A Single Action Potential In A Presynaptic Cell Leads To An Essay

In physiology, an action potential occurs when the membrane potential of a specific axon location rapidly rises and falls:[1] this depolarisation then causes adjacent locations to similarly depolarise. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, endocrine cells, and in some plant cells.

In neurons, action potentials play a central role in cell-to-cell communication by providing for—or, with regard to saltatory conduction, assisting—the propagation of signals along the neuron's axon towards synaptic boutons situated at the ends of an axon; these signals can then connect with other neurons at synapses, or to motor cells or glands. 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.[a] 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, or nerve impulse, is often said to "fire".

Action potentials are generated by special types of voltage-gated ion channels embedded in a cell's plasma membrane.[b] These channels are shut when the membrane potential is near the (negative) resting potential of the cell, but they rapidly begin to open if the membrane increases to a precisely defined threshold voltage, depolarising the transmembrane potential.[b] 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. This then causes more channels to open, producing a greater electric current across the cell membrane, 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. As the sodium channels close, sodium ions can no longer enter the neuron, and then they are actively transported back 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. After an action potential has occurred, there is a transient negative shift, called the afterhyperpolarization.

In animal cells, there are two primary types of action potentials. One type is generated by voltage-gated sodium channels, the other by voltage-gated calcium channels. Sodium-based action potentials usually last for under one millisecond[citation needed], but calcium-based action potentials may last for 100 milliseconds or longer[citation needed]. 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[citation needed].

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 depolarised due to released ion interference with neighbouring channels. Measurements of ion diffusion and radii have since shown this not to be possible. Moreover, contradictory measurements of entropy changes and timing disputed the capacitance model as acting alone.


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 of approximately one-fifteenth of a volt 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 also in plants, an action potential may last three seconds or more.

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[citation needed] 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.

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.

Biophysical basis[edit]

Action potentials result from the presence in a cell's membrane of special types of voltage-gated ion channels.[2] 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.

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 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.[3] 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.[3][6][note 1] The frequency at which cellular action potentials are produced is known as its 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, 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 chlorideanions 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.

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.[8] 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.

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.[9] 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.[9]

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.[9]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.[10] Second, the delayed rectifier, a potassium channel current, increases to 3.5 times its initial strength.[9]

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.[11] 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.[12]

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.[9]


Main article: Neurotransmission

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,[13] 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. 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.


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.[3][15] There are several ways in which this depolarization can occur.


Action potentials are most commonly initiated by excitatory postsynaptic potentials from a presynaptic neuron.[17] Typically, neurotransmitter molecules are released by the presynapticneuron. 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.[18] 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.

"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. In both cases, the frequency of action potentials is correlated with the intensity of a stimulus.

Sensory neurons[edit]

Main article: Sensory neuron

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.[21] 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![22] 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]

Main article: Pacemaker potential

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. The voltage traces of such cells are known as pacemaker potentials.[24] 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.[25] The external stimuli do not cause the cell's repetitive firing, but merely alter its timing.[24] 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.

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 the membrane voltageVm. This changes the membrane's permeability to those ions. 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.[3][29] 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.[30][i] For example, although raising Vmopens most gates in the voltage-sensitive sodium channel, it also closes the channel's "inactivation gate", albeit more slowly.[31] 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.[β] 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,[32] and they do not always open and close independently.[j]

Stimulation and rising phase[edit]

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; 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. 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.[34] The 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.[3]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.[3][29] 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.[3][35] The sharp rise in Vm and sodium permeability correspond to the rising phase of the action potential.[3][35]

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 the deactivated state. The period during which no new action potential can be fired is called the absolute refractory period.[39] 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.[39]

Peak and falling 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.[31] 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.[31] 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][41]


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. 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. 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.[40]

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.[39] 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. 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.


Main article: Nerve conduction velocity

The action potential generated at the axon hillock propagates as a wave along the axon.[44] 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. 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 millisecond 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, the absolute refractory period ensures that the action potential moves in only one direction along an axon. The currents flowing in due to an action potential spread out in both directions along the axon.[46] 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.[47] 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]

Main articles: Myelination 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. 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.

As an action potential (nerve impulse) travels down an axon there is a change in polarity across the membrane of the axon. In response to a signal from another neuron, sodium- (Na+) and potassium- (K+) gated ion channels open and close as the membrane reaches its threshold potential. Na+ channels open at the beginning of the action potential, and Na+ moves into the axon, causing depolarization. Repolarization occurs when the K+ channels open and K+ moves out of the axon, creating a change in polarity between the outside of the cell and the inside. The impulse travels down the axon in one direction only, to the axon terminal where it signals other neurons.
Illustrated video explanation of an action potential (~10.5 minutes)
Shape of a typical action potential. The membrane potential remains near a baseline level until at some point in time, it abruptly spikes upward and then rapidly falls.
Approximate plot of a typical action potential shows its various phases as the action potential passes a point on a cell membrane. The membrane potential starts out at −70 mV at time zero. A stimulus is applied at time = 1 ms, which raises the membrane potential above −55 mV (the threshold potential). After the stimulus is applied, the membrane potential rapidly rises to a peak potential of +40 mV at time = 2 ms. Just as quickly, the potential then drops and overshoots to −90 mV at time = 3 ms, and finally the resting potential of −70 mV is reestablished at time = 5 ms.
Action potential propagation along an axon
When an action potential arrives at the end of the pre-synaptic axon (top), it causes the release of neurotransmitter molecules that open ion channels in the post-synaptic neuron (bottom). The combined excitatory and inhibitory postsynaptic potentials of such inputs can begin a new action potential in the post-synaptic neuron.
In pacemaker potentials, the cell spontaneously depolarizes (straight line with upward slope) until it fires an action potential.
In saltatory conduction, an action potential at one node of Ranvier causes inwards currents that depolarize the membrane at the next node, provoking a new action potential there; the action potential appears to "hop" from node to node.

Presynaptic spikes are broadened by Kv1.1 blockade

To understand the normal role of Kv1.1 in basket cells we examined the effect of the highly specific Kv1.1 blocker DTx-K25 on action potential shape. Targeted patch-clamp recordings were obtained from somata or terminals of basket cells in acute cerebellar slices from wild-type mice, bred on the same background as Kcna1V408A/+ mice described below18. Somatic recordings from basket cells showed no effect of 200 nM DTx-K on action potential width (Fig. 1a,b). A likely explanation is that Kv1.1 is predominantly expressed in axons and terminals of basket cells9,11, and plays only a small role in somata. Patch-clamp recordings from basket cells have indeed detected potassium currents with biophysical and pharmacological properties consistent with Kv1.1 or Kv1.2 (refs 21, 26). We therefore targeted basket cell terminals for patch-clamp recordings.

Presynaptic terminals were initially identified under infrared differential interference contrast (DIC), and had a high input resistance, little or no sag potential, and were able to spike upon 1-ms current injection (passive membrane properties are given in Supplementary Table 1). Prolonged depolarizing current pulses failed to evoke stable trains of action potentials (see also Supplementary Fig. 1a). Instead, repeated brief pulses reliably triggered action potentials at either 55 or 100 Hz (see also Supplementary Fig. 1b,c), with modest progressive spike broadening. Evoked presynaptic action potentials were followed by a prominent afterdepolarization (ADP), which reversed between –50 and –40 mV (see also Supplementary Fig. 2a,b). Because GABAA autoreceptors are prominent in another type of cerebellar interneurons, stellate cells27, we asked whether the ADP was abolished by blocking these receptors. Bath application of picrotoxin (PTx, 100 μM), however, only led to a small albeit significant decrease in the area of the ADP (Supplementary Fig. 2c,d), suggesting that GABA release from basket cell terminals acting on autoreceptors plays only a small role.

In contrast to somatic action potentials, presynaptic spike width (measured at –30 mV) was robustly prolonged by DTx-K (Fig. 1a,b; baseline: 0.96±0.03 ms; DTx-K: 1.15±0.02 ms; P<0.001, paired t-test, n=11). The ADP was however unaffected. We compared the effects of DTx-K to those of charybdotoxin (ChTx), a blocker of the large conductance calcium- and voltage-activated potassium channel BKCa, which is usually abundantly expressed at presynaptic terminals in close association with the active zone28 (but see ref. 29). Unexpectedly, ChTx (100 nM) led to spike broadening at the soma (Fig. 1c: baseline: 1.28±0.10 ms; ChTx: 1.55±0.13 ms; P<0.05, paired t-test, n=7) but not in presynaptic boutons. Thus, two K+ channels show complementary roles in determining spike shape in basket cells.

Kv1.1 modulates presynaptic Ca2+ influx and GABA release

A previous study reported no effect of α-DTx on action potential-evoked Ca2+ fluorescence transients measured in basket cell terminals23. We re-examined the role of Kv1.1 in presynaptic spike-evoked Ca2+ influx by patch clamping basket cell bodies in wild-type mice. Two-photon fluorescence excitation microscopy was used to image individual boutons apposed to Purkinje cell somata (Fig. 2a). Line scans were taken before and after bath perfusion of 200 nM DTx-K (Fig. 2b,c, see Methods for detailed protocols and calibration of Ca2+ responses). To improve the signal-to-noise ratio, we took the integral of the Fluo-4 fluorescence signal for 200 ms from the first action potential, as a measure of total action potential-evoked Ca2+ influx Δ[Ca2+]. A non-stationary single-compartment model30 incorporating the Ca2+ buffer parvalbumin provided a good fit to the fluorescence transients (Fig. 2c), confirmed that the 200 ms integral varied linearly with Δ[Ca2+] (see also Supplementary Fig. 3), and further yielded an estimate of the absolute Ca2+ concentration change.

DTx-K perfusion led to a 21±9% increase in the normalized Ca2+ fluorescence integral (P<0.05, Wilcoxon signed-rank test for paired data), which was not seen in control experiments followed for the same time (Fig. 2d). Dividing the estimated total Ca2+ concentration change (Δ[Ca2+] ∼10 μM per action potential under baseline conditions) into the approximate bouton volume (estimated from DIC or Alexa images as roughly 1 fL), we further estimated that ∼6.0 × 106 Ca2+ ions (equivalent to a charge of 1.93 fC) enter the bouton for each action potential under baseline conditions. A six-state kinetic model of P/Q-type Ca2+ channels31, which predominate in basket cells32, yields an estimate of their gating kinetics when driven by a presynaptic action potential waveform that incorporates the ADP recorded in boutons. Taking into account the single channel conductance and driving force30, we estimate that ∼ 0.04 fC enters via each Ca2+ channel. This yields an estimate of ∼50 P/Q-type Ca2+ channels present in a typical bouton. Although the driving force for Ca2+ entry increases following repolarization, we found that subtracting the ADP from the action potential waveform actually led to a ∼3% decrease in the total Ca2+ influx (Supplementary Fig. 4), consistent with accelerated deactivation. In contrast, prolonging the decay phase of the action potential led to a linear increase in Ca2+ influx over a wide range (Fig. 2e). This gives an independent estimate of the effect of spike broadening due to DTx-K, corresponding to an 18% increase in Ca2+ influx.

Two independent approaches (Ca2+ fluorescence imaging and kinetic modelling of P/Q-type channels), thus converge on the conclusion that Kv1.1 channel blockade causes ∼20% more Ca2+ influx per action potential.

Previous studies using α-DTx revealed a large increase in spontaneous IPSC amplitude and frequency in Purkinje cells22,23. We asked how DTx-K affects evoked IPSCs by recording from Purkinje cells, while activating axons in the Purkinje cell layer. Kv1.1 blockade with DTx-K led to a 45±19% increase in pharmacologically isolated monosynaptic IPSCs (n=15, P<0.05, Wilcoxon matched pairs signed-rank test; Supplementary Fig. 5). This is consistent with a ∼20% increase in Ca2+ influx, assuming a Ca2+ current cooperativity (m) of ∼2 (refs 33, 34).

Thus, delayed repolarization secondary to Kv1.1 blockade leads to increased Ca2+ influx and enhanced neurotransmitter release. How does the acute effect of manipulating Kv1.1 channels compare to genetic disruption of Kv1.1 in EA1?

Increased spike width and GABA release in Kcna1V408A/+ mice

We repeated action potential recordings from basket cells in Kcna1V408A/+ mice, which harbour a missense mutation that underlies EA1 (ref. 18), and their wild-type littermates (Kcna1+/+). Data were acquired and analysed blind to genotype. Passive membrane properties and current threshold for eliciting action potentials were unaffected by the mutation (Supplementary Table 1). Recordings of somatic action potentials also failed to reveal a significant difference in action potential width between genotypes (Fig. 3a). A robust difference in duration was however observed in presynaptic boutons. Action potential width was ∼35% greater in Kcna1V408A/+ mice (1.26±0.08 ms, n=13) than in Kcna1+/+ mice (0.93±0.03 ms, n=20; unpaired t-test: P<0.002; Fig. 3a,b). Trains of action potentials elicited at 55 and 100 Hz showed a similar spike broadening as in wild-type mice (Supplementary Fig. 1c), showing no evidence of occlusion between the effects of repetitive spiking and genotype. DTx-K failed to broaden action potential duration recorded from the presynaptic terminals of basket cells in Kcna1V408A/+ mice, consistent with the loss of function of Kv1.1-containing channels (Supplementary Fig. 6). We also observed no difference in the ADP between the genotypes.

The Kcna1V408A/+ mutation thus broadens the spike at least as much as acute application of DTx-K in wild-type boutons. We observed no evidence of homoeostatic compensation by other channels correcting for loss of Kv1 channel function in the knock-in model of EA1.

Increased inhibition of Purkinje cells in Kcna1V408A/+ mice

An increase in spontaneous GABAergic IPSCs has previously been reported in Purkinje cells of the Kcna1V408A/+ mouse18. It is technically difficult to compare presynaptic Ca2+ influx between genotypes, and the amplitudes of evoked IPSCs are uninformative when evoked by extracellular stimulation of multiple axons. Instead, we compared the paired-pulse ratio of IPSCs recorded in Purkinje cells as a surrogate measure of action potential-evoked neurotransmitter release probability. Paired-pulse ratio was significantly lower in Kcna1V408A/+ mice (0.49±0.06, n=6) than in Kcna1+/+ mice (0.77±0.07, n=7; P<0.01, unpaired t-test; Fig. 4a,b), consistent with an increased release probability. DTx-K had no significant effect on IPSC amplitude in Kcna1V408A/+ mice (4±5%, n=5). To examine the downstream consequences for Purkinje cells, we compared their spontaneous activity between Kcna1V408A/+ and Kcna1+/+ littermates, using cell-attached recordings to minimize disruption of intrinsic excitability. All Purkinje cells irrespective of genotype exhibited periods of tonic firing alternating with periods of quiescence or burst firing (Fig. 4c), as previously reported in wild-type mice and rats35. Overall, spike frequency recorded in Kcna1V408A/+ mice was significantly lower (55.4±10.7 Hz, n=13) compared with Kcna1+/+ littermates (96.3±12.1 Hz, n=20, P<0.02, Mann–Whitney U test). The average inter-spike interval during tonic firing was significantly longer in Kcna1V408A/+ mice (20.6±2.8 ms, n=19) than in Kcna1+/+ mice (10.9±1.3 ms, n=20; P<0.01, Mann–Whitney U test; Fig. 4d,e). The number of spikes per burst was also lower in mutant mice (10.9±3.3, n=5) than in wild-type mice (27.9±3.0, n=11; P<0.01, unpaired t-test; Fig. 4f). No significant difference was observed in burst duration or the inter-burst interval between the genotypes. There was also no difference in action potential width in Purkinje cells between the genotypes, as estimated by integrating the cell-attached recordings36 (Supplementary Fig. 7).

Finally, we asked if enhanced spontaneous GABA release contributed to the lower activity of Purkinje cells. Bath application of blockers of GABAA and GABAB receptors (100 μM PTx and 1 μM CGP 52432, respectively) led to a greater decrease in inter-spike interval in Kcna1V408A/+ mice (33.7±4.6%, n=10) than in Kcna1+/+ mice (17.1±4.1%, n=8; P<0.05, unpaired t-test; Fig. 4g,h). Indeed, the inter-spike interval in the presence of GABA receptor blockers was not significantly different between wild-type and Kcna1V408A/+ mice (11.3±1.9 ms and 15.6±2.1 ms; P=0.36, unpaired t-test). We thus conclude that enhanced GABA release indeed contributes to decreased spontaneous activity of Purkinje cells, with no evidence for a homoeostatic compensation in the EA1 mouse model.

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