Voltagedependent Sodium Channels ofthe Neuron Membrane

Recall that ions must cross the membrane through transmembrane pores or channels. A dramatic increase in sodium permeability like that shown in Figure 6-4 requires a dramatic increase in the number of membrane channels that allow sodium ions to enter the cell. Thus, the resting pNa of the membrane of an excitable cell is only a small fraction of what it could be because most membrane sodium channels are closed at rest. What stimulus causes these hidden channels to open and produces the positive swing of Em during an action potential? It turns out that the conducting state of sodium channels of excitable cells depends on membrane potential. When Em is at the usual resting level or more negative, these sodium channels are closed, Na+ cannot flow through them, and pNa is low. These channels open, however, when the membrane is depolarized. The stimulus for opening of the voltage-dependent sodium channels of excitable cells is a reduction of the membrane potential.

Because the voltage-dependent sodium channels respond to depolarization, the response of the membrane to depolarization is regenerative, or explosive. This is illustrated in Figure 6-5. When the membrane is depolarized, pNa increases, allowing sodium ions to carry positive charge into the cell. This depolarizes the cell further, causing a greater increase in pNa and more depolarization. Such a process is inherently explosive and tends to continue until all sodium channels are open and the membrane potential has been driven up to

Figure 6-5 The explosive cycle leading to depolarizing phase of an action potential.

near ENa. This explains the all-or-none behavior of the nerve action potential: once triggered, the process tends to run to completion.

Why should there be a threshold level of depolarization? Under the scheme discussed above, it might seem that any small depolarization would set the action potential off. However, in considering the effect of a depolarization, we must take into account the total current that flows across the membrane in response to the depolarization, not just the current carried by sodium ions. Recall that, at the resting Em, pK is very much greater than pNa; therefore, flow of K+ out of the cell can counteract the influx of Na+ even if pNa is moderately increased by a depolarization. Thus, for a moderate depolarization, the efflux of potassium might be larger than the influx of sodium, resulting in a net outward membrane current that keeps the membrane potential from depolarizing further and prevents the explosive cycle underlying the action potential. In order for the explosive process to be set in motion and an action potential to be generated, a depolarization must produce a net inward membrane current, which will in turn produce a further depolarization. A depolarization that produces an action potential must be sufficiently large to open quite a few sodium channels in order to overcome the efflux of potassium ions resulting from the depolarization. The threshold potential will be reached at that value ofEm where the influx of Na+ exactly balances the efflux of K+; any further depolarization will allow Na+ influx to dominate, resulting in an explosive action potential.

Factors that influence the actual value of the threshold potential for a particular neuron include the density of voltage-sensitive sodium channels in the plasma membrane and the strength of the connection between depolarization and opening of those channels. Thus, if voltage-sensitive sodium channels are densely packed in the membrane, opening only a small fraction of them will produce a sizable inward sodium current, and we would expect that the threshold depolarization would be smaller than if the channels were sparse. Often, the density of voltage-sensitive sodium channels is highest just at the point (called the initial segment) where a neuron's axon leaves the cell body; this results in that portion of the cell having the lowest threshold for action potential generation. Another important factor in determining the threshold is the steepness of the relation between depolarization and sodium channel opening. In some cases the sodium channels have "hair triggers," and only a small depolarization from the resting Em is required to open large numbers of channels. In such cases we would expect the threshold to be close to the resting membrane potential. In other neurons, larger depolarizations are necessary to open appreciable numbers of sodium channels, and the threshold is further from resting Em.

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