Ion Gating in Axons

The changes in membrane potential just described—depolarization, repolarization, and hyperpolarization—are caused by changes in the net flow of ions through ion channels in the membrane. Ions such as Na+, K+, and others pass through ion channels in the plasma membrane that are said to be gated channels. The "gates" are part of the proteins that comprise the channels, and can open or close the ion channels in response to particular changes. When ion channels are closed, the plasma membrane is less permeable, and when the channels are open, the membrane is more permeable to an ion (fig. 7.12).

The ion channels for Na+ and K+ are fairly specific for each of these ions. It is believed that there are two types of channels for K+; one type is always open, whereas the other type is closed in the resting cell. Channels for Na+, by contrast, are always closed in the resting cell. The resting cell is thus more permeable to K+ than to Na+. (As described in chapter 6, some Na+ does leak into the cell; this leakage may occur in a nonspecific manner through open K+ channels.) Because of the slight inward leakage of Na+, the resting membrane potential is a little less negative than the equilibrium potential for K+.

Depolarization of a small region of an axon can be experimentally induced by a pair of stimulating electrodes that act as if they were injecting positive charges into the axon. If two recording electrodes are placed in the same region (one electrode within the axon and one outside), an upward deflection of the oscilloscope line will be observed as a result of this depolarization. If a certain level of depolarization is achieved (from -70 mV to -55 mV, for example) by this artificial stimulation, a sudden and very rapid change in the membrane potential will be observed. This is because depolarization to a threshold level causes the Na+ channels to open. Now the permeability properties of the membrane are changed, and Na+ diffuses down its concentration gradient into the cell.

A fraction of a second after the Na+ channels open, they close again. Just before they do, the depolarization stimulus causes the K+ gates to open. This makes the membrane more permeable to K+ than it is at rest, and K+ diffuses down its con-

Channel closed at resting membrane potential

(fii'Sfc

Channel closed at resting membrane potential

Channel inactivated during refractory period

Channel inactivated during refractory period

■ Figure 7.12 A model of a voltage-gated ion channel. The channel is closed at the resting membrane potential but opens in response to a threshold level of depolarization. This permits the diffusion of ions required for action potentials. After a brief period of time, the channel is inactivated by the "ball and chain" portion of a polypeptide chain (discussed in the section on refractory periods in the text).

Membrane potential — depolarizes from -70 mV to +30 mV

Membrane potential (millivolts)

Membrane potential (millivolts)

Threshold

Threshold

Membrane potential repolarizes from +30 mV to -70 mV

■ Figure 7.13 Depolarization of an axon affects Na+ and K+ diffusion in sequence. (1) Na+ gates open and Na+ diffuses into the cell. (2) After a brief period, K+ gates open and K+ diffuses out of the cell. An inward diffusion of Na+ causes further depolarization, which in turn causes further opening of Na+ gates in a positive feedback (+) fashion. The opening of K+ gates and outward diffusion of K+ makes the inside of the cell more negative, and thus has a negative feedback effect (-) on the initial depolarization.

Local anesthetics block the conduction of action potentials in sensory axons. They do this by reversibly binding to specific sites within the voltage-gated Na+ channels, reducing the ability of membrane depolarization to produce action potentials. Cocaine was the first local anesthetic to be used, but because of its toxicity and potential for abuse, alternatives have been developed. The first synthetic analog of cocaine used for local anesthesia, procaine, was produced in 1905. Other local anesthetics of this type include lidocaine and tetracaine.

nature of the stimulus in vivo (in the body), and the manner by which electrical events are conducted to different points along the axon, will be described in later sections.

When the axon membrane has been depolarized to a threshold level—in the previous example, by stimulating electrodes—the Na+ gates open and the membrane becomes permeable to Na+. This permits Na+ to enter the axon by diffusion, which further depolarizes the membrane (makes the inside less negative, or more positive). Since the gates for the Na+ channels of the axon membrane are voltage regulated, this additional depolarization opens more Na+ channels and makes the membrane even more permeable to Na+. As a result, more Na+ can enter the cell and induce a depolarization that opens even more voltage-regulated Na+ gates. A positive feedback loop (fig. 7.13) is thus created, causing the rate of Na+ entry and depolarization to accelerate in an explosive fashion.

The explosive increase in Na+ permeability results in a rapid reversal of the membrane potential in that region from -70 mV to +30 mV (fig. 7.13). At that point in time, the channels for Na+ close (they actually become inactivated, as illustrated in figure 7.12), causing a rapid decrease in Na+ permeability. Also at this time, as a result of a time-delayed effect of the depolarization, voltage-gated K+ channels open and K+ diffuses rapidly out of the cell.

Since K+ is positively charged, the diffusion of K+ out of the cell makes the inside of the cell less positive, or more negative, and acts to restore the original resting membrane potential of -70 mV. This process is called repolarization and represents the completion of a negative feedback loop (fig. 7.13). These changes in Na+ and K+ diffusion and the resulting changes in the membrane potential they produce constitute an event called the action potential, or nerve impulse.

The correlation between ion movements and changes in membrane potential is shown in figure 7.14. The bottom portion of this figure illustrates the movement of Na+ and K+ through the axon membrane in response to a depolarization stimulus. Notice that the explosive increase in Na+ diffusion causes rapid depolarization to 0 mV and then overshoot of the membrane potential so that the inside of the membrane actually becomes positively charged (almost +30 mV) compared to the outside (top portion of fig. 7.14). The greatly increased permeability to Na+ thus drives the membrane potential toward the equilibrium potential for Na+ (chapter 6). The Na+ permeability then rapidly decreases and the diffusion of K+ increases, resulting in repolar-ization to the resting membrane potential.

Once an action potential has been completed, the Na+/K+ pumps will extrude the extra Na+ that has entered the axon and recover the K+ that has diffused out of the axon. This active transport of ions occurs very quickly because the events described occur across only a very small area of membrane. Only

The Nervous System: Neurons and Synapses 163

The Nervous System: Neurons and Synapses 163

Time (milliseconds)

■ Figure 7.14 Membrane potential changes and ion movements during an action potential. An action potential (top) is produced by an increase in sodium diffusion that is followed, after a short delay, by an increase in potassium diffusion (bottom). This drives the membrane potential first toward the sodium equilibrium potential and then toward the potassium equilibrium potential.

a relatively small amount of Na+ and K+ actually diffuse through the membrane during the production of an action potential, and so the total concentrations of Na+ and K+ in the axon and in the extracellular fluid are not significantly changed.

Notice that active transport processes are not directly involved in the production of an action potential; both depolarization and repolarization are produced by the diffusion of ions down their concentration gradients. A neuron poisoned with cyanide, so that it cannot produce ATP, can still produce action potentials for a period of time. After awhile, however, the lack of ATP for active transport by the Na+/K+ pumps will result in a decline in the concentration gradients, and therefore in the ability of the axon to produce action potentials. This shows that the Na+/K+ pumps are not directly involved; rather, they are required to maintain the concentration gradients needed for the diffusion of Na+ and K+ during action potentials.

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