Action potentials result from the presence in a cell's membrane of special types of voltage-gated ion channels. A voltage-gated ion channel is a cluster of proteins embedded in the membrane that has three key properties:
- It is capable of assuming more than one conformation.
- At least one of the conformations creates a channel through the membrane that is permeable to specific types of ions.
- 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 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. 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 deactivated→activated→inactivated→deactivated. 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. 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.
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 chloride anions are involved in a few types of action potentials, such as the cardiac action potential and the action potential in the single-cell alga Acetabularia, respectively.
Although action potentials are generated locally on patches of excitable membrane, the resulting currents can trigger action potentials on neighboring stretches of membrane, precipitating a domino-like propagation. In contrast to passive spread of electric potentials (electrotonic potential), action potentials are generated anew along excitable stretches of membrane and propagate without decay. 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. These are thought to have a role in spike-timing-dependent plasticity.
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