Action potential

In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and endocrine cells, as well as in some plant cells.Sony VAIO VGN-SZ691N/X Battery

In neurons, they play a central role in cell-to-cell communication. In other types of cells, their main function is to activate intracellular processes. In muscle cells, for example, an action potential is the first step in the chain of events leading to contraction. In beta cells of the pancreas, they provoke release of insulin.Sony VAIO VGN-SZ71E/B Battery

Action potentials in neurons are also known as "nerve impulses" or "spikes", and the temporal sequence of action potentials generated by a neuron is called its "spike train". A neuron that emits an action potential is often said to "fire".

Action potentials are generated by special types of voltage-gated ion channels embedded in a cell's plasma membrane.Sony VAIO VGN-SZ71VN/X Battery

These channels are shut when the membrane potential is near the resting potential of the cell, but they rapidly begin to open if the membrane potential increases to a precisely defined threshold value. When the channels open, they allow an inward flow of sodium ions, which changes the electrochemical gradient, which in turn produces a further rise in the membrane potential. Sony VAIO VGN-SZ71WN/C Battery

This then causes more channels to open, producing a greater electric current, and so on. The process proceeds explosively until all of the available ion channels are open, resulting in a large upswing in the membrane potential. The rapid influx of sodium ions causes the polarity of the plasma membrane to reverse, and the ion channels then rapidly inactivate. Sony VAIO VGN-SZ74B/B Battery

As the sodium channels close, sodium ions can no longer enter the neuron, and they are actively transported out of the plasma membrane. Potassium channels are then activated, and there is an outward current of potassium ions, returning the electrochemical gradient to the resting state. Sony VAIO VGN-SZ750N/C Battery

After an action potential has occurred, there is a transient negative shift, called the afterhyperpolarization or refractory period, due to additional potassium currents. This is the mechanism which prevents an action potential traveling back the way it just came.Sony VAIO VGN-SZ75B/B Battery

In animal cells, there are two primary types of action potentials, one type generated by voltage-gated sodium channels, the other by voltage-gated calcium channels. Sodium-based action potentials usually last for less than one millisecond, whereas calcium-based action potentials may last for 100 milliseconds or longer.Sony VAIO VGN-SZ76 Battery

In some types of neurons, slow calcium spikes provide the driving force for a long burst of rapidly-emitted sodium spikes. In cardiac muscle cells, on the other hand, an initial fast sodium spike provides a "primer" to provoke the rapid onset of a calcium spike, which then produces muscle contraction.Sony VAIO VGN-SZ770N/C Battery

Function

Nearly all cells from animals, plants and fungi function as batteries, in the sense that they maintain a voltage difference between the interior and the exterior of the cell, with the interior being the negative pole of the battery. Sony VAIO VGN-SZ77N Battery

The voltage of a cell is usually measured in millivolts (mV), or thousandths of a volt. A typical voltage for an animal cell is –70 mV—approximately one-fifteenth of a volt. Because cells are so small, voltages of this magnitude give rise to very strong electric forces within the cell membrane.Sony VAIO VGN-SZ780 Battery

In the majority of cells, the voltage changes very little over time. There are some types of cells, however, that are electrically active in the sense that their voltages fluctuate. In some of these, the voltages sometimes show very rapid up-and-down fluctuations that have a stereotyped form: These up-and-down cycles are known as action potentials.Sony VAIO VGN-SZ78N Battery

The durations of action potentials vary across a wide range. In brain cells of animals, the entire up-and-down cycle may take place in less than a thousandth of a second. In other types of cells, the cycle may last for several seconds.

The electrical properties of an animal cell are determined by the structure of the membrane that surrounds it.Sony VAIO VGN-SZ791N/X Battery

A cell membrane consists of a layer of lipid molecules with larger protein molecules embedded in it. The lipid layer is highly resistant to movement of electrically charged ions, so it functions mainly as an insulator. The large membrane-embedded molecules, in contrast, provide channels through which ions can pass across the membrane, and some of the large molecules are capable of actively moving specific types of ions from one side of the membrane to the other.Sony VAIO VGN-SZ84NS Battery

Process in a typical neuron

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. Sony VAIO VGN-SZ84PS Battery

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. Sony VAIO VGN-SZ84S Battery

As a result, some parts of the membrane of a neuron may be excitable (capable of generating action potentials), whereas others are not. The most excitable part of a neuron is usually theaxon hillock (the point where the axon leaves the cell body), but the axon and cell body are also excitable in most cases.Sony VAIO VGN-SZ84US Battery

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.Sony VAIO VGN-SZ85NS Battery

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.Sony VAIO VGN-SZ85S Battery

When an action potential is triggered, the membrane potential abruptly shoots upward, often reaching as high as +100 mV, 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;Sony VAIO VGN-SZ85US Battery

that is, 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 less than a thousandth of a second.Sony VAIO VGN-SZ94NS Battery

Many types of neurons emit action potentials constantly at rates of up to 10-100 per second; some types, however, are much quieter, and may go for minutes or longer without emitting any action potentials.

Biophysical basis

Action potentials result from the presence in a cell's membrane of special types of voltage-gated ion channels. Sony VAIO VGN-SZ94PS Battery

A voltage-gated ion channel is a cluster of proteins embedded in the membrane 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.Sony VAIO VGN-SZ94S Battery

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. Ions channels switch between conformations at unpredictable times:Sony VAIO VGN-SZ94US Battery

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.Sony VAIO VGN-SZ95NS Battery

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 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.Sony VAIO VGN-SZ95S Battery

Several types of channels that are capable of producing the positive feedback necessary to generate an action potential 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.Sony VAIO VGN-SZ95US Battery

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. Sony VAIO VGN-TZ121 Battery

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".)Sony VAIO VGN-TZ13 Battery

An NaV channel has three possible states, known asdeactivated, 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. Sony VAIO VGN-TZ130N/B Battery

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.Sony VAIO VGN-TZ131 Battery

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 cycledeactivated?activated?inactivated?deactivated. Sony VAIO VGN-TZ132/N Battery

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 theinactivated state is refractory until it has transitioned back to the deactivated state.Sony VAIO VGN-TZ132N Battery

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. Sony VAIO VGN-TZ150N/B Battery

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.Sony VAIO VGN-TZ150N/N Battery

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, Sony VAIO VGN-TZ160CB Battery

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.Sony VAIO VGN-TZ160N/B Battery

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. However, if the voltage increases past a critical threshold, typically 15 mV higher than the resting value, the sodium current dominates. Sony VAIO VGN-TZ16GN/B Battery

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.

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.Sony VAIO VGN-TZ16N Battery

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, and synaptic potentials, Sony VAIO VGN-TZ16N/B Battery

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.Sony VAIO VGN-TZ17/N Battery

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.Sony VAIO VGN-TZ170N/B Battery

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 algaAcetabularia, respectively.Sony VAIO VGN-TZ170N/N Battery

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.Sony VAIO VGN-TZ17GN/B Battery

In contrast to passive spread of electric potentials (electrotonic potential), action potentials are generated anew along excitable stretches of membrane and propagate without decay. Myelinated sections of axons are not excitable and do not produce action potentials and the signal is propagated passively as electrotonic potential.Sony VAIO VGN-TZ17N Battery

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. Sony VAIO VGN-TZ18/N Battery

In addition, backpropagating action potentials have been recorded in the dendrites of pyramidal neurons, which are ubiquitous in the neocortex. These are thought to have a role in spike-timing-dependent plasticity.

Anatomy of a neuron

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). Sony VAIO VGN-TZ180N/RC Battery

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. The dendrite is one of the two types of synapses, the other being the axon terminal boutons. Sony VAIO VGN-TZ185N/WC Battery

Dendrites form protrusions in response to the axon terminal boutons. These protrusions, or spines, are designed to capture the neurotransmitters released by the presynaptic neuron. They have a high concentration of ligand activated channels. It is, therefore, here where synapses from two neurons communicate with one another. Sony VAIO VGN-TZ18GN/X Battery

These spines have a thin neck connecting a bulbous protrusion to the main dendrite. This ensures that changes occurring inside the spine are less likely to affect the neighbouring spines. The dendritic spine can, therefore, with rare exception (seeLTP), act as an independent unit. The dendrites then connect onto the soma. Sony VAIO VGN-TZ18N Battery

The soma houses the nucleus, which acts as the regulator for the neuron. 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. Sony VAIO VGN-TZ190N/B Battery

This region is characterized by having an incredibly high concentration of voltage-activated sodium channels. In general, it is considered to be the spike initiation zone for action potentials. Multiple signals generated at the spines, and transmitted by the soma all converge here. Immediately after the axon hillock is the axon. Sony VAIO VGN-TZ190N/BC Battery

This is a thin tubular protrusion traveling away from the soma. The axon is insulated by a myelin sheath. Myelin is composed of Schwann cells that wrap themselves multiple times around the axonal segment. This forms a thick fatty layer that prevents ions from entering or escaping the axon.Sony VAIO VGN-TZ191N/XC Battery

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.Sony VAIO VGN-TZ195N/XC Battery

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 axon terminals then end in the form the second class of synapses, axon terminal buttons.Sony VAIO VGN-TZ198N/RC Battery

These buttons have voltage-activated calcium channels, which come into play when signaling other neurons.

Initiation

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. Sony VAIO VGN-TZ250N/B Battery

The basic requirement is that the membrane voltage at the hillock be raised above the threshold for firing.[9] There are several ways in which this depolarization can occur.

Dynamics

Action potentials are most commonly initiated by excitatory postsynaptic potentials from a presynaptic neuron.Sony VAIO VGN-TZ250N/N Battery

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.Sony VAIO VGN-TZ250N/P Battery

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 decreased or increased, the change propagates passively to nearby regions of the membrane (as described by the cable equation and its refinements).Sony VAIO VGN-TZ27/N Battery

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. Sony VAIO VGN-TZ270N/B Battery

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.Sony VAIO VGN-TZ27N Battery

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.Sony VAIO VGN-TZ28/N Battery

Electrical synapses are found in all nervous systems, including the human brain, although they are a distinct minority.

"All-or-none" principle

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. Sony VAIO VGN-TZ285N/RC Battery

Therefore, action potentials are said to be all-or-none (or boolean), since either they occur fully or they do not occur at all. Instead, the frequencyof action potentials is what encodes for the intensity of a stimulus. This is in contrast to receptor potentials, whose amplitudes are dependent on the intensity of a stimulus.Sony VAIO VGN-TZ28N Battery

Sensory neurons

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. Sony VAIO VGN-TZ290EAB Battery

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. Examples in humans include the olfactory receptor neuron and Meissner's corpuscle, which are critical for the sense of smell and touch, respectively.Sony VAIO VGN-TZ290EAN Battery

However, not all sensory neurons convert their external signals into action potentials; some do not even have an axon! 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. Sony VAIO VGN-TZ290EAP Battery

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 humanretina, the initial photoreceptor cells and the next two layers of cells (bipolar cells and horizontal cells) do not produce action potentials;Sony VAIO VGN-TZ295N/XC Battery

only some amacrine cells and the third layer, the ganglion cells, produce action potentials, which then travel up the optic nerve.

Pacemaker potentials

In sensory neurons, action potentials result from an external stimulus. However, some excitable cells require no such stimulus to fire: Sony VAIO VGN-TZ298N/XC Battery

They spontaneously depolarize their axon hillock and fire action potentials at a regular rate, like an internal clock.[16]The voltage traces of such cells are known as pacemaker potentials.[17] The cardiac pacemaker cells of the sinoatrial node in theheart provide a good example.Sony VAIO VGN-TZ33/B Battery

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 parasympatheticnerves. The external stimuli do not cause the cell's repetitive firing, but merely alter its timing.Sony VAIO VGN-TZ33/N Battery

In some cases, the regulation of frequency can be more complex, leading to patterns of action potentials, such as bursting.

Phases

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. Sony VAIO VGN-TZ33/W Battery

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 hyperpolarizes (becomes more negative).Sony VAIO VGN-TZ350N/B Battery

The undershoot phase is the point during which the membrane potential becomes temporarily more negatively charged than when at rest. 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.Sony VAIO VGN-TZ350N/N Battery

The course of the action potential is determined by two coupled effects. First, voltage-sensitive ion channels open and close in response to changes in themembrane voltage Vm. This changes the membrane's permeability to those ions. Second, according to the Goldman equation,Sony VAIO VGN-TZ350N/P Battery

this change in permeability changes in the equilibrium potential Em, and, thus, the membrane voltage Vm.[23] 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.Sony VAIO VGN-TZ370N/B Battery

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. For example, although raising Vmopens most gates in the voltage-sensitive sodium channel, it also closes the channel's "inactivation gate", albeit more slowly.Sony VAIO VGN-TZ37N/G Battery

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, for which they were awarded the Nobel Prize in Physiology or Medicine in 1963.Sony VAIO VGN-TZ37N/P Battery

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,[28]and they do not always open and close independently.Sony VAIO VGN-TZ37N/R Battery

Stimulation and rising phase

A typical action potential begins at the axon hillock 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;Sony VAIO VGN-TZ37N/X Battery

these cations can come from a wide variety of sources, such as chemical synapses, sensory neurons orpacemaker potentials.

For a neuron at rest, there is a high concentration of sodium and chlorine 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. Sony VAIO VGN-TZ38N/X Battery

This concentration gradient along with potassium leak channelspresent on the membrane of the neuron causes an efflux of potassium ions making the resting potential close to EK? –75 mV. The depolarization opens both the sodium and potassium channels in the membrane, allowing the ions to flow into and out of the axon, respectively.Sony VAIO VGN-TZ398U/XC Battery

If the depolarization is small (say, increasing Vmfrom ?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. 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:Sony VAIO VGN-TZ50B Battery

the more inward current there is, the more Vm increases, which in turn further increases the inward current.[4] 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. Sony VAIO VGN-TZ90HS Battery

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.[9] The sharp rise in Vm and sodium permeability correspond to the rising phase of the action potential.Sony VAIO VGN-TZ90NS Battery

The critical threshold voltage for this runaway condition is usually around ?45 mV, but it depends on the recent activity of the axon. A membrane that has just fired an action potential cannot fire another one immediately, since the ion channels have not returned to their usual state. Sony VAIO VGN-TZ90S Battery

The period during which no new action potential can be fired is called the absolute refractory period. 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 only with a much stronger depolarization, e.g., ?30 mV.Sony VAIO VPC CW2MFX/PU Battery

The period during which action potentials are unusually difficult to provoke is called the relative refractory period.

Peak and falling phase

The positive feedback of the rising phase slows and comes to a halt as the sodium ion channels become maximally open. Sony VAIO VPC S11V9E/B Battery

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.Sony VAIO VPCB119GJ/B Battery

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.Sony VAIO VPCB11AGJ Battery

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.

Afterhyperpolarization

The raised voltage opened many more potassium channels than usual, and some of these do not close right away when the membrane returns to its normal resting voltage. Sony VAIO VPCB11AVJ Battery

In addition, further potassium channels open in response to the influx of calcium ions during the action potential. The potassium permeability of the membrane is transiently unusually high, driving the membrane voltage Vm even closer to the potassium equilibrium voltage EK.Sony VAIO VPCB11V9E Battery

Hence, there is an undershoot or hyperpolarization, termed an afterhyperpolarization in technical language, that persists until the membrane potassium permeability returns to its usual value.

Refractory period

Each action potential is followed by a refractory period, which can be divided into an absolute refractory period, Sony VAIO VPCB11X9E Battery

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. These two refractory periods are caused by changes in the state of sodium and potassium channel molecules. Sony VAIO VPCCW18FJ/P Battery

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, Sony VAIO VPCCW18FJ/R Battery

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.Sony VAIO VPCCW18FJ/W Battery

The absolute refractory period is largely responsible for the unidirectional propagation of action potentials along axons. 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.Sony VAIO VPCCW19FJ/W Battery

Propagation

The action potential generated at the axon hillock propagates as a wave along the axon. 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.Sony VAIO VPCCW1AFJ Battery

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. Sony VAIO VPCCW1AHJ Battery

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, thisabsolute 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.Sony VAIO VPCCW1S1E Battery

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. Sony VAIO VPCCW1S1E/B Battery

On the other hand, all neuronal voltage-activated sodium channels inactivate within several millisecond during strong depolarization, thus making following depolarization impossible until a substantial fraction of sodium channels is not returned to their closed state.Sony VAIO VPCCW1S1E/L Battery

Although it limits the frequency of firing, the absolute refractory period ensures that the action potential moves in only one direction along an axon.[35] The currents flowing in due to an action potential spread out in both directions along the axon.[40] However, only the unfired part of the axon can respond with an action potential;Sony VAIO VPCCW1S1E/P Battery

the part that has just fired is unresponsive until the action potential is safely out of range and cannot restimulate that part. In the usualorthodromic 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.Sony VAIO VPCCW1S1E/R Battery

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

In order to enable fast and efficient transduction of electrical signals in the nervous system, certain neuronal axons are covered with myelin sheaths.Sony VAIO VPCCW1S1E/W Battery

Myelin is a multilamellar membrane that enwraps the axon in segments separated by intervals known as nodes of Ranvier, is produced by specialized cells, Schwann cells exclusively in the peripheral nervous system, and by oligodendrocytesexclusively in the central nervous system.Sony VAIO VPCCW21FX/B Battery

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. Myelination is found mainly in vertebrates, but an analogous system has been discovered in a few invertebrates, such as some species ofshrimp.Sony VAIO VPCCW21FX/L Battery

Not all neurons in vertebrates are myelinated; for example, axons of the neurons comprising autonomous (vegetative) nervous system are not myelinated in general.

Myelin prevents ions from entering or leaving the axon along myelinated segments. As a general rule, myelination increases theconduction velocity of action potentials and makes them more energy-efficient.Sony VAIO VPCCW21FX/R Battery

Whether saltatory or not, the mean conduction velocity of an action potential ranges from 1 m/s to over 100 m/s, and, in general, increases with axonal diameter.

Action potentials cannot propagate through the membrane in myelinated segments of the axon.Sony VAIO VPCCW21FX/W Battery

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. Sony VAIO VPCCW26EC Battery

Although the mechanism of saltatory conduction was suggested in 1925 by Ralph Lillie, the first experimental evidence for saltatory conduction came from Ichiji Tasaki[48] and Taiji Takeuchi[49]and from Andrew Huxley and Robert Stämpfli.[50] By contrast, in unmyelinated axons, the action potential provokes another in the membrane immediately adjacent, and moves continuously down the axon like a wave.Sony VAIO VPCCW26FX/B Battery

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.[53] Conversely, for a given conduction velocity, myelinated fibers are smaller than their unmyelinated counterparts. Sony VAIO VPCCW28EC Battery

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.Sony VAIO VPCCW28FJ/P Battery

This saving is a significant selective advantage, since the human nervous system uses approximately 20% of the body's metabolic energy.

The length of axons' myelinated segments is important to the success of saltatory conduction. Sony VAIO VPCCW28FJ/R Battery

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.Sony VAIO VPCCW28FJ/W Battery

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.Sony VAIO VPCCW29FJ/W Battery

Some diseases degrade myelin and impair saltatory conduction, reducing the conduction velocity of action potentials.[55] The most well-known of these is multiple sclerosis, in which the breakdown of myelin impairs coordinated movement.Sony VAIO VPCCW2AFJ Battery

Cable theory

The flow of currents within an axon can be described quantitatively by cable theory[57] and its elaborations, such as the compartmental model.[58] Cable theory was developed in 1855 by Lord Kelvin to model the transatlantic telegraph cable[59] and was shown to be relevant to neurons by Hodgkin and Rushton in 1946.Sony VAIO VPCCW2AHJ Battery

In simple cable theory, the neuron is treated as an electrically passive, perfectly cylindrical transmission cable, which can be described by apartial differential equation[57]

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 ? and ? are the characteristic length and time scales on which those voltages decay in response to a stimulus.Sony VAIO VPCCW2S1E Battery

Referring to the circuit diagram above, these scales can be determined from the resistances and capacitances per unit length[61]

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. Sony VAIO VPCCW2S1E/B Battery

For example, the time-scale ? 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. Sony VAIO VPCCW2S1E/L Battery

In 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 ? becomes longer and theconduction velocity of an action potential should increase. Sony VAIO VPCCW2S1E/P Battery

If the transmembrane resistance rm is increased, that lowers the average "leakage" current across the membrane, likewise causing ?to become longer, increasing the conduction velocity.

In general, action potentials that reach the synaptic knobs cause a neurotransmitter to be released into the synaptic cleft.Sony VAIO VPCCW2S1E/R Battery

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; Sony VAIO VPCCW2S1E/W Battery

the influx of calcium causes vesicles filled with neurotransmitter to migrate to the cell's surface and release their contents into the synaptic cleft.[63] This complex process is inhibited by the neurotoxins tetanospasmin and botulinum toxin, which are responsible for tetanus and botulism, respectively.Sony VAIO VPCCW2S5C CN1 Battery

Some synapses dispense with the "middleman" of the neurotransmitter, and connect the presynaptic and postsynaptic cells together.[65] 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 connexins.Sony VAIO VPCF112FX/B Battery

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.Sony VAIO VPCF115FG/B Battery

Neuromuscular junctions

A special case of a chemical synapse is the neuromuscular junction, in which the axon of a motor neuron terminates on a muscle fiber. 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.Sony VAIO VPCF116FGBI Battery

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. Sony VAIO VPCF117FJ/W Battery

Some poisons inactivate acetylcholinesterase to prevent this control, such as the nerve agents sarin and tabun, and the insecticidesdiazinon and malathion.

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.Sony VAIO VPCF117HG/BI Battery

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.Sony VAIO VPCF118FJ/W Battery

The cardiac cells of thesinoatrial 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. Sony VAIO VPCF119FC Battery

Action potentials from the AV node travel through the bundle of His and thence to the Purkinje fibers.[note 1] Conversely, anomalies in the cardiac action potential—whether due to a congenital mutation or injury—can lead to human pathologies, especially arrhythmias.Sony VAIO VPCF119FC/BI Battery

Several anti-arrhythmia drugs act on the cardiac action potential, such as quinidine, lidocaine, beta blockers, and verapamil.

Muscular action potentials

The action potential in a normal skeletal muscle cell is similar to the action potential in neurons. Sony VAIO VPCF119FJ/BI Battery

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.Sony VAIO VPCF11AFJ Battery

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.Sony VAIO VPCF11AGJ Battery

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.

Plant action potentials

Plant and fungal cells are also electrically excitable. The fundamental difference to 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.Sony VAIO VPCF11AHJ Battery

Together with the following release of positive potassium ions, which is common to plant and animal action potentials, the action potential in plants infers, therefore, an osmotic loss of salt (KCl), whereas the animal action potential is osmotically neutral, when equal amounts of entering sodium and leaving potassium cancel each other osmotically. Sony VAIO VPCF11JFX/B Battery

The interaction of electrical and osmotic relations in plant cells indicates an osmotic function of electrical excitability in the common, unicellular ancestors of plants and animals under changing salinity conditions, whereas the present function of rapid signal transmission is seen as a younger accomplishment of metazoan cells in a more stable osmotic environment.Sony VAIO VPCF11M1E Battery

It must be assumed that the familiar signalling function of action potentials in some vascular plants (e.g. Mimosa pudica), arose independently from that in metazoan excitable cells.

Taxonomic distribution and evolutionary advantages

Action potentials are found throughout multicellular organisms, including plants, invertebrates such as insects, and vertebrates such as reptiles and mammals.Sony VAIO VPCF11M1E/H Battery

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. The resting potential, as well as the size and duration of the action potential, Sony VAIO VPCF11MFX/B Battery

have not varied much with evolution, although the conduction velocity does vary dramatically with axonal diameter and myelination.

Given its conservation throughout evolution, the action potential seems to confer evolutionary advantages. Sony VAIO VPCF11S1E Battery

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.Sony VAIO VPCF11S1E/B Battery

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, Sony VAIO VPCF11Z1E Battery

one that has been exploited biologically to form central pattern generators and mimicked in artificial neural networks.

Experimental methods

The study of action potentials has required the development of new experimental methods. Sony VAIO VPCF11Z1E/BI Battery

The initial work, prior to 1955, focused on three goals: isolating signals from single neurons or axons, developing fast, sensitive electronics, and shrinkingelectrodes 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 genus Loligo.Sony VAIO VPCF11ZHJ Battery

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. However, the Loligo axons are not representative of all excitable cells, and numerous other systems with action potentials have been studied.Sony VAIO VPCF127HGBI Battery

The second problem was addressed with the crucial development of the voltage clamp, which permitted experimenters to study the ionic currents underlying an action potential in isolation, and eliminated a key source of electronic noise, the currentIC associated with the capacitance C of the membrane.Sony VAIO VPCF137HG/BI Battery

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. Sony VAIO VPCS111FM/S Battery

Other electronic advances included the use of Faraday cages and electronics with highinput impedance, so that the measurement itself did not affect the voltage being measured.

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, Sony VAIO VPCS115EC Battery

which was quickly adopted by other researchers. 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. 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 Ca2+ or to voltage.Sony VAIO VPCS115FG Battery

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 they were awarded the Nobel Prize in Physiology or Medicine in 1991.Sony VAIO VPCS117GG Battery

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. Sony VAIO VPCS117GGB Battery

Using voltage-sensitive dyes, action potentials have been optically recorded from a tiny patch of cardiomyocyte membrane.

Neurotoxins

Several neurotoxins, both natural and synthetic, are designed to block the action potential. Sony VAIO VPCS118EC Battery

Tetrodotoxin from the pufferfish andsaxitoxin from the Gonyaulax (the dinoflagellate genus responsible for "red tides") block action potentials by inhibiting the voltage-sensitive sodium channel; similarly, dendrotoxin from the black mamba snake inhibits the voltage-sensitive potassium channel. Sony VAIO VPCS119FJ/B Battery

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.Sony VAIO VPCS119GC Battery

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. Sony VAIO VPCS11AFJ Battery

The ion channels of insects are sufficiently different from their human counterparts that there are few side effects in humans. Many other neurotoxins interfere with the transmission of the action potential's effects at the synapses, especially at the neuromuscular junction.Sony VAIO VPCS11AGJ Battery

The role of electricity in the nervous systems of animals was first observed in dissectedfrogs by Luigi Galvani, who studied it from 1791 to 1797. Galvani's results stimulatedAlessandro 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.Sony VAIO VPCS11AHJ Battery

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). Sony VAIO VPCS11AVJ Battery

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 1848.Sony VAIO VPCS11J7E/B Battery

Theconduction velocity of action potentials was first measured in 1850 by du Bois-Reymond's friend, Hermann von Helmholtz. 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. Sony VAIO VPCS11M1E/W Battery

For their discoveries, Golgi and Ramón y Cajal were awarded the 1906 Nobel Prize in Physiology. 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.Sony VAIO VPCS11V9E Battery

The 20th century was a golden era for electrophysiology. In 1902 and again in 1912, Julius Bernstein advanced the hypothesis that the action potential resulted from a change in thepermeability of the axonal membrane to ions. Bernstein's hypothesis was confirmed by Ken Cole and Howard Curtis, who showed that membrane conductance increases during an action potential.Sony VAIO VPCS11V9E/B Battery

In 1907, Louis Lapicque suggested that the action potential was generated as a threshold was crossed, 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;Sony VAIO VPCS11X9E/B Battery

in particular, they demonstrated the crucial role of the sodium permeability for the action potential. 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.Sony VAIO VPCS123FGB Battery

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.Sony VAIO VPCS125EC Battery

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,[105] through the atomic-resolution crystal structures,[106] fluorescence distance measurements[107] and cryo-electron microscopy studies.Sony VAIO VPCS128EC Battery

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. The sodium–potassium pump was identified in 1957 and its properties gradually elucidated,culminating in the determination of its atomic-resolution structure by X-ray crystallography.Sony VAIO VPCS129GC Battery

The crystal structures of related ionic pumps have also been solved, giving a broader view of how these molecular machines work.

Quantitative models

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. Sony VAIO VPCS12C7E/B Battery

The most important and accurate of these models is the Hodgkin–Huxley model, which describes the action potential by a coupled set of four ordinary differential equations (ODEs). Although the Hodgkin–Huxley model may be a simplification of a realistic nervous membrane as it exists in nature, Sony VAIO VPCS12L9E/B Battery

its complexity has inspired several even-more-simplified models, such as the Morris–Lecar model and the FitzHugh–Nagumo model, 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, have been well-studied within mathematics,Sony VAIO VPCS12V9E/B Battery

computation and electronics. 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), researches can study neural computation and simple reflexes, such as escape reflexes and others controlled by central pattern generators.Sony VAIO VPCY115FGS Battery

Electrophysiology (from Greek ????????, ?lektron, "amber" [see the etymology of "electron"]; ?????, physis, "nature, origin"; and -?????, -logia) is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart. Sony VAIO VPCY115FX/BI Battery

In neuroscience, it includes measurements of the electrical activity of neurons, and particularlyaction potential activity. Recordings of large-scale electric signals from the nervous system such as electroencephalography, may also be referred to as electrophysiological recordings.Sony VAIO VPCY115FXBI Battery

Classical electrophysiological techniques

Electrophysiology is the science and branch of physiology that pertains to the flow of ions in biological tissues and, in particular, to the electrical recording techniques that enable the measurement of this flow. Classical electrophysiology techniques involve placing electrodes into various preparations of biological tissue. Sony VAIO VPCY118EC Battery

The principal types of electrodes are: 1) simple solid conductors, such as discs and needles (singles or arrays, often insulated except for the tip), 2) tracings on printed circuit boards, also insulated except for the tip, and 3) hollow tubes filled with an electrolyte, such as glass pipettes filled with potassium chloride solution or another electrolyte solution. Sony VAIO VPCY118GX/BI Battery

The principal preparations include 1) living organisms, 2) excised tissue (acute or cultured), 3) dissociated cells from excised tissue (acute or cultured), 4) artificially grown cells or tissues, or 5) hybrids of the above.

If an electrode is small enough (micrometers) in diameter, then the electro-physiologist may choose to insert the tip into a single cell. Sony VAIO VPCY119FJ/S Battery

Such a configuration allows direct observation and recording of the intracellular electrical activity of a single cell. However, at the same time such invasive setup reduces the life of the cell and causes a leak of substances across the cell membrane. Intracellular activity may also be observed using a specially formed (hollow) glass pipette containing an electrolyte. Sony VAIO VPCY11AFJ Battery

In this technique, the microscopic pipette tip is pressed against the cell membrane, to which it tightly adheres by an interaction between glass and lipids of the cell membrane. The electrolyte within the pipette may be brought into fluid continuity with the cytoplasm by delivering a pulse of pressure to the electrolyte in order to rupture the small patch of membrane encircled by the pipette rim (whole-cell recording).Sony VAIO VPCY11AGJ Battery

Alternatively, ionic continuity may be established by "perforating" the patch by allowing exogenous pore-forming agent within the electrolyte to insert themselves into the membrane patch (perforated patch recording). Finally, the patch may be left intact (patch recording).Sony VAIO VPCY11AHJ Battery

The electrophysiologist may choose not to insert the tip into a single cell. Instead, the electrode tip may be left in continuity with the extracellular space. If the tip is small enough, such a configuration may allow indirect observation and recording of action potentials from a single cell, and is termed single-unit recording. Sony VAIO VPCY11AVJ Battery

Depending on the preparation and precise placement, an extracellular configuration may pick up the activity of several nearby cells simultaneously, and this is termed multi-unit recording.

As electrode size increases, the resolving power decreases. Larger electrodes are sensitive only to the net activity of many cells, termed local field potentials. Sony VAIO VPCY11M1E/S Battery

Still larger electrodes, such as uninsulated needles and surface electrodes used by clinical and surgical neurophysiologists, are sensitive only to certain types of synchronous activity within populations of cells numbering in the millions.

Other classical electrophysiological techniques include single channel recording and amperometry.Sony VAIO VPCY11S1E Battery

Optical electrophysiological techniques

Optical electrophysiological techniques were created by scientists and engineers to overcome one of the main limitations of classical techniques. Classical techniques allow observation of electrical activity at approximately a single point within a volume of tissue.Sony VAIO VPCY11V9E/S Battery

Essentially, classical techniques singularize a distributed phenomenon. Interest in the spatial distribution of bioelectric activity prompted development of molecules capable of emitting light in response to their electrical or chemical environment. Examples are voltage sensitive dyes and fluorescing proteins.Sony VAIO VPCY218EC/BI Battery

After introducing one or more such compounds into tissue via perfusion, injection or gene expression, the 1 or 2-dimensional distribution of electrical activity may be observed and recorded.

Intracellular recording involves measuring voltage and/or current across the membrane of a cell. Sony VAIO VPCY218EC/G Battery

To make an intracellular recording, the tip of a fine (sharp) microelectrode must be inserted inside the cell, so that the membrane potential can be measured. Typically, the resting membrane potential of a healthy cell will be -60 to -80 mV, and during an action potential the membrane potential might reach +40 mV. Sony VAIO VPCY218EC/L Battery

In 1963, Alan Lloyd Hodgkin and Andrew Fielding Huxley won the Nobel Prize in Physiology or Medicine for their contribution to understanding the mechanisms underlying the generation of action potentials in neurons. Their experiments involved intracellular recordings from the giant axon of Atlantic squid (Loligo pealei), Sony VAIO VPCY218EC/P Battery

and were among the first applications of the "voltage clamp" technique. Today, most microelectrodes used for intracellular recording are glass micropipettes, with a tip diameter of < 1 micrometre, and a resistance of several megaohms. The micropipettes are filled with a solution that has a similar ionic composition to the intracellular fluid of the cell.Sony VAIO VPCY21S1E/L Battery

A chlorided silver wire inserted in to the pipet connects the electrolyte electrically to the amplifier and signal processing circuit. The voltage measured by the electrode is compared to the voltage of a reference electrode, usually a silver chloride-coated silver wire in contact with the extracellular fluid around the cell. Sony VAIO VPCY21S1E/P Battery

In general, the smaller the electrode tip, the higher its electrical resistance, so an electrode is a compromise between size (small enough to penetrate a single cell with minimum damage to the cell) and resistance (low enough so that small neuronal signals can be discerned from thermal noise in the electrode tip).Sony VAIO VPCY21S1E/SI Battery

Voltage clamp

The voltage clamp technique allows an experimenter to "clamp" the cell potential at a chosen value. This makes it possible to measure how much ionic current crosses a cell's membrane at any given voltage. Sony VAIO VPCCW2S5C CN1 Battery

This is important because many of the ion channels in the membrane of a neuron are voltage-gated ion channels, which open only when the membrane voltage is within a certain range. Voltage clamp measurements of current are made possible by the near-simultaneous digital subtraction of transient capacitive currents that pass as the recording electrode and cell membrane are charged to alter the cell's potential.Sony VAIO VPCEA20 Battery

Current clamp

The current clamp technique records the membrane potential by injecting current into a cell through the recording electrode. Unlike in the voltage clamp mode, where the membrane potential is held at a level determined by the experimenter,Sony VAIO VPCEB10 Battery

in "current clamp" mode the membrane potential is free to vary, and the amplifier records whatever voltage the cell generates on its own or as a result of stimulation. This technique is used to study how a cell responds when electric current enters a cell; this is important for instance for understanding how neurons respond to neurotransmittersthat act by opening membrane ion channels.Sony VAIO VPCEB11FM Battery

Most current-clamp amplifiers provide little or no amplification of the voltage changes recorded from the cell. The "amplifier" is actually an electrometer, sometimes referred to as a "unity gain amplifier"; its main job is to change the nature of small signals (in the mV range) produced by cells so that they can be accurately recorded by low-impedanceelectronics.Sony VAIO VPCEB11FM/BI Battery

The amplifier increases the current behind the signal while decreasing the resistance over which that current passes. Consider this example based on Ohm's law: A voltage of 10 mV is generated by passing 10 nanoamperes of current across 1 M? of resistance. The electrometer changes this "high impedance signal" to a "low impedance signal" by using a voltage follower circuit. Sony VAIO VPCEB11FM/T Battery

A voltage follower reads the voltage on the input (caused by a small current through a big resistor). It then instructs a parallel circuit that has a large current source behind it (the electrical mains) and adjusts the resistance of that parallel circuit to give the same output voltage, but across a lower resistance.Sony VAIO VPCEB11FM/WI Battery

The patch-clamp technique

This technique was developed by Erwin Neher and Bert Sakmann who received the Nobel Prize in 1991.[2] Conventional intracellular recording involves impaling a cell with a fine electrode; patch-clamp recording takes a different approach. A patch-clamp microelectrode is a micropipette with a relatively large tip diameter. Sony VAIO VPCEB11FX Battery

The microelectrode is placed next to a cell, and gentle suction is applied through the microelectrode to draw a piece of the cell membrane (the 'patch') into the microelectrode tip; the glass tip forms a high resistance 'seal' with the cell membrane. Sony VAIO VPCEB11FX/BI Battery

This configuration is the "cell-attached" mode, and it can be used for studying the activity of the ion channels that are present in the patch of membrane. If more suction is now applied, the small patch of membrane in the electrode tip can be displaced, leaving the electrode sealed to the rest of the cell. This "whole-cell" mode allows very stable intracellular recording. Sony VAIO VPCEB11FX/T Battery

A disadvantage (compared to conventional intracellular recording with sharp electrodes) is that the intracellular fluid of the cell mixes with the solution inside the recording electrode, and so some important components of the intracellular fluid can be diluted. A variant of this technique, the "perforated patch" technique, tries to minimise these problems.Sony VAIO VPCEB11FX/WI Battery

Instead of applying suction to displace the membrane patch from the electrode tip, it is also possible to make small holes on the patch with pore-forming agents so that large molecules such as proteins can stay inside the cell and ions can pass through the holes freely. Also the patch of membrane can be pulled away from the rest of the cell. Sony VAIO VPCEB11GX Battery

This approach enables the membrane properties of the patch to be analysed pharmacologically.

Sharp electrode technique

In situations where one wants to record the potential inside the cell membrane with minimal effect on the ionic constitution of the intracellular fluid a sharp electrode can be used.Sony VAIO VPCEB11GX/BI Battery

These micropipettes (electrodes) are again like those for patch clamp pulled from glass capillaries, but the pore is much smaller so that there is very little ion exchange between the intracellular fluid and the electrolyte in the pipette. The resistance of the micropipette electrode is tens or hundreds of M?.Sony VAIO VPCEB11GX/T Battery

Often the tip of the electrode is filled with various kinds of dyes like Lucifer yellow to fill the cells recorded from, for later confirmation of their morphology under a microscope. The dyes are injected by applying a positive or negative, DC or pulsed voltage to the electrodes depending on the polarity of the dye.Sony VAIO VPCEB11GX/WI Battery

Single-unit recording

An electrode introduced into the brain of a living animal will detect electrical activity that is generated by the neurons adjacent to the electrode tip. If the electrode is a microelectrode, with a tip size of about 1 micrometre, the electrode will usually detect the activity of at most one neuron. Recording in this way is in general called "single-unit" recording. Sony VAIO VPCEB12FX Battery

The action potentials recorded are very much like the action potentials that are recorded intracellularly, but the signals are very much smaller (typically about 1 mV). Most recordings of the activity of single neurons in anesthetized animals are made in this way, and all recordings of single neurons in conscious animals. Sony VAIO VPCEB12FX/BI Battery

Recordings of single neurons in living animals have provided important insights into how the brain processes information. For example, David Hubel and Torsten Wiesel recorded the activity of single neurons in the primary visual cortex of the anesthetized cat, and showed how single neurons in this area respond to very specific features of a visual stimulus.Sony VAIO VPCEB12FX/BIC Battery

Hubel and Wiesel were awarded the Nobel Prize in Physiology or Medicine in 1981. If the electrode tip is slightly larger, then the electrode might record the activity generated by several neurons. This type of recording is often called "multi-unit recording", and is often used in conscious animals to record changes in the activity in a discrete brain area during normal activity.Sony VAIO VPCEB12FX/T Battery

Recordings from one or more such electrodes that are closely spaced can be used to identify the number of cells around it as well as which of the spikes come from which cell. This process is called spike sorting and is suitable in areas where there are identified types of cells with well defined spike characteristics. Sony VAIO VPCEB14FX Battery

If the electrode tip is bigger still, in general the activity of individual neurons cannot be distinguished but the electrode will still be able to record a field potential generated by the activity of many cells.

Field potentials

Extracellular field potentials are local current sinks or sources that are generated by the collective activity of many cells. Sony VAIO VPCEB14FX/BI Battery

Usually, a field potential is generated by the simultaneous activation of many neurons by synaptic transmission. The diagram to the right shows hippocampal synaptic field potentials. At the right, the lower trace shows a negative wave that corresponds to a current sink caused by positive charges entering cells through postsynaptic glutamate receptors,Sony VAIO VPCEB14FX/T Battery

while the upper trace shows a positive wave that is generated by the current that leaves the cell (at the cell body) to complete the circuit. For more information, see local field potential.

Amperometry

Amperometry uses a carbon electrode to record changes in the chemical composition of the oxidized components of a biological solution. Sony VAIO VPCEB14FX/WI Battery

Oxidation and reduction is accomplished by changing the voltage at the active surface of the recording electrode in a process known as "scanning". Because certain brain chemicals lose or gain electrons at characteristic voltages, individual species can be identified. Amperometry has been used for studying exocytosis in the neural and endocrine systems. Sony VAIO VPCEB15FM Battery

Many monoamineneurotransmitters; e.g., norepinephrine (noradrenalin), dopamine, and serotonin (5-HT) are oxidizable. The method can also be used with cells that do not secrete oxidizable neurotransmitters by "loading" them with 5-HT or dopamine.

Planar patch clamp is a novel method developed for high throughput electrophysiology. Sony VAIO VPCEB15FM/BI Battery

Instead of positioning a pipette on an adherent cell, cell suspension is pipetted on a chip containing a microstructured aperture.

A single cell is then positioned on the hole by suction and a tight connection (Gigaseal) is formed. The planar geometry offers a variety of advantages compared to the classical experiment: -Sony VAIO VPCEB15FM/T Battery

it allows for integration of microfluidics, which enables automatic compound application for ion channelscreening. - the system is accessible for optical or scanning probe techniques - perfusion of theintracellular side can be performed.Sony VAIO VPCEB15FM/WI Battery

Solid-supported membrane (SSM) based

With this electrophysiological approach, proteoliposomes, membrane vesicles, or membrane fragments containing the channel or transporter of interest are adsorbed to a lipid monolayer painted over a functionalized electrode. This electrode consists of a glass support, a chromium layer, a gold layer, and an octadecyl mercaptanemonolayer. Sony VAIO VPCEB15FX Battery

Because the painted membrane is supported by the electrode, it is called a solid-supported membrane. It is important to note that mechanical perturbations, which usually destroy a biological lipid membrane, do not influence the life-time of an SSM.Sony VAIO VPCEB15FX/BI Battery

The capacitive electrode (composed of the SSM and the absorbed vesicles) is so mechanically stable that solutions may be rapidly exchanged at its surface. This property allows the application of rapid substrate/ligand concentration jumps to investigate the electrogenic activity of the protein of interest, measured via capacitive coupling between the vesicles and the electrode.Sony VAIO VPCEB15FX/T Battery

Bioelectric recognition assay (BERA)

The bioelectric recognition assay (BERA) is a novel method for determination of various chemical and biological molecules by measuring changes in the membrane potential of cells immobilized in a gel matrix. Apart from the increased stability of the electrode-cell interface, immobilization preserves the viability and physiological functions of the cells. Sony VAIO VPCEB15FX/WI Battery

BERA is used primarily in biosensor applications in order to assay analytes that can interact with the immobilized cells by changing the cell membrane potential. In this way, when a positive sample is added to the sensor, a characteristic, ‘signature-like’ change in electrical potential occurs. Sony VAIO VPCEB16FX Battery

BERA has been used for the detection for human viruses (Hepatitis B and C viruses, herpes viruses) and veterinary disease agents (foot and mouth disease virus, prions, blue tongue virus) and plants (tobacco and cucumber viruses) in a highly specific, rapid (1–2 minutes), reproducible and cost-efficient fashion. Sony VAIO VPCEB16FX/B Battery

The method has also been used for the detection of environmental toxins, such as herbicides and the determination of very low concentrations of superoxide anion in clinical samples.

A recent advance in the evolution of the BERA technology is the development of a technique called molecular identification through membrane engineering (MIME). Sony VAIO VPCEB16FX/G Battery

This technique allows for building cells with absolutely defined specificity for virtually any molecule of interest, by embedding thousand of artificial receptors into the cell membrane.

Reporting guidelines for electrophysiology experiments

Minimum Information (MI) standards or reporting guidelines specify the minimum amount of meta data (information) and data required to meet a specific aims or aims. Sony VAIO VPCEB16FX/L Battery

Usually the aim is to provide enough meta data and data to enable the unambiguous reproduction and interpretation of an experiment. MI guidelines are normally informal human readable specifications that inform the development of formal data models (e.g. XML or UML), data exchange formats (e.g. FuGE, MAGE-ML, MAGE-TAB) or knowledge models such as an ontology (e.g. OBI, MGED-Ontology).Sony VAIO VPCEB16FX/P Battery

The Minimum Information about a Neuroscience investigation (MINI) family of reporting guideline documents, produced by community consultation and continually available for public comment aims to provide a consistent set of guidelines in order to report an electrophysiology experiment.Sony VAIO VPCEB16FX/W Battery

A MINI module represents the minimum information that should be reported about a dataset to facilitate computational access and analysis to allow a reader to interpret and critically evaluate the processes performed and the conclusions reached, and to support their experimental corroboration. Sony VAIO VPCEB17FX Battery

In practice a MINI module comprises a checklist of information that should be provided (for example about the protocols employed) whena data set is described for publication. The full specification of the MINI module can be found here.Sony VAIO VPCEB17FX/B Battery,Sony VAIO VPCEB17FX/G Battery,Sony VAIO VPCEB17FX/L Battery,Sony VAIO VPCEB17FX/P Battery,Sony VAIO VPCEB17FX/W Battery