The cell membranes of nerves, like those of other cells, contain many different types of ion channels. Some of these are voltage-gated and others are ligand-gated. It is the behavior of these channels, and particularly Na+ and K+ channels, that explains the electrical events in neurons.
The changes in membrane conductance of Na+ and K+ that occur during the action potentials are shown by steps 1 through 7 in Figure1. The conductance of an ion is the reciprocal of its electrical resistance in the membrane and is a measure of the membrane permeability to that ion. In response to a depolarizing stimulus, some of the voltage-gated Na+ channels open and Na+ enters the cell and the membrane is brought to its threshold potential (step 2) and the voltage-gated Na+ channels overwhelm the K+ and other channels. The entry of Na+ causes the opening of more voltage-gated Na+ channels and further depolarization, setting up a positive feedback loop. The rapid upstroke in the membrane potential ensues (step 3). The membrane potential moves toward the equilibrium potential for Na+ (+60 mV) but does not reach it during the action potential (step 4), primarily because the increase in Na+ conductance is short-lived. The Na+ channels rapidly enter a closed state called the inactivated state and remain in this state for a few milliseconds before returning to the resting state, when they again can be activated. In addition, the direction of the electrical gradient for Na+ is reversed during the overshoot because the membrane potential is reversed, and this limits Na+ influx; also the voltage-gated K+ channels open. These factors contribute to repolarization. The opening of voltage-gated K+ channels is slower and more prolonged than the opening of the Na+ channels, and consequently, much of the increase in K+ conductance comes after the increase in Na+ conductance (step 5). The net movement of positive charge out of the cell due to K+ efflux at this time helps complete the process of repolarization. The slow return of the K+ channels to the closed state also explains the after-hyperpolarization (step 6), followed by a return to the resting membrane potential (step 7). Thus, voltage-gated K+ channels bring the action potential to an end and cause closure of their gates through a negative feedback process. Figure 2 shows the sequential feedback control in voltage-gated K+ and Na+ channels during the action potential.
Fig1. Changes in membrane potential and relative membrane permeability to Na+ and K+ during an action potential. Steps 1 through 7 are detailed in the text. These changes in threshold for activation (excitability) are correlated with the phases of the action potential. (Modified with permission from Silverthorn DU: Human Physiology: An Integrated Approach, 5th ed. Pearson, 2010.)
Fig2. Feedback control in voltage-gated ion channels in the membrane. A) Na+ channels exert positive feedback. B) K+ channels exert negative feedback. PNa , PK is permeability to Na+ and K+, respectively. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. New York, NY: McGraw-Hill; 2008.)
Decreasing the external Na+ concentration reduces the size of the action potential but has little effect on the resting membrane potential. The lack of much effect on the resting membrane potential would be predicted, since the permeability of the membrane to Na+ at rest is relatively low. In contrast, since the resting membrane potential is close to the equilibrium potential for K+, changes in the external concentration of this ion can have major effects on the resting membrane potential. If the extracellular level of K+ is increased (hyperkalemia), the resting potential moves closer to the threshold for eliciting an action potential, thus the neuron becomes more excitable. If the extracellular level of K+ is decreased (hypokalemia), the membrane potential is reduced and the neuron is hyperpolarized.
Although Na+ enters the nerve cell and K+ leaves it during the action potential, very few ions actually move across the membrane. It has been estimated that only 1 in 100,000 K+ ions cross the membrane to change the membrane potential from +30 mV (peak of the action potential) to –70 mV (resting potential). Significant differences in ion concentrations can be measured only after prolonged, repeated stimulation.
Other ions, notably Ca2+, can affect the membrane potential through both channel movement and membrane interactions. A decrease in extracellular Ca2+ concentration increases the excitability of nerve and muscle cells by decreasing the amount of depolarization necessary to initiate the changes in the Na+ and K+ conductance that produce the action potential. Conversely, an increase in extracellular Ca2+ concentration can stabilize the membrane by decreasing excitability.
