Action potential

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Image:Action potential vert.png

As the traveling signals of nerves and as the localized changes that contract muscle cells, action potentials are an essential feature of animal life. They set the pace of thought and action, may constrain the sizes of evolving anatomies and enable centralized control and coordination of organs and tissues. Non-propagating action potentials occur also in some plants.

Contents 1 Basic features 2 Underlying mechanism 3 Initiation 4 Action potential propagation 5 Saltatory conduction 6 Refractory period 7 Noteworthy characteristics of the action potential 8 Detection and observation 9 Detailed features 10 References 10.1 General sources 10.2 Primary sources 11 Related topics

Basic features

When a biological cell or patch of membrane undergoes an action potential—or electrical excitation—the polarity of the transmembrane voltage swings rapidly from negative to positive and back. Within any one excitable cell, consecutive action potentials typically are indistinguishable. Also between different cells, the amplitudes of the voltage swings tend to be roughly the same. However, the speed and simplicity of action potentials vary significantly between cells, in particular between different cell types.

Minimally, an action potential involves a depolarization, a repolarization, and finally a hyperpolarization (or "undershoot"). In specialized muscle cells of the heart, such as the pacemaker cells, a plateau phase of intermediate voltage may precede repolarization.

Underlying mechanism

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The transmembrane voltage changes that take place during an action potential result from changes in the permeability of the membrane to specific ions, the internal and external concentrations of which cells maintain in an imbalance. In the axon fibers of nerves, depolarization results from the inward rush of sodium ions, while repolarization and hyperpolarization arise from an outward rush of potassium ions. Calcium ions make up most or all of the depolarizing currents at an axon's presynaptic terminus, in muscle cells (including the heart's) and in some dendrites.

The imbalance of ions that makes possible not only action potentials but also the resting cell potential arises through the work of pumps, in particular the sodium-potassium exchanger. While the cell is at resting cell potential the electric forces between the sodium and potassium of the neuron is counterbalanced by the "diffusive forces," creating a state of equilibrium.

Changes in membrane permeability and the onset and cessation of ionic currents reflect the opening and closing of voltage-gated ion channels, which provide portals through the membrane for ions. Residing in and spanning the membrane, these proteins sense and respond to changes in transmembrane potential (see [1] for an illustration).

The depolarization phase of an action potential is due to the opening of voltage-gated ion channels, either sodium channels or calcium channels or a combination of both, depending on the particular membrane. Sodium ions and calcium ions are positively charged. When a voltage-gated sodium channel or calcium channel opens, positively charged ions move into the cell. Voltage-gated sodium channels automatically gate shut after about a millisecond. Calcium-mediated action potentials can be much longer in duration. The repolarization phase of an action potential is due to the opening of voltage-gated potassium channels. Cells normally keep the concentration of potassium ions high inside cells. When voltage-gated potassium channels open, positively charged potassium ions move out of the cell, causing the membrane potential to return to a negative inside potential.

Initiation

Action potentials are triggered by an initial depolarization to the point of threshold. This threshold potential varies but generally is about 15 millivolts above the resting potential of the cell, occurring when the inward sodium current exceeds the outward potassium current. The influx of sodium opens voltage-gated sodium channels, which activate in response to depolarization, resulting in a positive-feedback cycle.

Image:Whole cell IV showing rest and AP thresh.jpg

Thus the membrane potential at which the transmembrane current becomes net-inward, is the point where the sodium current becomes regenerative. The voltage-value of the threshold of the action potential can thus be shifted by changing the balance between sodium and potassium (and other) currents. The most common manifestation of this is the action potential's own refractory period. During this time following an action potential, sodium channels are (as a population) fully or partially inactivated, and thus unavailable to open and carry current. This effectively (albeit temporarily) decreases the density of available sodium channels, thus decreasing the amount of sodium current that can be generated by the membrane. As a result, during the refractory period, the threshold of the action potential is pushed to more-depolarized values, since there is less sodium current at a given voltage to counteract the potassium current.

The nature of an excitable cell's behavior can perhaps be better understood by examination of an I/V curve (right) of a hypothetical cell that has only two transmembrane ion channels: a non-voltage-dependent K⁺ channel and a voltage-gated Na⁺ channel. The current/voltage relationship of the K⁺ channel is illustrated by the blue line. The current/voltage relationship of the Na⁺ channel is illustrated by the yellow line. Since both of these ion channels are present, the total current/voltage behavior of the cell will be the algebraic sum of the two currents. This summed current is illustrated by the green line.

Four significant points in the summed I/V are indicated by arrows.

1. The green arrow indicates the resting potential of the cell and also the value of the equilibrium potential for potassium (E_k). Since the K⁺ channel is the only one open at these negative voltages, the cell will rest at E_k. Note that a stable resting potential will be present at any voltage where the summed I/V (green line) crosses the zero current (x-axis) point with a positive slope, such as at the green arrow. Consider why: any perturbation of the membrane potential in the negative direction will result in inward current that will depolarize the cell back toward the crossing point, while, any perturbation of the membrane potential in the positive direction will result in an outward current that will hyperpolarize the cell back toward the crossing point. Thus, any perturbation of the membrane potential around a positive slope crossing will tend to return the voltage to that crossing value.
2. The yellow arrow indicates the equilibrium potential for Na⁺ (E_Na. In this two-ion system, E_Na is the natural limit of membrane potential beyond which a cell cannot pass. Current values illustrated in this graph that exceed E_Na are measured by artificially pushing the cell's voltage past its natural limit. Note however, that E_Na could only be reached if the potassium current were absent.
3. The blue arrow indicates the maximum voltage that the peak of the action potential can approach. This is the actual natural maximum membrane potential that this cell can reach. It cannot reach E_Na because of the counteracting influence of the potassium current.
4. The red arrow indicates the action potential threshold. This is the point where I_sum becomes net-inward. Note that this is a zero-current crossing, but with a negative slope. Any such "negative slope crossing" of the zero current level in an I/V plot is an unstable point. At any voltage negative to this crossing, the current is outward and so a cell will tend to return to its resting potential. At any voltage positive of this crossing, the current is inward and will tend to depolarize the cell. This depolarization leads to more inward current, thus the sodium current become regenerative. Note that the point at which the green line reaches its most negative value is the point where all sodium channels are open. Depolarizations beyond that point thus decrease the sodium current as the driving force decreases as the membrane potential approaches E_Na.

Note that persons first trying to understand action potential threshold will oftentimes mistake the origin of the AP threshold with the "threshold" of sodium channel opening. This is incorrect because

1. Sodium channels have no threshold. They open in response to depolarization in a stochastic manner. Depolarization does not so much open the channel as it increases the probability of the channel being open. Even at hyperpolarized potentials, a sodium channel will open very occasionally.
2. AP threshold as described above is not at the voltage where sodium current becomes significant, but rather at the point where it exceeds potassium current.

Biologically in neurons, depolarization typically originates in the dendrites at synapses. In principle, however, an action potential may be initiated anywhere along a nerve fiber. In his discovery of "animal electricity," Luigi Galvani made a leg of a dead frog kick as in life by touching a sciatic nerve with his scalpel, to which he had inadvertently transferred a negative, static-electric charge, thus initiating an action potential.

Action potential propagation

In unmyelinated axons, action potentials propagate as an interaction between passively spreading membrane depolarization and voltage-gate sodium channels. A spatially localized depolarization opens sodium channels, allowing positive ion flux into the cell and locally depolarizing the membrane potential. This depolarization "spreads" to adjacent membrane via the diffusion of positive ions along the axon's lumen. This causes the discharge of the membrane capacitance in the adjacent membrane, and thus a depolarization of the membrane potential in that adjacent membrane. This depolarization then opens sodium channels in that location and the process repeats all the way down the axon.

To understand propagatory properties of action potentials in biological membranes, it is useful to have a basic understanding of the electrical properties of the membrane and its surrounding fluids. It would also be useful to have a basic understanding of cable properties, an understanding of which was first required for submarine telegraph cables. Any given patch of membrane containing ion channels, will have the basic properties of an RC circuit. An RC circuit is perhaps the simplest of all electronic circuits. The most basic RC circuit consists of only two elements, a resistor and a capacitor. It would look something like the diagram shown in Part A of the first illustration of this section.

In such a circuit, the resistor would be the ion channel(s) across the membrane, while the capacitor would be formed by the conducting fluid inside and outside the membrane, separated by the insulating lipid membrane itself. However, to understand how action potentials are propagated in such a circuit, it is necessary to add additional elements to account for those proteins in, and conditions across, the cell membrane that participate in the action potential, namely the individual sodium and potassium channels, and the membrane potential that is generated by the concentration gradient of potassium and sodium across the membrane. In part B of the diagram, three resistors are shown in parallel across the membrane. Two are variable resistors (resistor with an arrow across it), because they represent ion channels that change their resistance, in this case because they are voltage-gated. More specifically, the green variable resistor represents the voltage gated "delayed rectifier" potassium channel, while the blue represents the voltage-gated sodium channel. The black "fixed" resistor represents the baseline potassium conductance of the membrane, which is primarily responsible for maintaining the cell's resting potential. The two "batteries" in the circuit, represent the voltages generated by the potassium and sodium concentration gradients (technical note: it would be most accurate to draw this diagram without the "sodium battery" in the baseline cases where the membrane is at a hyperpolarized potential where the sodium channel is closed. Only permeant ions contribute voltage to the membrane potential, so it is not until the sodium channel opens that the battery "appears" in the diagram).

In one such isolated "patch" of membrane, the action potential can be understood in the absence of propagation (indeed, in the 'single patch' electrical model, there is nowhere for it to propagate to! In this simple model, the membrane resting potential is maintained by the non-voltage-dependent (leak) potassium channel (black non-variable resistor). The action potential rising phase occurs when the sodium channel opens (blue resistor decreases its resistance) causing the sodium permeability to become much higher than the potassium permeability (see the Goldman-Hodgkin-Katz equation). This drives the membrane potential toward E_Na. With a time delay, two things happen. The voltage-dependent potassium channel opens (known as the delayed rectifier channel) and the sodium channel closes due to inactivation. This drives the membrane potential back toward the resting potential, creating the falling phase of the action potential. Indeed, since the potassium permeability is now larger than it was before the action potential (two K channels are open), the membrane potential approaches even closer to E_K than it does at rest, causing the action potential undershoot. The delayed rectifier, being voltage-dependent is then closed by the hyperpolarized voltage, and the cell returns to resting potential.

To build on these ideas, one needs to make the electrical membrane model more complex, i.e. one must provide a place to which the action potential can propagate. To do this, one simply appends multiple copies of the "patch of membrane" circuit end to end. When a single patch of membrane is depolarized sufficiently to open the local voltage-gated sodium channels, positive charges carried by sodium ions enter the cell (see T1 in the second diagram; the red arrow represents sodium ion current into the inside of the cell). Once inside the cell, the positive charges carried by the sodium ions travel down the relatively low axial resistance of the axon (sideways extension of the red arrow in T2). It is important to note that the sodium current across the membrane is carried by the facilitated diffusion of ions across the membrane. That is, individual ions actually travel from the outside to the inside of the cell. In contrast, the current along the axial resistance inside a cell or axon travels not by diffusion, but rather, as sodium ions diffuse away from their site of entry, they "nudge" adjacent ions down the axon by electrostatic repulsion (this is the same principle which makes the Newton's cradle toy work, but the energy transfer between ions is electrostatic rather than kinetic), or attract negative ions away from adjacent membrane areas. Either way, a wave of positivity moves down the axon without any individual ion moving very far. Once the adjacent patch of membrane is depolarized, the sodium channels in that adjacent patch open, regenerating the whole process. Thus, the action potential doesn't so much travel down the membrane as it is regenerated at each membrane segment.

The propagation speed of these impulses is faster in axons of larger diameter, other things being equal. This is primarily because the axial resistance of the lumen of the axon is lower the larger the diameter. Since the action potential propagates primarily through the axial movement of positive charges, a larger diameter axon equals faster propagation. In detail, the reason why larger diameter axons propagate action potentials faster is that changes in diameter change the cross sectional area of the axon more than they change the membrane surface area. As will be discussed in more detail in the next section, membrane surface area is the main factor that slows action potential propagation in an unmyelinated axon. Thus, a change in the cross sectional area / membrane surface area is particularly effective in speeding action potential propagation, as it decreases axial resistance relative to surface area.

Perhaps the extreme example of an animal using axon diameter as a means of speeding action potential conduction is found in the cephalopod squid, including the common Atlantic squid (Loligo vulgaris). The behavior of these squid includes an predator escape response where the squid can move quickly through the water by squirting a jet of water through an opening at the "tentacle end" of the animal. This water is ejected from the body of the squid by the contraction of muscles under the control of a "giant axon". The squid giant axon can be upwards of 1 mm in diameter. Its large diameter is presumably an adaptive trait to allow very fast activation of the escape response behavior. An axon so large maximizes the benefits of cross sectional area / membrane surface area in the extreme. Indeed, the velocity of nerve impulses in these fibers is among the fastest in nature.

In their Nobel Prize-winning work uncovering ionic mechanism of action potentials, Alan Hodgkin and Andrew Huxley performed experiments on the giant axon of the Atlantic squid. The advantage for Hodgkin and Huxley was the great diameter of the axon. This allowed them to insert voltage clamp electrodes inside the lumen of the axon, a major experimental advantage. To this day, no experimental preparation yields greater accuracy in the measurement of action potential characteristics, and is still widely used in their study.

In an ironic twist of fate, at least in the waters around Plymouth, England and Woods Hole, Massachusetts, the top predator of the squid became scientists intent on dissecting their predator escape mechanisms.

Saltatory conduction

The main impediment to conduction speed in unmyelinated axons is membrane capacitance. In general, a capacitor is any two conducting plates held close together in parallel planes with an insulator between them. Capacitors "store" charge because when a voltage is applied across the capacitor, positive charges accumulating on one plate attract negative charges on the other plate by electrostatic forces. A capacitor is said to be "full" when the force of electrostatic repulsion between the charges on each plate and the entering charges of the same polarity, equals the voltage force pushing the charges onto the capacitor. In an RC circuit the "wires" leading into the capacitor have negligible resistance, so when voltage is applied to an RC circuit, the current will flow first to the capacitor and only as it approaches "fullness" will current flow through the resistor. Any capacitor has a property called a time constant. The time constant is a measure of how long it take to charge or discharge the capacitor (more precisely, the time constant is the time it takes to charge (or discharge) a capacitor to within 1/e of it being full). The longer the time constant, the longer it takes to charge the capacitor. The capacity (and thus the time constant) of a capacitor can be increased in two ways:

1. by increasing the size of the plates, so that the capacitor can hold more charge, or
2. by decreasing the distance between the plates, thus increasing electrostatic attraction across the plates relative to electrostatic repulsion within each plate.

It is the same in the RC circuits of biological membranes. In the membrane, the plates of the capacitor are the saline solutions on each side of the membrane, while the insulator separating those plates is the membrane itself. This capacitance is highly relevant to the propagation of the action potential because as the action potential propagates down the axon, the speed of depolarization of each new patch of membrane is slowed by the time it takes to discharge the membrane capacitance. Thus, one strategy that the nervous system has evolved to speed action potential propagation is the decrease membrane capacitance. Just as there are two ways of increasing capacitance (list above), membrane capacitance can be decreased by doing the opposite. In the case of the nervous system, the main strategy that has evolved is to move the conducting plates farther apart by myelinating the axon. Myelin as an insulating sheath that is wrapped around axons, by Schwann cells. Schwann cells are neuroglia that have specialized to flatten out their somata to form large sheets made up mostly of memebrane. These sheets of membrane are then wrapped around the axon, producing a thick layer of insulation. This moves the conducting plates (the intra and extracellular fluid) farther apart, thus decreasing membrane capacitance. Interestingly, the use of Myelin has also allowed for the co-evolution of smaller axons, thus decreasing the membrane surface area (i.e. the size of the capacitor plates).

The problem that is created by myelination is that myelin so effectively insulates the membrane, that ions can no longer flow across the membrane. Thus, action potential generation is abolished in myelinated membrane. Neurons have evolved a solution to this problem in that spaces of bare axonal membrane occur at intervals down the axon. These spaces are known as nodes of Ranvier. The myelin segment between each node is produced by a single Schwann cell. The nodes themselves are specialized membrane. Nodes of Ranvier contain a significantly higher density of voltage gated sodium channels than is found in unmyelinated axons (4 orders of magnitude higher)[[2]]. A higher density of sodium channels translates directly into a lower action potential threshold (see initiation, above: more sodium channels produce more sodium current, which overbalances the potassium current at a more negative voltage, thus lowering the threshold).

Because of the properties of myelin and nodes of Ranvier, action potential conduction is transformed into a mixture of passive and active alternating phases. The myelinated portion of the axon has become more-or-less like a passive wire. An action potential generated at the beginning of an axon moves through the first myelinated segment by purely passive charge movement down this wire (as it would in a telephone cable). It moves quickly because the membrane capacitance is minimized by the myelin and the signal travels a relatively long distance without significant degradation because the resistance of myelinated membrane is so high. When this passively propagated signal reaches a node, it is of sufficient size to fire an action potential at that node. That nodal action potential then passively travels to the next node where a new action potential is generated. Action potential conduction velocity is greatly increased by this means, because the passive transmission in the internodal regions is essentially instantaneous. Generating an action potential is time consuming, but now the axon must do this only at the nodes. Because of this, there is still some advantage to large axon diameters. Larger diameters can tolerate longer internodal distances, thus increasing the proportion of the axon length that can utilize passive charge travel over the slower action potential generation.

The internodal distance is important. It should be as long as possible — to maximize the length of fast passive conduction — but not so long that the decay of this passive signal is too great to reach threshold at the next node. Interestingly, internodal distance seems to occur such that the passively propagated signal can travel for at least two nodes retaining enough amplitude to fire an action potential at that second or third node. Thus, the safety factor of saltatory conduction is high — Even if one node is damaged, transmission can still effectively bypass that node. Almost incredibly, the myelinating Schwann cells seem to "know" the diameter of any particular axon, in that these cells will sheath a longer length of axon in larger diameter axons, and a shorter length in smaller diameter axons. The means by which this happens is not known.

Thus, the process of saltatory conduction is essentially one of the action potential "jumping" from node to node, being regenerated anew at each node. The advantage is that it maximizes the speed of conduction for a given axon diameter. This has undoubtedly played an important role in the evolution of larger and more complex organisms. The conduction velocity of the largest human myelinated axons significantly exceeds that of squid giant axon (~120 m/s vs. ~25 m/s) [[3]]. Imagine the constraints if the only way one could achieve high conduction velocities was to increase axon diameter. It would certainly be true that the nervous system of most higher animals would not fit into their bodies (and indeed, this constraint would likely have severely restricted body size).

Some diseases exert their pathology by degrading saltatory conduction. The most well-known of these is multiple sclerosis ("many scars" the name derived from the scarred myelin tissue on the afflicted's brain and spinal cord). Multiple sclerosis (MS) is caused by the breakdown of myelin, most likely by an autoimmune process. Some theories hold that the incidence of MS is higher in persons who have suffered maladies that might compromise the blood brain barrier. In theory, such compromise might give the immune system temporary access to brain tissue. Since the immune system is normally excluded from the brain, it is hypothesized that the immune system does not recognize the brain tissue as "self" and produces antibodies that have cross-reactivity to Schwann cells. There are other hypotheses as well. The breakdown of myelin in MS is a problem not so much in that action potential conduction fails in the nerves with damaged myelin, but rather than the action potential is slowed, and slowed different amounts in different axons. Much of our ability to move depends on nerve impulses arriving at the muscles in precisely timed patterns, so a disease that causes a more-or-less random change in the conduction velocity in each individual axon, will disrupt the ability for coordinated movement.

Refractory period

In the previous section, it was shown that sodium currents entering a cell at a node of Ranvier travel passively down the axon to the next node. However, since the movement of charge from node to node is passive, it will travel both directions down the axon. Why then does the regeneration of the action potential at each node not generate new action potentials travelling both directions along the axon? It is, of course, because the node "behind" the propagating action potential is refractory. Where membrane has undergone an action potential, a refractory period follows. This refractory period arises primarily because of the voltage-dependent inactivation of sodium channels. As was first described by Hodgkin and Huxley in 1952, sodium channels have two voltage-dependencies. They open in a voltage-dependent manner, and inactivate in a voltage dependent manner. The inactivation takes longer to develop, so the effect is that, upon depolarization, the channel opens and then closes due to inactivation. Furthermore, inactivation essentially "locks" the channel closed. At the end of an action potential, when the membrane has returned to rest, inactivation remains in that it takes significant time for the channel to return to a "closed but available" state. Immediately after the action potential, virtually all the sodium channels are inactivated, and thus it is impossible to fire another action potential in that membrane. This is known as the absolute refractory period. As milliseconds proceed, sodium channels leave the inactivated state via a [4] process. As sodium channels begin to come available again, it is possible to fire an action potential, but it has a much higher threshold. This is the “relative refractory period”. Together the absolute and relative refractory periods last about 5 ms, although this time varies from cell type to cell type. As an aside, while the sodium channel goes through this closed to open to inactivated (and closed) sequence during an action potential, biophysically, the channel does not need to go through the open state to reach the inactivated state. Very slow depolarizations of the membrane will not induce an action potential because the channels are inactivated before they are activated.

Noteworthy characteristics of the action potential

The initiation of an action potential is "all-or-none" and the subsequent wave travels by "active propagation." The same passive conduction that spreads depolarization from one node to another in a myelinated axon occurs over a shorter distance in unmyelinated cells, such that excitation in any patch of membrane will depolarize a neighborhood around it and bring it to threshold. This "regenerates" the action potential in this neighboring region from the energy that stored in the ionic imbalance there and advances the wave. As a result, the peak amplitude of the depolarization does not decrease as an action potential propagates allowing it to cover distances that a passive electrical wave or signal could not. This active mode propagation is slower, however.

Detection and observation

Action potentials (APs) are measured with the recording techniques of electrophysiology. In the case of an archetypal nerve action potential (signal) on an oscilloscope, the relatively large swing to a more positive value, followed by the repolarization recovery and undershoot together trace an arc that could be described as a distorted sine wave—or like the blips on hospital EKG machines that can be seen on TV (these EKG waves are a smear of all the action potentials in one heartbeat, so they enact more slowly than any individual AP and have a somewhat more complicated shape). In an unmyelinated axon that is firing an action potential, the transmembrane potential at any instant will vary from point to point along the fiber, with its amplitude depending on whether the AP wave has reached that point or passed it, and how long ago. A recording from a single point will show the various stages of the action potential enacted—depolarization, repolarization, hyperpolarization—as the wave passes.

A neurochip containing EOSFETs is a new method to monitor neurons.

Detailed features

Prototypically, depolarization and repolarization together are complete in about two milliseconds, while undershoots can last hundreds of milliseconds, depending on the cell. In neurons, the exact length of the roughly two-millisecond delay in repolarization can have a strong effect on the amount of neurotransmitter released at a synapse. The duration of the hyperpolarization determines a nerve's refractory period (how long until it may conduct another action potential) and hence the frequency at which it will fire under continuous stimulation. Both of these properties are subject to biological regulation, primarily (among the mechanisms discovered so far) acting on ion channels selective for potassium.

In pacemaker and other cardiac muscle cells, inward calcium currents determine shape and duration of the plateau phase, which in turn controls the strength and duration of contraction. See cardiac action potential, ventricular action potential, atrial action potential, and pacemaker action potential for more details.

References

General sources

• Bear, M.F., B.W. Connors, and M.A. Paradiso. 2001. Neuroscience: Exploring the Brain. Baltimore: Lippincott.[5]
• Kandel, Eric, James Schwartz, and Thomas Jessel. 2000. Principles of Neural Science. 4th ed. McGraw-Hill, New York.[6]
• Dale Purves, et al. Neuroscience, 2nd ed. 2001. Sinauer Associates, Inc. Ion Channels Underlying Action Potentials. [7]

Primary sources

• Hodgkin, A.L. and Huxley, A.F., 1952. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J. Physiol. 116, pp. 449–472.
• Hodgkin, A.L. and Huxley, A.F., 1952. The components of membrane conductance in the giant axon of Loligo. J. Physiol. 116, pp. 473–496.
• Hodgkin, A.L. and Huxley, A.F., 1952. The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J. Physiol. 116, pp. 497–506.
• Hodgkin, A.L. and Huxley, A.F., 1952. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, pp. 500–544.
• Clay J.R., 2005. Axonal excitability revisited. Prog Biophys Mol Biol. 88, pp. 59-90.

Related topics

• signals (biology)
• depolarization
• hyperpolarization
• membrane potential
• Cardiac action potential
• Ventricular action potential