the entire empirical and experimental process, including stimulus generation, experimental control, data collection, data analysis and modeling. Thus a wide variety of computational problems can be addressed in a single programming environment. The idea is to empower advanced undergraduates and beginning graduate students by allowing them to design and implement their own analytical tools. As students advance in their research careers, they will have achieved the fluency required to understand and adapt more specialized tools as opposed to treating them as "black boxes".

Virtually all computational approaches in the book are covered by using genuine experimental data that are either collected as part of the lab project or were collected in the labs of the authors, providing the casual student with the look and feel of real data. In some cases, published data from classical papers are used to illustrate important concepts, giving students a computational understanding of critically important research.


Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders

Changes of voltage-gated ion channels and ligand-gated receptor channels caused by mutation or autoimmune attack are the cause of so-called channelopathies in the central and peripheral nervous system. We present the pathophysiology of channelopathies of the neuromuscular junction in terms of loss-of-function and gain-of-function principles. Autoantibodies generally have reduced access to the central nervous system, but in some cases this is enough to cause disease. A review is provided of recent findings implicating autoantibodies against ligand-activated receptor channels and potassium channels in psychiatric and neurological disorders, including schizophrenia and limbic encephalitis. The emergence of channelopathy-related neuropsychiatric disorders has implications for research and practice.

Keywords: AMPA receptor Caspr2 GABA receptor Lgi1 NMDA receptor acetylcholine receptor glycine receptor potassium channel.


Ligand-gated ion channels as operators - Psychology

All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited.

Feature Papers represent the most advanced research with significant potential for high impact in the field. Feature Papers are submitted upon individual invitation or recommendation by the scientific editors and undergo peer review prior to publication.

The Feature Paper can be either an original research article, a substantial novel research study that often involves several techniques or approaches, or a comprehensive review paper with concise and precise updates on the latest progress in the field that systematically reviews the most exciting advances in scientific literature. This type of paper provides an outlook on future directions of research or possible applications.

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to authors, or important in this field. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.


Contents

Types Edit

This system [1] IPSPs can be temporally summed with subthreshold or suprathreshold EPSPs to reduce the amplitude of the resultant postsynaptic potential. Equivalent EPSPs (positive) and IPSPs (negative) can cancel each other out when summed. The balance between EPSPs and IPSPs is very important in the integration of electrical information produced by inhibitory and excitatory synapses.

Factors Edit

The size of the neuron can also affect the inhibitory postsynaptic potential. Simple temporal summation of postsynaptic potentials occurs in smaller neurons, whereas in larger neurons larger numbers of synapses and ionotropic receptors as well as a longer distance from the synapse to the soma enables the prolongation of interactions between neurons.

GABA is a very common neurotransmitter used in IPSPs in the adult mammalian brain and retina. [1] [6] GABA receptors are pentamers most commonly composed of three different subunits (α, β, γ), although several other subunits (δ,ε, θ, π, ρ) and conformations exist. The open channels are selectively permeable to chloride or potassium ions (depending on the type of receptor) and allow these ions to pass through the membrane. If the electrochemical potential of the ion is more negative than that of the action potential threshold then the resultant conductance change that occurs due to the binding of GABA to its receptors keeps the postsynaptic potential more negative than the threshold and decreases the probability of the postsynaptic neuron completing an action potential. Glycine molecules and receptors work much in the same way in the spinal cord, brain, and retina.

There are two types of inhibitory receptors:

Ionotropic receptors Edit

Ionotropic receptors (also known as ligand-gated ion channels) play an important role in inhibitory postsynaptic potentials. [1] A neurotransmitter binds to the extracellular site and opens the ion channel that is made up of a membrane-spanning domain that allows ions to flow across the membrane inside the postsynaptic cell. This type of receptor produces very fast postsynaptic actions within a couple of milliseconds of the presynaptic terminal receiving an action potential. These channels influence the amplitude and time-course of postsynaptic potentials as a whole. Ionotropic GABA receptors are used in binding for various drugs such as barbiturates (Phenobarbital, pentobarbital), steroids, and picrotoxin. Benzodiazepines (Valium) bind to the α and γ subunits of GABA receptors to improve GABAergic signaling. Alcohol also modulates ionotropic GABA receptors.

Metabotropic receptors Edit

Metabotropic receptors, often G-protein-coupled receptors, do not use ion channels in their structure they, instead, consist of an extracellular domain that binds to a neurotransmitter and an intracellular domain that binds to G-protein. [1] This begins the activation of the G-protein, which then releases itself from the receptor and interacts with ion channels and other proteins to open or close ion channels through intracellular messengers. They produce slow postsynaptic responses (from milliseconds to minutes) and can be activated in conjunction with ionotropic receptors to create both fast and slow postsynaptic potentials at one particular synapse. Metabotropic GABA receptors, heterodimers of R1 and R2 subunits, use potassium channels instead of chloride. They can also block calcium ion channels to hyperpolarize postsynaptic cells.

There are many applications of inhibitory postsynaptic potentials to the real world. Drugs that affect the actions of the neurotransmitter can treat neurological and psychological disorders through different combinations of types of receptors, G-proteins, and ion channels in postsynaptic neurons.

For example, studies researching opioid receptor-mediated receptor desensitizing and trafficking in the locus cereleus of the brain are being performed. When a high concentration of agonist is applied for an extended amount of time (fifteen minutes or more), hyperpolarization peaks and then decreases. This is significant because it is a prelude to tolerance the more opioids one needs for pain the greater the tolerance of the patient. These studies are important because it helps us to learn more about how we deal with pain and our responses to various substances that help treat pain. By studying our tolerance to pain, we can develop more efficient medications for pain treatment. [7]

In addition, research is being performed in the field of dopamine neurons in the ventral tegmental area, which deals with reward, and the substantia nigra, which is involved with movement and motivation. Metabotropic responses occur in dopamine neurons through the regulation of the excitability of cells. Opioids inhibit GABA release this decreases the amount of inhibition and allows them to fire spontaneously. Morphine and opioids relate to inhibitory postsynaptic potentials because they induce disinhibition in dopamine neurons. [7]

IPSPs can also be used to study the input-output characteristics of an inhibitory forebrain synapse used to further study learned behavior—for example in a study of song learning in birds at the University of Washington. [8] Poisson trains of unitary IPSPs were induced at a high frequency to reproduce postsynaptic spiking in the medial portion of the dorsalateral thalamic nucleus without any extra excitatory inputs. This shows an excess of thalamic GABAergic activation. This is important because spiking timing is needed for proper sound localization in the ascending auditory pathways. Songbirds use GABAergic calyceal synaptic terminals and a calcyx-like synapse such that each cell in the dorsalateral thalamic nucleus receives at most two axon terminals from the basal ganglia to create large postsynaptic currents.

Inhibitory postsynaptic potentials are also used to study the basal ganglia of amphibians to see how motor function is modulated through its inhibitory outputs from the striatum to the tectum and tegmentum. [9] Visually guided behaviors may be regulated through the inhibitory striato-tegmental pathway found in amphibians in a study performed at the Baylor College of Medicine and the Chinese Academy of Sciences. The basal ganglia in amphibians is very important in receiving visual, auditory, olfactory, and mechansensory inputs the disinhibitory striato-protecto-tectal pathway is important in prey-catching behaviors of amphibians. When the ipsilateral striatum of an adult toad was electrically stimulated, inhibitory postsynaptic potentials were induced in binocular tegmental neurons, which affects the visual system of the toad.

Inhibitory postsynaptic potentials can be inhibited themselves through a signaling process called "depolarized-induced suppression of inhibition (DSI)" in CA1 pyramidal cells and cerebellar Purkinje cells. [10] [11] In a laboratory setting step depolarizations the soma have been used to create DSIs, but it can also be achieved through synaptically induced depolarization of the dendrites. DSIs can be blocked by ionotropic receptor calcium ion channel antagonists on the somata and proximal apical dendrites of CA1 pyramidal cells. Dendritic inhibitory postsynaptic potentials can be severely reduced by DSIs through direct depolarization.

Along these lines, inhibitory postsynaptic potentials are useful in the signaling of the olfactory bulb to the olfactory cortex. [12] EPSPs are amplified by persistent sodium ion conductance in external tufted cells. Low-voltage activated calcium ion conductance enhances even larger EPSPs. The hyperpolarization activated nonselective cation conductance decreases EPSP summation and duration and they also change inhibitory inputs into postsynaptic excitation. IPSPs come into the picture when the tufted cells membranes are depolarized and IPSPs then cause inhibition. At resting threshold IPSPs induce action potentials. GABA is responsible for much of the work of the IPSPs in the external tufted cells.

Another interesting study of inhibitory postsynaptic potentials looks at neuronal theta rhythm oscillations that can be used to represent electrophysiological phenomena and various behaviors. [13] [14] Theta rhythms are found in the hippocampus and GABAergic synaptic inhibition helps to modulate them. They are dependent on IPSPs and started in either CA3 by muscarinic acetylcholine receptors and within C1 by the activation of group I metabotropic glutamate receptors. When interneurons are activated by metabotropic acetylcholine receptors in the CA1 region of rat hippocampal slices, a theta pattern of IPSPs in pyramidal cells occurs independent of the input. This research also studies DSIs, showing that DSIs interrupt metabotropic acetylcholine-initiated rhythm through the release of endocannabinoids. An endocannabinoid-dependent mechanism can disrupt theta IPSPs through action potentials delivered as a burst pattern or brief train. In addition, the activation of metabotropic glutamate receptors removes any theta IPSP activity through a G-protein, calcium ion–independent pathway.

Inhibitory postsynaptic potentials have also been studied in the Purkinje cell through dendritic amplification. The study focused in on the propagation of IPSPs along dendrites and its dependency of ionotropic receptors by measuring the amplitude and time-course of the inhibitory postsynaptic potential. The results showed that both compound and unitary inhibitory postsynaptic potentials are amplified by dendritic calcium ion channels. The width of a somatic IPSP is independent of the distance between the soma and the synapse whereas the rise time increases with this distance. These IPSPs also regulate theta rhythms in pyramidal cells. On the other hand, inhibitory postsynaptic potentials are depolarizing and sometimes excitatory in immature mammalian spinal neurons because of high concentrations of intracellular chloride through ionotropic GABA or glycine chloride ion channels. [15] These depolarizations activate voltage-dependent calcium channels. They later become hyperpolarizing as the mammal matures. To be specific, in rats, this maturation occurs during the perinatal period when brain stem projects reach the lumbar enlargement. Descending modulatory inputs are necessary for the developmental shift from depolarizing to hyperpolarizing inhibitory postsynaptic potentials. This was studied through complete spinal cord transections at birth of rats and recording IPSPs from lumbar motoneurons at the end of the first week after birth.

Glutamate, an excitatory neurotransmitter, is usually associated with excitatory postsynaptic potentials in synaptic transmission. However, a study completed at the Vollum Institute at the Oregon Health Sciences University demonstrates that glutamate can also be used to induce inhibitory postsynaptic potentials in neurons. [16] This study explains that metabotropic glutamate receptors feature activated G proteins in dopamine neurons that induce phosphoinositide hydrolysis. The resultant products bind to inositol triphosphate (IP3) receptors through calcium ion channels. The calcium comes from stores and activate potassium conductance, which causes a pure inhibition in the dopamine cells. The changing levels of synaptically released glutamate creates an excitation through the activation of ionotropic receptors, followed by the inhibition of metabotropic glutamate receptors.


Contents

Nearly all cell membranes in animals, plants and fungi maintain a voltage difference between the exterior and interior of the cell, called the membrane potential. A typical voltage across an animal cell membrane is −70 mV. This means that the interior of the cell has a negative voltage relative to the exterior. In most types of cells, the membrane potential usually stays fairly constant. Some types of cells, however, are electrically active in the sense that their voltages fluctuate over time. In some types of electrically active cells, including neurons and muscle cells, the voltage fluctuations frequently take the form of a rapid upward spike followed by a rapid fall. These up-and-down cycles are known as action potentials. In some types of neurons, the entire up-and-down cycle takes place in a few thousandths of a second. In muscle cells, a typical action potential lasts about a fifth of a second. In some other types of cells and plants, an action potential may last three seconds or more. [3]

The electrical properties of a cell are determined by the structure of the membrane that surrounds it. A cell membrane consists of a lipid bilayer of molecules in which larger protein molecules are embedded. The lipid bilayer is highly resistant to movement of electrically charged ions, so it functions as an insulator. The large membrane-embedded proteins, in contrast, provide channels through which ions can pass across the membrane. Action potentials are driven by channel proteins whose configuration switches between closed and open states as a function of the voltage difference between the interior and exterior of the cell. These voltage-sensitive proteins are known as voltage-gated ion channels.

Process in a typical neuron Edit

All cells in animal body tissues are electrically polarized – in other words, they maintain a voltage difference across the cell's plasma membrane, known as the membrane potential. This electrical polarization results from a complex interplay between protein structures embedded in the membrane called ion pumps and ion channels. In neurons, the types of ion channels in the membrane usually vary across different parts of the cell, giving the dendrites, axon, and cell body different electrical properties. As a result, some parts of the membrane of a neuron may be excitable (capable of generating action potentials), whereas others are not. Recent studies have shown that the most excitable part of a neuron is the part after the axon hillock (the point where the axon leaves the cell body), which is called the initial segment, but the axon and cell body are also excitable in most cases. [4]

Each excitable patch of membrane has two important levels of membrane potential: the resting potential, which is the value the membrane potential maintains as long as nothing perturbs the cell, and a higher value called the threshold potential. At the axon hillock of a typical neuron, the resting potential is around –70 millivolts (mV) and the threshold potential is around –55 mV. Synaptic inputs to a neuron cause the membrane to depolarize or hyperpolarize that is, they cause the membrane potential to rise or fall. Action potentials are triggered when enough depolarization accumulates to bring the membrane potential up to threshold. When an action potential is triggered, the membrane potential abruptly shoots upward and then equally abruptly shoots back downward, often ending below the resting level, where it remains for some period of time. The shape of the action potential is stereotyped this means that the rise and fall usually have approximately the same amplitude and time course for all action potentials in a given cell. (Exceptions are discussed later in the article). In most neurons, the entire process takes place in about a thousandth of a second. Many types of neurons emit action potentials constantly at rates of up to 10–100 per second. However, some types are much quieter, and may go for minutes or longer without emitting any action potentials.

Action potentials result from the presence in a cell's membrane of special types of voltage-gated ion channels. [5] A voltage-gated ion channel is a transmembrane protein that has three key properties:

  1. It is capable of assuming more than one conformation.
  2. At least one of the conformations creates a channel through the membrane that is permeable to specific types of ions.
  3. The transition between conformations is influenced by the membrane potential.

Thus, a voltage-gated ion channel tends to be open for some values of the membrane potential, and closed for others. In most cases, however, the relationship between membrane potential and channel state is probabilistic and involves a time delay. Ion channels switch between conformations at unpredictable times: The membrane potential determines the rate of transitions and the probability per unit time of each type of transition.

Voltage-gated ion channels are capable of producing action potentials because they can give rise to positive feedback loops: The membrane potential controls the state of the ion channels, but the state of the ion channels controls the membrane potential. Thus, in some situations, a rise in the membrane potential can cause ion channels to open, thereby causing a further rise in the membrane potential. An action potential occurs when this positive feedback cycle (Hodgkin cycle) proceeds explosively. The time and amplitude trajectory of the action potential are determined by the biophysical properties of the voltage-gated ion channels that produce it. Several types of channels capable of producing the positive feedback necessary to generate an action potential do exist. Voltage-gated sodium channels are responsible for the fast action potentials involved in nerve conduction. Slower action potentials in muscle cells and some types of neurons are generated by voltage-gated calcium channels. Each of these types comes in multiple variants, with different voltage sensitivity and different temporal dynamics.

The most intensively studied type of voltage-dependent ion channels comprises the sodium channels involved in fast nerve conduction. These are sometimes known as Hodgkin-Huxley sodium channels because they were first characterized by Alan Hodgkin and Andrew Huxley in their Nobel Prize-winning studies of the biophysics of the action potential, but can more conveniently be referred to as NaV channels. (The "V" stands for "voltage".) An NaV channel has three possible states, known as deactivated, activated, and inactivated. The channel is permeable only to sodium ions when it is in the activated state. When the membrane potential is low, the channel spends most of its time in the deactivated (closed) state. If the membrane potential is raised above a certain level, the channel shows increased probability of transitioning to the activated (open) state. The higher the membrane potential the greater the probability of activation. Once a channel has activated, it will eventually transition to the inactivated (closed) state. It tends then to stay inactivated for some time, but, if the membrane potential becomes low again, the channel will eventually transition back to the deactivated state. During an action potential, most channels of this type go through a cycle deactivatedactivatedinactivateddeactivated. This is only the population average behavior, however – an individual channel can in principle make any transition at any time. However, the likelihood of a channel's transitioning from the inactivated state directly to the activated state is very low: A channel in the inactivated state is refractory until it has transitioned back to the deactivated state.

The outcome of all this is that the kinetics of the NaV channels are governed by a transition matrix whose rates are voltage-dependent in a complicated way. Since these channels themselves play a major role in determining the voltage, the global dynamics of the system can be quite difficult to work out. Hodgkin and Huxley approached the problem by developing a set of differential equations for the parameters that govern the ion channel states, known as the Hodgkin-Huxley equations. These equations have been extensively modified by later research, but form the starting point for most theoretical studies of action potential biophysics.

As the membrane potential is increased, sodium ion channels open, allowing the entry of sodium ions into the cell. This is followed by the opening of potassium ion channels that permit the exit of potassium ions from the cell. The inward flow of sodium ions increases the concentration of positively charged cations in the cell and causes depolarization, where the potential of the cell is higher than the cell's resting potential. The sodium channels close at the peak of the action potential, while potassium continues to leave the cell. The efflux of potassium ions decreases the membrane potential or hyperpolarizes the cell. For small voltage increases from rest, the potassium current exceeds the sodium current and the voltage returns to its normal resting value, typically −70 mV. [6] [7] [8] However, if the voltage increases past a critical threshold, typically 15 mV higher than the resting value, the sodium current dominates. This results in a runaway condition whereby the positive feedback from the sodium current activates even more sodium channels. Thus, the cell fires, producing an action potential. [6] [9] [10] [note 1] The frequency at which a neuron elicits action potentials is often referred to as a firing rate or neural firing rate.

Currents produced by the opening of voltage-gated channels in the course of an action potential are typically significantly larger than the initial stimulating current. Thus, the amplitude, duration, and shape of the action potential are determined largely by the properties of the excitable membrane and not the amplitude or duration of the stimulus. This all-or-nothing property of the action potential sets it apart from graded potentials such as receptor potentials, electrotonic potentials, subthreshold membrane potential oscillations, and synaptic potentials, which scale with the magnitude of the stimulus. A variety of action potential types exist in many cell types and cell compartments as determined by the types of voltage-gated channels, leak channels, channel distributions, ionic concentrations, membrane capacitance, temperature, and other factors.

The principal ions involved in an action potential are sodium and potassium cations sodium ions enter the cell, and potassium ions leave, restoring equilibrium. Relatively few ions need to cross the membrane for the membrane voltage to change drastically. The ions exchanged during an action potential, therefore, make a negligible change in the interior and exterior ionic concentrations. The few ions that do cross are pumped out again by the continuous action of the sodium–potassium pump, which, with other ion transporters, maintains the normal ratio of ion concentrations across the membrane. Calcium cations and chloride anions are involved in a few types of action potentials, such as the cardiac action potential and the action potential in the single-cell alga Acetabularia, respectively.

Although action potentials are generated locally on patches of excitable membrane, the resulting currents can trigger action potentials on neighboring stretches of membrane, precipitating a domino-like propagation. In contrast to passive spread of electric potentials (electrotonic potential), action potentials are generated anew along excitable stretches of membrane and propagate without decay. [11] Myelinated sections of axons are not excitable and do not produce action potentials and the signal is propagated passively as electrotonic potential. Regularly spaced unmyelinated patches, called the nodes of Ranvier, generate action potentials to boost the signal. Known as saltatory conduction, this type of signal propagation provides a favorable tradeoff of signal velocity and axon diameter. Depolarization of axon terminals, in general, triggers the release of neurotransmitter into the synaptic cleft. In addition, backpropagating action potentials have been recorded in the dendrites of pyramidal neurons, which are ubiquitous in the neocortex. [c] These are thought to have a role in spike-timing-dependent plasticity.

In the Hodgkin–Huxley membrane capacitance model, the speed of transmission of an action potential was undefined and it was assumed that adjacent areas became depolarized due to released ion interference with neighbouring channels. Measurements of ion diffusion and radii have since shown this not to be possible. [ citation needed ] Moreover, contradictory measurements of entropy changes and timing disputed the capacitance model as acting alone. [ citation needed ] Alternatively, Gilbert Ling's adsorption hypothesis, posits that the membrane potential and action potential of a living cell is due to the adsorption of mobile ions onto adsorption sites of cells. [12]

Maturation of the electrical properties of the action potential Edit

A neuron's ability to generate and propagate an action potential changes during development. How much the membrane potential of a neuron changes as the result of a current impulse is a function of the membrane input resistance. As a cell grows, more channels are added to the membrane, causing a decrease in input resistance. A mature neuron also undergoes shorter changes in membrane potential in response to synaptic currents. Neurons from a ferret lateral geniculate nucleus have a longer time constant and larger voltage deflection at P0 than they do at P30. [13] One consequence of the decreasing action potential duration is that the fidelity of the signal can be preserved in response to high frequency stimulation. Immature neurons are more prone to synaptic depression than potentiation after high frequency stimulation. [13]

In the early development of many organisms, the action potential is actually initially carried by calcium current rather than sodium current. The opening and closing kinetics of calcium channels during development are slower than those of the voltage-gated sodium channels that will carry the action potential in the mature neurons. The longer opening times for the calcium channels can lead to action potentials that are considerably slower than those of mature neurons. [13] Xenopus neurons initially have action potentials that take 60–90 ms. During development, this time decreases to 1 ms. There are two reasons for this drastic decrease. First, the inward current becomes primarily carried by sodium channels. [14] Second, the delayed rectifier, a potassium channel current, increases to 3.5 times its initial strength. [13]

In order for the transition from a calcium-dependent action potential to a sodium-dependent action potential to proceed new channels must be added to the membrane. If Xenopus neurons are grown in an environment with RNA synthesis or protein synthesis inhibitors that transition is prevented. [15] Even the electrical activity of the cell itself may play a role in channel expression. If action potentials in Xenopus myocytes are blocked, the typical increase in sodium and potassium current density is prevented or delayed. [16]

This maturation of electrical properties is seen across species. Xenopus sodium and potassium currents increase drastically after a neuron goes through its final phase of mitosis. The sodium current density of rat cortical neurons increases by 600% within the first two postnatal weeks. [13]

Anatomy of a neuron Edit

Several types of cells support an action potential, such as plant cells, muscle cells, and the specialized cells of the heart (in which occurs the cardiac action potential). However, the main excitable cell is the neuron, which also has the simplest mechanism for the action potential.

Neurons are electrically excitable cells composed, in general, of one or more dendrites, a single soma, a single axon and one or more axon terminals. Dendrites are cellular projections whose primary function is to receive synaptic signals. Their protrusions, known as dendritic spines, are designed to capture the neurotransmitters released by the presynaptic neuron. They have a high concentration of ligand-gated ion channels. These spines have a thin neck connecting a bulbous protrusion to the dendrite. This ensures that changes occurring inside the spine are less likely to affect the neighboring spines. The dendritic spine can, with rare exception (see LTP), act as an independent unit. The dendrites extend from the soma, which houses the nucleus, and many of the "normal" eukaryotic organelles. Unlike the spines, the surface of the soma is populated by voltage activated ion channels. These channels help transmit the signals generated by the dendrites. Emerging out from the soma is the axon hillock. This region is characterized by having a very high concentration of voltage-activated sodium channels. In general, it is considered to be the spike initiation zone for action potentials, [17] i.e. the trigger zone. Multiple signals generated at the spines, and transmitted by the soma all converge here. Immediately after the axon hillock is the axon. This is a thin tubular protrusion traveling away from the soma. The axon is insulated by a myelin sheath. Myelin is composed of either Schwann cells (in the peripheral nervous system) or oligodendrocytes (in the central nervous system), both of which are types of glial cells. Although glial cells are not involved with the transmission of electrical signals, they communicate and provide important biochemical support to neurons. [18] To be specific, myelin wraps multiple times around the axonal segment, forming a thick fatty layer that prevents ions from entering or escaping the axon. This insulation prevents significant signal decay as well as ensuring faster signal speed. This insulation, however, has the restriction that no channels can be present on the surface of the axon. There are, therefore, regularly spaced patches of membrane, which have no insulation. These nodes of Ranvier can be considered to be "mini axon hillocks", as their purpose is to boost the signal in order to prevent significant signal decay. At the furthest end, the axon loses its insulation and begins to branch into several axon terminals. These presynaptic terminals, or synaptic boutons, are a specialized area within the axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles.

Initiation Edit

Before considering the propagation of action potentials along axons and their termination at the synaptic knobs, it is helpful to consider the methods by which action potentials can be initiated at the axon hillock. The basic requirement is that the membrane voltage at the hillock be raised above the threshold for firing. [6] [7] [19] [20] There are several ways in which this depolarization can occur.

Dynamics Edit

Action potentials are most commonly initiated by excitatory postsynaptic potentials from a presynaptic neuron. [21] Typically, neurotransmitter molecules are released by the presynaptic neuron. These neurotransmitters then bind to receptors on the postsynaptic cell. This binding opens various types of ion channels. This opening has the further effect of changing the local permeability of the cell membrane and, thus, the membrane potential. If the binding increases the voltage (depolarizes the membrane), the synapse is excitatory. If, however, the binding decreases the voltage (hyperpolarizes the membrane), it is inhibitory. Whether the voltage is increased or decreased, the change propagates passively to nearby regions of the membrane (as described by the cable equation and its refinements). Typically, the voltage stimulus decays exponentially with the distance from the synapse and with time from the binding of the neurotransmitter. Some fraction of an excitatory voltage may reach the axon hillock and may (in rare cases) depolarize the membrane enough to provoke a new action potential. More typically, the excitatory potentials from several synapses must work together at nearly the same time to provoke a new action potential. Their joint efforts can be thwarted, however, by the counteracting inhibitory postsynaptic potentials.

Neurotransmission can also occur through electrical synapses. [22] Due to the direct connection between excitable cells in the form of gap junctions, an action potential can be transmitted directly from one cell to the next in either direction. The free flow of ions between cells enables rapid non-chemical-mediated transmission. Rectifying channels ensure that action potentials move only in one direction through an electrical synapse. [ citation needed ] Electrical synapses are found in all nervous systems, including the human brain, although they are a distinct minority. [23]

"All-or-none" principle Edit

The amplitude of an action potential is independent of the amount of current that produced it. In other words, larger currents do not create larger action potentials. Therefore, action potentials are said to be all-or-none signals, since either they occur fully or they do not occur at all. [d] [e] [f] This is in contrast to receptor potentials, whose amplitudes are dependent on the intensity of a stimulus. [24] In both cases, the frequency of action potentials is correlated with the intensity of a stimulus.

Sensory neurons Edit

In sensory neurons, an external signal such as pressure, temperature, light, or sound is coupled with the opening and closing of ion channels, which in turn alter the ionic permeabilities of the membrane and its voltage. [25] These voltage changes can again be excitatory (depolarizing) or inhibitory (hyperpolarizing) and, in some sensory neurons, their combined effects can depolarize the axon hillock enough to provoke action potentials. Some examples in humans include the olfactory receptor neuron and Meissner's corpuscle, which are critical for the sense of smell and touch, respectively. However, not all sensory neurons convert their external signals into action potentials some do not even have an axon. [26] Instead, they may convert the signal into the release of a neurotransmitter, or into continuous graded potentials, either of which may stimulate subsequent neuron(s) into firing an action potential. For illustration, in the human ear, hair cells convert the incoming sound into the opening and closing of mechanically gated ion channels, which may cause neurotransmitter molecules to be released. In similar manner, in the human retina, the initial photoreceptor cells and the next layer of cells (comprising bipolar cells and horizontal cells) do not produce action potentials only some amacrine cells and the third layer, the ganglion cells, produce action potentials, which then travel up the optic nerve.

Pacemaker potentials Edit

In sensory neurons, action potentials result from an external stimulus. However, some excitable cells require no such stimulus to fire: They spontaneously depolarize their axon hillock and fire action potentials at a regular rate, like an internal clock. [27] The voltage traces of such cells are known as pacemaker potentials. [28] The cardiac pacemaker cells of the sinoatrial node in the heart provide a good example. [g] Although such pacemaker potentials have a natural rhythm, it can be adjusted by external stimuli for instance, heart rate can be altered by pharmaceuticals as well as signals from the sympathetic and parasympathetic nerves. [29] The external stimuli do not cause the cell's repetitive firing, but merely alter its timing. [28] In some cases, the regulation of frequency can be more complex, leading to patterns of action potentials, such as bursting.

The course of the action potential can be divided into five parts: the rising phase, the peak phase, the falling phase, the undershoot phase, and the refractory period. During the rising phase the membrane potential depolarizes (becomes more positive). The point at which depolarization stops is called the peak phase. At this stage, the membrane potential reaches a maximum. Subsequent to this, there is a falling phase. During this stage the membrane potential becomes more negative, returning towards resting potential. The undershoot, or afterhyperpolarization, phase is the period during which the membrane potential temporarily becomes more negatively charged than when at rest (hyperpolarized). Finally, the time during which a subsequent action potential is impossible or difficult to fire is called the refractory period, which may overlap with the other phases. [30]

The course of the action potential is determined by two coupled effects. [31] First, voltage-sensitive ion channels open and close in response to changes in the membrane voltage Vm. This changes the membrane's permeability to those ions. [32] Second, according to the Goldman equation, this change in permeability changes the equilibrium potential Em, and, thus, the membrane voltage Vm. [h] Thus, the membrane potential affects the permeability, which then further affects the membrane potential. This sets up the possibility for positive feedback, which is a key part of the rising phase of the action potential. [6] [9] A complicating factor is that a single ion channel may have multiple internal "gates" that respond to changes in Vm in opposite ways, or at different rates. [33] [i] For example, although raising Vm opens most gates in the voltage-sensitive sodium channel, it also closes the channel's "inactivation gate", albeit more slowly. [34] Hence, when Vm is raised suddenly, the sodium channels open initially, but then close due to the slower inactivation.

The voltages and currents of the action potential in all of its phases were modeled accurately by Alan Lloyd Hodgkin and Andrew Huxley in 1952, [i] for which they were awarded the Nobel Prize in Physiology or Medicine in 1963. [lower-Greek 2] However, their model considers only two types of voltage-sensitive ion channels, and makes several assumptions about them, e.g., that their internal gates open and close independently of one another. In reality, there are many types of ion channels, [35] and they do not always open and close independently. [j]

Stimulation and rising phase Edit

A typical action potential begins at the axon hillock [36] with a sufficiently strong depolarization, e.g., a stimulus that increases Vm. This depolarization is often caused by the injection of extra sodium cations into the cell these cations can come from a wide variety of sources, such as chemical synapses, sensory neurons or pacemaker potentials.

For a neuron at rest, there is a high concentration of sodium and chloride ions in the extracellular fluid compared to the intracellular fluid, while there is a high concentration of potassium ions in the intracellular fluid compared to the extracellular fluid. The difference in concentrations, which causes ions to move from a high to a low concentration, and electrostatic effects (attraction of opposite charges) are responsible for the movement of ions in and out of the neuron. The inside of a neuron has a negative charge, relative to the cell exterior, from the movement of K + out of the cell. The neuron membrane is more permeable to K + than to other ions, allowing this ion to selectively move out of the cell, down its concentration gradient. This concentration gradient along with potassium leak channels present on the membrane of the neuron causes an efflux of potassium ions making the resting potential close to EK ≈ –75 mV. [37] Since Na + ions are in higher concentrations outside of the cell, the concentration and voltage differences both drive them into the cell when Na + channels open. Depolarization opens both the sodium and potassium channels in the membrane, allowing the ions to flow into and out of the axon, respectively. If the depolarization is small (say, increasing Vm from −70 mV to −60 mV), the outward potassium current overwhelms the inward sodium current and the membrane repolarizes back to its normal resting potential around −70 mV. [6] [7] [8] However, if the depolarization is large enough, the inward sodium current increases more than the outward potassium current and a runaway condition (positive feedback) results: the more inward current there is, the more Vm increases, which in turn further increases the inward current. [6] [9] A sufficiently strong depolarization (increase in Vm) causes the voltage-sensitive sodium channels to open the increasing permeability to sodium drives Vm closer to the sodium equilibrium voltage ENa≈ +55 mV. The increasing voltage in turn causes even more sodium channels to open, which pushes Vm still further towards ENa. This positive feedback continues until the sodium channels are fully open and Vm is close to ENa. [6] [7] [38] [39] The sharp rise in Vm and sodium permeability correspond to the rising phase of the action potential. [6] [7] [38] [39]

The critical threshold voltage for this runaway condition is usually around −45 mV, but it depends on the recent activity of the axon. A cell that has just fired an action potential cannot fire another one immediately, since the Na + channels have not recovered from the inactivated state. The period during which no new action potential can be fired is called the absolute refractory period. [40] [41] [42] At longer times, after some but not all of the ion channels have recovered, the axon can be stimulated to produce another action potential, but with a higher threshold, requiring a much stronger depolarization, e.g., to −30 mV. The period during which action potentials are unusually difficult to evoke is called the relative refractory period. [40] [41] [42]

Peak phase Edit

The positive feedback of the rising phase slows and comes to a halt as the sodium ion channels become maximally open. At the peak of the action potential, the sodium permeability is maximized and the membrane voltage Vm is nearly equal to the sodium equilibrium voltage ENa. However, the same raised voltage that opened the sodium channels initially also slowly shuts them off, by closing their pores the sodium channels become inactivated. [34] This lowers the membrane's permeability to sodium relative to potassium, driving the membrane voltage back towards the resting value. At the same time, the raised voltage opens voltage-sensitive potassium channels the increase in the membrane's potassium permeability drives Vm towards EK. [34] Combined, these changes in sodium and potassium permeability cause Vm to drop quickly, repolarizing the membrane and producing the "falling phase" of the action potential. [40] [43] [39] [44]

Afterhyperpolarization Edit

The depolarized voltage opens additional voltage-dependent potassium channels, and some of these do not close right away when the membrane returns to its normal resting voltage. In addition, further potassium channels open in response to the influx of calcium ions during the action potential. The intracellular concentration of potassium ions is transiently unusually low, making the membrane voltage Vm even closer to the potassium equilibrium voltage EK. The membrane potential goes below the resting membrane potential. Hence, there is an undershoot or hyperpolarization, termed an afterhyperpolarization, that persists until the membrane potassium permeability returns to its usual value, restoring the membrane potential to the resting state. [45] [43]

Refractory period Edit

Each action potential is followed by a refractory period, which can be divided into an absolute refractory period, during which it is impossible to evoke another action potential, and then a relative refractory period, during which a stronger-than-usual stimulus is required. [40] [41] [42] These two refractory periods are caused by changes in the state of sodium and potassium channel molecules. When closing after an action potential, sodium channels enter an "inactivated" state, in which they cannot be made to open regardless of the membrane potential—this gives rise to the absolute refractory period. Even after a sufficient number of sodium channels have transitioned back to their resting state, it frequently happens that a fraction of potassium channels remains open, making it difficult for the membrane potential to depolarize, and thereby giving rise to the relative refractory period. Because the density and subtypes of potassium channels may differ greatly between different types of neurons, the duration of the relative refractory period is highly variable.

The absolute refractory period is largely responsible for the unidirectional propagation of action potentials along axons. [46] At any given moment, the patch of axon behind the actively spiking part is refractory, but the patch in front, not having been activated recently, is capable of being stimulated by the depolarization from the action potential.

The action potential generated at the axon hillock propagates as a wave along the axon. [47] The currents flowing inwards at a point on the axon during an action potential spread out along the axon, and depolarize the adjacent sections of its membrane. If sufficiently strong, this depolarization provokes a similar action potential at the neighboring membrane patches. This basic mechanism was demonstrated by Alan Lloyd Hodgkin in 1937. After crushing or cooling nerve segments and thus blocking the action potentials, he showed that an action potential arriving on one side of the block could provoke another action potential on the other, provided that the blocked segment was sufficiently short. [k]

Once an action potential has occurred at a patch of membrane, the membrane patch needs time to recover before it can fire again. At the molecular level, this absolute refractory period corresponds to the time required for the voltage-activated sodium channels to recover from inactivation, i.e., to return to their closed state. [41] There are many types of voltage-activated potassium channels in neurons. Some of them inactivate fast (A-type currents) and some of them inactivate slowly or not inactivate at all this variability guarantees that there will be always an available source of current for repolarization, even if some of the potassium channels are inactivated because of preceding depolarization. On the other hand, all neuronal voltage-activated sodium channels inactivate within several milliseconds during strong depolarization, thus making following depolarization impossible until a substantial fraction of sodium channels have returned to their closed state. Although it limits the frequency of firing, [48] the absolute refractory period ensures that the action potential moves in only one direction along an axon. [46] The currents flowing in due to an action potential spread out in both directions along the axon. [49] However, only the unfired part of the axon can respond with an action potential the part that has just fired is unresponsive until the action potential is safely out of range and cannot restimulate that part. In the usual orthodromic conduction, the action potential propagates from the axon hillock towards the synaptic knobs (the axonal termini) propagation in the opposite direction—known as antidromic conduction—is very rare. [50] However, if a laboratory axon is stimulated in its middle, both halves of the axon are "fresh", i.e., unfired then two action potentials will be generated, one traveling towards the axon hillock and the other traveling towards the synaptic knobs.

Myelin and saltatory conduction Edit

In order to enable fast and efficient transduction of electrical signals in the nervous system, certain neuronal axons are covered with myelin sheaths. Myelin is a multilamellar membrane that enwraps the axon in segments separated by intervals known as nodes of Ranvier. It is produced by specialized cells: Schwann cells exclusively in the peripheral nervous system, and oligodendrocytes exclusively in the central nervous system. Myelin sheath reduces membrane capacitance and increases membrane resistance in the inter-node intervals, thus allowing a fast, saltatory movement of action potentials from node to node. [l] [m] [n] Myelination is found mainly in vertebrates, but an analogous system has been discovered in a few invertebrates, such as some species of shrimp. [o] Not all neurons in vertebrates are myelinated for example, axons of the neurons comprising the autonomous nervous system are not, in general, myelinated.

Myelin prevents ions from entering or leaving the axon along myelinated segments. As a general rule, myelination increases the conduction velocity of action potentials and makes them more energy-efficient. Whether saltatory or not, the mean conduction velocity of an action potential ranges from 1 meter per second (m/s) to over 100 m/s, and, in general, increases with axonal diameter. [p]

Action potentials cannot propagate through the membrane in myelinated segments of the axon. However, the current is carried by the cytoplasm, which is sufficient to depolarize the first or second subsequent node of Ranvier. Instead, the ionic current from an action potential at one node of Ranvier provokes another action potential at the next node this apparent "hopping" of the action potential from node to node is known as saltatory conduction. Although the mechanism of saltatory conduction was suggested in 1925 by Ralph Lillie, [q] the first experimental evidence for saltatory conduction came from Ichiji Tasaki [r] and Taiji Takeuchi [s] [51] and from Andrew Huxley and Robert Stämpfli. [t] By contrast, in unmyelinated axons, the action potential provokes another in the membrane immediately adjacent, and moves continuously down the axon like a wave.

Myelin has two important advantages: fast conduction speed and energy efficiency. For axons larger than a minimum diameter (roughly 1 micrometre), myelination increases the conduction velocity of an action potential, typically tenfold. [v] Conversely, for a given conduction velocity, myelinated fibers are smaller than their unmyelinated counterparts. For example, action potentials move at roughly the same speed (25 m/s) in a myelinated frog axon and an unmyelinated squid giant axon, but the frog axon has a roughly 30-fold smaller diameter and 1000-fold smaller cross-sectional area. Also, since the ionic currents are confined to the nodes of Ranvier, far fewer ions "leak" across the membrane, saving metabolic energy. This saving is a significant selective advantage, since the human nervous system uses approximately 20% of the body's metabolic energy. [v]

The length of axons' myelinated segments is important to the success of saltatory conduction. They should be as long as possible to maximize the speed of conduction, but not so long that the arriving signal is too weak to provoke an action potential at the next node of Ranvier. In nature, myelinated segments are generally long enough for the passively propagated signal to travel for at least two nodes while retaining enough amplitude to fire an action potential at the second or third node. Thus, the safety factor of saltatory conduction is high, allowing transmission to bypass nodes in case of injury. However, action potentials may end prematurely in certain places where the safety factor is low, even in unmyelinated neurons a common example is the branch point of an axon, where it divides into two axons. [53]

Some diseases degrade myelin and impair saltatory conduction, reducing the conduction velocity of action potentials. [w] The most well-known of these is multiple sclerosis, in which the breakdown of myelin impairs coordinated movement. [54]

Cable theory Edit

The flow of currents within an axon can be described quantitatively by cable theory [55] and its elaborations, such as the compartmental model. [56] Cable theory was developed in 1855 by Lord Kelvin to model the transatlantic telegraph cable [x] and was shown to be relevant to neurons by Hodgkin and Rushton in 1946. [y] In simple cable theory, the neuron is treated as an electrically passive, perfectly cylindrical transmission cable, which can be described by a partial differential equation [55]

where V(x, t) is the voltage across the membrane at a time t and a position x along the length of the neuron, and where λ and τ are the characteristic length and time scales on which those voltages decay in response to a stimulus. Referring to the circuit diagram on the right, these scales can be determined from the resistances and capacitances per unit length. [57]

These time and length-scales can be used to understand the dependence of the conduction velocity on the diameter of the neuron in unmyelinated fibers. For example, the time-scale τ increases with both the membrane resistance rm and capacitance cm. As the capacitance increases, more charge must be transferred to produce a given transmembrane voltage (by the equation Q = CV) as the resistance increases, less charge is transferred per unit time, making the equilibration slower. In a similar manner, if the internal resistance per unit length ri is lower in one axon than in another (e.g., because the radius of the former is larger), the spatial decay length λ becomes longer and the conduction velocity of an action potential should increase. If the transmembrane resistance rm is increased, that lowers the average "leakage" current across the membrane, likewise causing λ to become longer, increasing the conduction velocity.

Chemical synapses Edit

In general, action potentials that reach the synaptic knobs cause a neurotransmitter to be released into the synaptic cleft. [z] Neurotransmitters are small molecules that may open ion channels in the postsynaptic cell most axons have the same neurotransmitter at all of their termini. The arrival of the action potential opens voltage-sensitive calcium channels in the presynaptic membrane the influx of calcium causes vesicles filled with neurotransmitter to migrate to the cell's surface and release their contents into the synaptic cleft. [aa] This complex process is inhibited by the neurotoxins tetanospasmin and botulinum toxin, which are responsible for tetanus and botulism, respectively. [ab]

Electrical synapses Edit

Some synapses dispense with the "middleman" of the neurotransmitter, and connect the presynaptic and postsynaptic cells together. [ac] When an action potential reaches such a synapse, the ionic currents flowing into the presynaptic cell can cross the barrier of the two cell membranes and enter the postsynaptic cell through pores known as connexons. [ad] Thus, the ionic currents of the presynaptic action potential can directly stimulate the postsynaptic cell. Electrical synapses allow for faster transmission because they do not require the slow diffusion of neurotransmitters across the synaptic cleft. Hence, electrical synapses are used whenever fast response and coordination of timing are crucial, as in escape reflexes, the retina of vertebrates, and the heart.

Neuromuscular junctions Edit

A special case of a chemical synapse is the neuromuscular junction, in which the axon of a motor neuron terminates on a muscle fiber. [ae] In such cases, the released neurotransmitter is acetylcholine, which binds to the acetylcholine receptor, an integral membrane protein in the membrane (the sarcolemma) of the muscle fiber. [af] However, the acetylcholine does not remain bound rather, it dissociates and is hydrolyzed by the enzyme, acetylcholinesterase, located in the synapse. This enzyme quickly reduces the stimulus to the muscle, which allows the degree and timing of muscular contraction to be regulated delicately. Some poisons inactivate acetylcholinesterase to prevent this control, such as the nerve agents sarin and tabun, [ag] and the insecticides diazinon and malathion. [ah]

Cardiac action potentials Edit

The cardiac action potential differs from the neuronal action potential by having an extended plateau, in which the membrane is held at a high voltage for a few hundred milliseconds prior to being repolarized by the potassium current as usual. [ai] This plateau is due to the action of slower calcium channels opening and holding the membrane voltage near their equilibrium potential even after the sodium channels have inactivated.

The cardiac action potential plays an important role in coordinating the contraction of the heart. [ai] The cardiac cells of the sinoatrial node provide the pacemaker potential that synchronizes the heart. The action potentials of those cells propagate to and through the atrioventricular node (AV node), which is normally the only conduction pathway between the atria and the ventricles. Action potentials from the AV node travel through the bundle of His and thence to the Purkinje fibers. [note 2] Conversely, anomalies in the cardiac action potential—whether due to a congenital mutation or injury—can lead to human pathologies, especially arrhythmias. [ai] Several anti-arrhythmia drugs act on the cardiac action potential, such as quinidine, lidocaine, beta blockers, and verapamil. [aj]

Muscular action potentials Edit

The action potential in a normal skeletal muscle cell is similar to the action potential in neurons. [58] Action potentials result from the depolarization of the cell membrane (the sarcolemma), which opens voltage-sensitive sodium channels these become inactivated and the membrane is repolarized through the outward current of potassium ions. The resting potential prior to the action potential is typically −90mV, somewhat more negative than typical neurons. The muscle action potential lasts roughly 2–4 ms, the absolute refractory period is roughly 1–3 ms, and the conduction velocity along the muscle is roughly 5 m/s. The action potential releases calcium ions that free up the tropomyosin and allow the muscle to contract. Muscle action potentials are provoked by the arrival of a pre-synaptic neuronal action potential at the neuromuscular junction, which is a common target for neurotoxins. [ag]

Plant action potentials Edit

Plant and fungal cells [ak] are also electrically excitable. The fundamental difference from animal action potentials is that the depolarization in plant cells is not accomplished by an uptake of positive sodium ions, but by release of negative chloride ions. [al] [am] [an] In 1906, J. C. Bose published the first measurements of action potentials in plants, which had previously been discovered by Burdon-Sanderson and Darwin. [59] An increase in cytoplasmic calcium ions may be the cause of anion release into the cell. This makes calcium a precursor to ion movements, such as the influx of negative chloride ions and efflux of positive potassium ions, as seen in barley leaves. [60]

The initial influx of calcium ions also poses a small cellular depolarization, causing the voltage-gated ion channels to open and allowing full depolarization to be propagated by chloride ions.

Some plants (e.g. Dionaea muscipula) use sodium-gated channels to operate movements and essentially "count". Dionaea muscipula, also known as the Venus flytrap, is found in subtropical wetlands in North and South Carolina. [61] When there are poor soil nutrients, the flytrap relies on a diet of insects and animals. [62] Despite research on the plant, there lacks an understanding behind the molecular basis to the Venus flytraps, and carnivore plants in general. [63]

However, plenty of research has been done on action potentials and how they affect movement and clockwork within the Venus flytrap. To start, the resting membrane potential of the Venus flytrap (-120mV) is lower than animal cells (usually -90mV to -40mV). [63] [64] The lower resting potential makes it easier to activate an action potential. Thus, when an insect lands on the trap of the plant, it triggers a hair-like mechanoreceptor. [63] This receptor then activates an action potential which lasts around 1.5 ms. [65] Ultimately, this causes an increase of positive Calcium ions into the cell, slightly depolarizing it.

However, the flytrap doesn't close after one trigger. Instead, it requires the activation of 2 or more hairs. [62] [63] If only one hair is triggered, it throws the activation as a false positive. Further, the second hair must be activated within a certain time interval (0.75 s - 40 s) for it to register with the first activation. [63] Thus, a buildup of calcium starts and slowly falls from the first trigger. When the second action potential is fired within the time interval, it reaches the Calcium threshold to depolarize the cell, closing the trap on the prey within a fraction of a second. [63]

Together with the subsequent release of positive potassium ions the action potential in plants involves an osmotic loss of salt (KCl). Whereas, the animal action potential is osmotically neutral because equal amounts of entering sodium and leaving potassium cancel each other osmotically. The interaction of electrical and osmotic relations in plant cells [ao] appears to have arisen from an osmotic function of electrical excitability in a common unicellular ancestors of plants and animals under changing salinity conditions. Further, the present function of rapid signal transmission is seen as a newer accomplishment of metazoan cells in a more stable osmotic environment. [66] It is likely that the familiar signaling function of action potentials in some vascular plants (e.g. Mimosa pudica) arose independently from that in metazoan excitable cells.

Unlike the rising phase and peak, the falling phase and after-hyperpolarization seem to depend primarily on cations that are not calcium. To initiate repolarization, the cell requires movement of potassium out of the cell through passive transportation on the membrane. This differs from neurons because the movement of potassium does not dominate the decrease in membrane potential In fact, to fully repolarize, a plant cell requires energy in the form of ATP to assist in the release of hydrogen from the cell – utilizing a transporter commonly known as H+-ATPase. [67] [63]

Action potentials are found throughout multicellular organisms, including plants, invertebrates such as insects, and vertebrates such as reptiles and mammals. [ap] Sponges seem to be the main phylum of multicellular eukaryotes that does not transmit action potentials, although some studies have suggested that these organisms have a form of electrical signaling, too. [aq] The resting potential, as well as the size and duration of the action potential, have not varied much with evolution, although the conduction velocity does vary dramatically with axonal diameter and myelination.

Comparison of action potentials (APs) from a representative cross-section of animals [68]
Animal Cell type Resting potential (mV) AP increase (mV) AP duration (ms) Conduction speed (m/s)
Squid (Loligo) Giant axon −60 120 0.75 35
Earthworm (Lumbricus) Median giant fiber −70 100 1.0 30
Cockroach (Periplaneta) Giant fiber −70 80–104 0.4 10
Frog (Rana) Sciatic nerve axon −60 to −80 110–130 1.0 7–30
Cat (Felis) Spinal motor neuron −55 to −80 80–110 1–1.5 30–120

Given its conservation throughout evolution, the action potential seems to confer evolutionary advantages. One function of action potentials is rapid, long-range signaling within the organism the conduction velocity can exceed 110 m/s, which is one-third the speed of sound. For comparison, a hormone molecule carried in the bloodstream moves at roughly 8 m/s in large arteries. Part of this function is the tight coordination of mechanical events, such as the contraction of the heart. A second function is the computation associated with its generation. Being an all-or-none signal that does not decay with transmission distance, the action potential has similar advantages to digital electronics. The integration of various dendritic signals at the axon hillock and its thresholding to form a complex train of action potentials is another form of computation, one that has been exploited biologically to form central pattern generators and mimicked in artificial neural networks.

The common prokaryotic/eukaryotic ancestor, which lived perhaps four billion years ago, is believed to have had voltage-gated channels. This functionality was likely, at some later point, cross-purposed to provide a communication mechanism. Even modern single-celled bacteria can utilize action potentials to communicate with other bacteria in the same biofilm. [69]

The study of action potentials has required the development of new experimental methods. The initial work, prior to 1955, was carried out primarily by Alan Lloyd Hodgkin and Andrew Fielding Huxley, who were, along John Carew Eccles, awarded the 1963 Nobel Prize in Physiology or Medicine for their contribution to the description of the ionic basis of nerve conduction. It focused on three goals: isolating signals from single neurons or axons, developing fast, sensitive electronics, and shrinking electrodes enough that the voltage inside a single cell could be recorded.

The first problem was solved by studying the giant axons found in the neurons of the squid (Loligo forbesii and Doryteuthis pealeii, at the time classified as Loligo pealeii). [ar] These axons are so large in diameter (roughly 1 mm, or 100-fold larger than a typical neuron) that they can be seen with the naked eye, making them easy to extract and manipulate. [i] [as] However, they are not representative of all excitable cells, and numerous other systems with action potentials have been studied.

The second problem was addressed with the crucial development of the voltage clamp, [at] which permitted experimenters to study the ionic currents underlying an action potential in isolation, and eliminated a key source of electronic noise, the current IC associated with the capacitance C of the membrane. [71] Since the current equals C times the rate of change of the transmembrane voltage Vm, the solution was to design a circuit that kept Vm fixed (zero rate of change) regardless of the currents flowing across the membrane. Thus, the current required to keep Vm at a fixed value is a direct reflection of the current flowing through the membrane. Other electronic advances included the use of Faraday cages and electronics with high input impedance, so that the measurement itself did not affect the voltage being measured. [72]

The third problem, that of obtaining electrodes small enough to record voltages within a single axon without perturbing it, was solved in 1949 with the invention of the glass micropipette electrode, [au] which was quickly adopted by other researchers. [av] [aw] Refinements of this method are able to produce electrode tips that are as fine as 100 Å (10 nm), which also confers high input impedance. [73] Action potentials may also be recorded with small metal electrodes placed just next to a neuron, with neurochips containing EOSFETs, or optically with dyes that are sensitive to Ca 2+ or to voltage. [ax]

While glass micropipette electrodes measure the sum of the currents passing through many ion channels, studying the electrical properties of a single ion channel became possible in the 1970s with the development of the patch clamp by Erwin Neher and Bert Sakmann. For this discovery, they were awarded the Nobel Prize in Physiology or Medicine in 1991. [lower-Greek 3] Patch-clamping verified that ionic channels have discrete states of conductance, such as open, closed and inactivated.

Optical imaging technologies have been developed in recent years to measure action potentials, either via simultaneous multisite recordings or with ultra-spatial resolution. Using voltage-sensitive dyes, action potentials have been optically recorded from a tiny patch of cardiomyocyte membrane. [ay]

Several neurotoxins, both natural and synthetic, are designed to block the action potential. Tetrodotoxin from the pufferfish and saxitoxin from the Gonyaulax (the dinoflagellate genus responsible for "red tides") block action potentials by inhibiting the voltage-sensitive sodium channel [az] similarly, dendrotoxin from the black mamba snake inhibits the voltage-sensitive potassium channel. Such inhibitors of ion channels serve an important research purpose, by allowing scientists to "turn off" specific channels at will, thus isolating the other channels' contributions they can also be useful in purifying ion channels by affinity chromatography or in assaying their concentration. However, such inhibitors also make effective neurotoxins, and have been considered for use as chemical weapons. Neurotoxins aimed at the ion channels of insects have been effective insecticides one example is the synthetic permethrin, which prolongs the activation of the sodium channels involved in action potentials. The ion channels of insects are sufficiently different from their human counterparts that there are few side effects in humans.

The role of electricity in the nervous systems of animals was first observed in dissected frogs by Luigi Galvani, who studied it from 1791 to 1797. [ba] Galvani's results stimulated Alessandro Volta to develop the Voltaic pile—the earliest-known electric battery—with which he studied animal electricity (such as electric eels) and the physiological responses to applied direct-current voltages. [bb]

Scientists of the 19th century studied the propagation of electrical signals in whole nerves (i.e., bundles of neurons) and demonstrated that nervous tissue was made up of cells, instead of an interconnected network of tubes (a reticulum). [74] Carlo Matteucci followed up Galvani's studies and demonstrated that cell membranes had a voltage across them and could produce direct current. Matteucci's work inspired the German physiologist, Emil du Bois-Reymond, who discovered the action potential in 1843. [75] The conduction velocity of action potentials was first measured in 1850 by du Bois-Reymond's friend, Hermann von Helmholtz. [76] To establish that nervous tissue is made up of discrete cells, the Spanish physician Santiago Ramón y Cajal and his students used a stain developed by Camillo Golgi to reveal the myriad shapes of neurons, which they rendered painstakingly. For their discoveries, Golgi and Ramón y Cajal were awarded the 1906 Nobel Prize in Physiology. [lower-Greek 4] Their work resolved a long-standing controversy in the neuroanatomy of the 19th century Golgi himself had argued for the network model of the nervous system.

The 20th century was a significant era for electrophysiology. In 1902 and again in 1912, Julius Bernstein advanced the hypothesis that the action potential resulted from a change in the permeability of the axonal membrane to ions. [bc] [77] Bernstein's hypothesis was confirmed by Ken Cole and Howard Curtis, who showed that membrane conductance increases during an action potential. [bd] In 1907, Louis Lapicque suggested that the action potential was generated as a threshold was crossed, [be] what would be later shown as a product of the dynamical systems of ionic conductances. In 1949, Alan Hodgkin and Bernard Katz refined Bernstein's hypothesis by considering that the axonal membrane might have different permeabilities to different ions in particular, they demonstrated the crucial role of the sodium permeability for the action potential. [bf] They made the first actual recording of the electrical changes across the neuronal membrane that mediate the action potential. [lower-Greek 5] This line of research culminated in the five 1952 papers of Hodgkin, Katz and Andrew Huxley, in which they applied the voltage clamp technique to determine the dependence of the axonal membrane's permeabilities to sodium and potassium ions on voltage and time, from which they were able to reconstruct the action potential quantitatively. [i] Hodgkin and Huxley correlated the properties of their mathematical model with discrete ion channels that could exist in several different states, including "open", "closed", and "inactivated". Their hypotheses were confirmed in the mid-1970s and 1980s by Erwin Neher and Bert Sakmann, who developed the technique of patch clamping to examine the conductance states of individual ion channels. [bg] In the 21st century, researchers are beginning to understand the structural basis for these conductance states and for the selectivity of channels for their species of ion, [bh] through the atomic-resolution crystal structures, [bi] fluorescence distance measurements [bj] and cryo-electron microscopy studies. [bk]

Julius Bernstein was also the first to introduce the Nernst equation for resting potential across the membrane this was generalized by David E. Goldman to the eponymous Goldman equation in 1943. [h] The sodium–potassium pump was identified in 1957 [bl] [lower-Greek 6] and its properties gradually elucidated, [bm] [bn] [bo] culminating in the determination of its atomic-resolution structure by X-ray crystallography. [bp] The crystal structures of related ionic pumps have also been solved, giving a broader view of how these molecular machines work. [bq]

Mathematical and computational models are essential for understanding the action potential, and offer predictions that may be tested against experimental data, providing a stringent test of a theory. The most important and accurate of the early neural models is the Hodgkin–Huxley model, which describes the action potential by a coupled set of four ordinary differential equations (ODEs). [i] Although the Hodgkin–Huxley model may be a simplification with few limitations [78] compared to the realistic nervous membrane as it exists in nature, its complexity has inspired several even-more-simplified models, [79] [br] such as the Morris–Lecar model [bs] and the FitzHugh–Nagumo model, [bt] both of which have only two coupled ODEs. The properties of the Hodgkin–Huxley and FitzHugh–Nagumo models and their relatives, such as the Bonhoeffer–Van der Pol model, [bu] have been well-studied within mathematics, [80] [bv] computation [81] and electronics. [bw] However the simple models of generator potential and action potential fail to accurately reproduce the near threshold neural spike rate and spike shape, specifically for the mechanoreceptors like the Pacinian corpuscle. [82] More modern research has focused on larger and more integrated systems by joining action-potential models with models of other parts of the nervous system (such as dendrites and synapses), researchers can study neural computation [83] and simple reflexes, such as escape reflexes and others controlled by central pattern generators. [84] [bx]


Ion Channels: From Structure to Function

Ion channels are intimately involved in the everyday physiological functions that enable us to live a full and varied life. When disease strikes, malfunction of ion channels or their dependent processes is often involved, either as the cause or effect of the illness. Thus, billions of dollars have been, and still are being, invested in research to understand the physiological and pathophysiological functions of ion channels in an attempt to develop novel therapeutic treatments for a wide range of diseases. This book provides a comprehensive overview of ion-channel structure and function. It co . More

Ion channels are intimately involved in the everyday physiological functions that enable us to live a full and varied life. When disease strikes, malfunction of ion channels or their dependent processes is often involved, either as the cause or effect of the illness. Thus, billions of dollars have been, and still are being, invested in research to understand the physiological and pathophysiological functions of ion channels in an attempt to develop novel therapeutic treatments for a wide range of diseases. This book provides a comprehensive overview of ion-channel structure and function. It comprises two major parts: the first part provides an introductory overview of the ion-channel superfamily and the generic aspects of ion-channel function. This part also reviews the methodologies by which ion-channel function can be studied from the perspective of performing detailed biophysical characterization through to the deployment of high-throughput approaches for identifying novel ion-channel ligands. The second part provides an in-depth review of the individual ion-channel subfamilies and, as such, is subdivided into four broad sections: voltage-gated ion channels, extracellular ligand-gated ion channels, intracellular ligand-gated ion channels, and polymodal-gated ion channels, with each chapter therein focused on specific family members. These chapters provide a detailed overview of the structure, biophysics, localization, pharmacology, physiology, and disease relevance of each particular ion-channel subfamily.

Bibliographic Information

Print publication date: 2009 Print ISBN-13: 9780199296750
Published to Oxford Scholarship Online: March 2012 DOI:10.1093/acprof:oso/9780199296750.001.0001

Authors

Affiliations are at time of print publication.

James Kew, editor
Director, Molecular and Cellular Biology, Schizophrenia & Cognitive Disorders Discovery Performance Unit, Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, U.K.

Ceri Davies, editor
Mood and Anxiety Doisorders Discovery Performance Unit, Neurosciences CEDD, GlaxoSmithKline, Medicines Research Center, Via A Fleming, Verona, Italy


Molecular mechanisms underlying behaviors related to nicotine addiction

Tobacco smoking results in more than 5 million deaths each year and accounts for almost 90% of all deaths from lung cancer. Nicotine, the major reinforcing component of tobacco smoke, acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are allosterically regulated, ligand-gated ion channels consisting of five membrane-spanning subunits. Twelve mammalian α subunits (α2-α10) and β subunits (β2-β4) have been cloned. The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits (denoted as α4β2* nAChRs). The α4β2* nAChRs mediate many behaviors related to nicotine addiction and are the primary targets for currently approved smoking cessation agents. Considering the large number of nAChR subunits in the brain, it is likely that nAChRs containing subunits in addition to α4 and β2 also play a role in tobacco smoking. Indeed, genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the α5, α3, and β4 nAChR subunits, respectively, has been shown to increase vulnerability to tobacco dependence and smoking-associated diseases including lung cancer. Moreover, mice in which expression of α5 or β4 subunits has been genetically modified have profoundly altered patterns of nicotine consumption. In addition to the reinforcing properties of nicotine, the effects of nicotine on appetite, attention, and mood are also thought to contribute to establishment and maintenance of the tobacco smoking habit. Here we review recent insights into the behavioral actions of nicotine and the nAChRs subtypes involved, which likely contribute to the development of tobacco dependence in smokers.


The past, present and future of light-gated ion channels and optogenetics

The discovery of the mechanisms underlying light-gated ion channels called channelrhodospins and the subsequent development of optogenetics illustrates how breakthroughs in science and technology can span multiple levels of scientific inquiry. Our knowledge of how channelrhodopsins work emerged from research at the microscopic level that investigated the structure and function of algal proteins. Optogenetics, on the other hand, exploits the power of channelrhodospins and similar proteins to investigate phenomena at the supra-macroscopic level, notably the neural circuits involved in animal behavior that may be relevant for understanding neuropsychiatric disease. This article is being published to celebrate Peter Hegemann, Karl Deisseroth and Ed Boyden receiving a 2018 Canada Gairdner International Award "for the discovery of light-gated ion channel mechanisms, and for the discovery of optogenetics, a technology that has revolutionized neuroscience".

Keywords: animal behavior cell biology channelrhodospins light-gated ion channels neural circuits neuropsychiatric disease neuroscience optogenetics.


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