Action Potential

For a neuron to transmit information, it must generate an electrical current, termed an action potential. Development of the action potential requires an electrical or chemical stimulus, which alters ion flow into the cell.

The electrical current that flows into and out of the cell is carried by ions, both positively charged (cations) and negatively charged (anions). The direction of current flow is conventionally defined as the direction of net movement of positive charge. Cations move in the direction of the electrical current, whereas anions move in the opposite direction. Depending on the exact nature of transmembrane ionic flow, the charge separation across the resting membrane is disturbed, altering the polarity of the membrane. A reduction of charge separation results in a less negative membrane potential and is termed depolarization, whereas an increase in charge separation leading to a more negative membrane potential is called hyperpolarization.

When the membrane potential reaches a threshold (—55 to -60 mV), the voltage-gated Na+ channels open rapidly. The influx of Na+ makes the interior of the cell more positive than before. This sudden marked increase in depolarization causes still more voltage-gated Na+ channels to open, resulting in further acceleration of the depolarization. This positive feed forward cycle initiates an action potential and is responsible for its all-or-none character. Once initiated, the action potential behaves independently of its stimulus. Because the Na+ conductance becomes so transiently large relative to other ionic conductances, the membrane potential approaches the equilibrium potential for Na+ (+60 mV) during an action potential. Depolarization during the action potential is very large, but very brief, lasting only 1 ms. These features of the action potential allow neuronal signaling with high fidelity at a very high rate (up to hundreds of action potentials per second). Termination of the action potential is caused by rapid inactivation of Na+ channels and delayed opening of voltage-gated K+ channels. The delayed increase in K+ efflux, combined with a decrease in Na+ influx, produces a net efflux of positive charge from the cell, which continues until the cell has repolar-ized. Indeed, after an action potential, there is a brief hyperpolarization, during which time the cell is more refractory to immediate depolarization, before reestablishing the resting membrane voltage. Figure 2 demonstrates the sequential opening of voltage-gated Na+ and K+ channels during the action potential.

During the action potential, Na+ channels undergo transitions among three different states: resting, activated, or inactivated. On depolarization, the channel goes from the resting (closed) state to the activated (open) state (Fig. 3). If the depolarization is brief, the channels go directly back to the resting state on repolarization. If the depolarization is

Fig. 2. Openings of channels during the action potential. The influx of Na+ makes the interior of the cell more positive than before, increasing the degree of depolarization, which causes still more voltage-gated Na+ channels to open, resulting in further acceleration of the depolarization. The positive feedback cycle initiates the action potential and is responsible for its all-or-none character. However, with the depolarization there is a greater electrical driving force on the K+ ions and K+ flow outward. The increase in K+ efflux combined with a decrease in Na+ influx results in an efflux of positive charge from the cell, which continues until the cell has repolarized to its resting membrane potential. Modified from Kandel et al., 2000 with permission.

Fig. 2. Openings of channels during the action potential. The influx of Na+ makes the interior of the cell more positive than before, increasing the degree of depolarization, which causes still more voltage-gated Na+ channels to open, resulting in further acceleration of the depolarization. The positive feedback cycle initiates the action potential and is responsible for its all-or-none character. However, with the depolarization there is a greater electrical driving force on the K+ ions and K+ flow outward. The increase in K+ efflux combined with a decrease in Na+ influx results in an efflux of positive charge from the cell, which continues until the cell has repolarized to its resting membrane potential. Modified from Kandel et al., 2000 with permission.

maintained, the channels go from the open state to the inactivated closed state. Once the channel is inactivated, it cannot be opened by further depolarization. Channel inactivation can be reversed only by repolarization of the membrane to its negative resting potential, which allows the channel to switch from the inactivated to the resting state. Each Na+ channel has two kinds of gates that must operate in conjunction for the channel to conduct Na+ ions. An activation gate closes when the membrane is at its negative resting potential and is rapidly opened by depolarization; an inactivation gate is open at the resting potential and closes slowly in response to depolarization. The channel conducts ions only for the brief period during a depolarization when both gates are open. Repolarization reverses the two processes; closing the activation gate rapidly and opening the inactivation gate more slowly. After the channel has returned to the resting state, it can again be reactivated by further depolarization.

After an action potential, the Na+ channels are inactivated and the K+ channels are activated for a brief period of time. These transitory events make it more difficult for another action potential to be generated quickly. This refractory period limits the number of action

A Resting (closed) g Activated (open)

A Resting (closed) g Activated (open)

Fig. 3. Voltage-gated Na+ channel. In the resting condition (A) the activation gate (black bar) is closed and the inactivation gate (ball and chain) is open. No Na+ flows because of the closed activation gate. With depolarization of the membrane, there is a conformational change of the channel and the activation gate opens (B). Na+ flow then occurs. This is followed by inactivation by closure of the inactivation gate (C), prohibiting the further flow of Na+ ions. With repolarization of the membrane, the inactivation gate opens and the activation gate closes and the channel is ready for another cycle (A). Modified from Kandel et al., 2000, with permission.

Fig. 3. Voltage-gated Na+ channel. In the resting condition (A) the activation gate (black bar) is closed and the inactivation gate (ball and chain) is open. No Na+ flows because of the closed activation gate. With depolarization of the membrane, there is a conformational change of the channel and the activation gate opens (B). Na+ flow then occurs. This is followed by inactivation by closure of the inactivation gate (C), prohibiting the further flow of Na+ ions. With repolarization of the membrane, the inactivation gate opens and the activation gate closes and the channel is ready for another cycle (A). Modified from Kandel et al., 2000, with permission.

potentials that a given nerve cell can produce per unit time. This phenomenon also explains why action potentials do not reverberate up and down the neuronal membrane.

Very small depolarizations do not trigger an action potential because they do not open a large enough number of Na+ channels and increase the driving force on K+ ions, favoring repolariza-tion, as the depolarized membrane potential is further from EK. Action potential threshold occurs when the inward Na+ current just exceeds K+ outflow. The net inward current produces an active depolarization, which initiates further Na+ channel opening and generation of the action potential.

Extracellular electrodes can detect action potentials from individual neurons only if the size of the electrode is comparable to the size of the cell (tens of micrometers) and if the electrode is very close to the cell soma, where the action potential is generated. The amplitude of the extracellularly recorded action potential is small, on the order of tens of microvolts, and the duration is less than a millisecond. With conventional EEG electrodes, the action potentials from individual neurons are too small to be detected. However, when many neurons fire action potentials simultaneously, which can occur, for instance, in epileptic patients, their summated action potentials can be detected in EEG recordings as a "population spike."

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