Nerve Action Potential

During a nerve action potential, sodium from outside flows across the membrane, and the resulting depolarizing voltage opens calcium channels, which allow entry of the calcium ions into the nerve and cause the release of acetylcholine. A nerve action potential is the normal activator that releases the transmitter acetylcholine. The number of quanta released by a stimulated nerve is greatly influenced by the concentration of ionized calcium in the extracellular fluid. If calcium is not present, depolarization of the nerve, even by electrical stimulation, will not produce release of transmitter. Doubling the extracellular calcium results in a 16-fold increase in the quantal content of an end-plate potential. The calcium current persists until the membrane potential is returned to normal by outward fluxes of potassium from inside the nerve cell. With the calcium channels on the nerve terminal are the potassium channels, including the voltage-gated and calcium-activated potassium channels, whose function is to limit calcium entry into nerve and therefore depolarization.^[13] The calcium current can be prolonged by potassium channel blockers (e.g., 4-aminopyridine, tetraethylammonium), which slow or prevent potassium efflux out of the nerve. The increase in quantal content produced in this way can reach astounding proportions. ^{[10] [26]} An effect of increasing the calcium in the nerve ending is also seen clinically as the so-called post-tetanic potentiation, which occurs after a nerve of a patient paralyzed with a nondepolarizing relaxant is stimulated at high, tetanic frequencies. Calcium enters the nerve with every stimulus, but because it cannot be excreted as quickly as the nerve is stimulated, it accumulates during the tetanic period. Because the nerve ending contains more than the normal amount of calcium for some time after the tetanus, a stimulus applied to the nerve during this time causes the release of more than the normal amount of acetylcholine. The abnormally large amount of acetylcholine antagonizes the relaxant and causes the characteristic increase in the size of the twitch (see Chapter 30 and Chapter 39 ).

Calcium enters the nerve through specialized proteins called calcium channels.^{[13] [25]} Of the several types of calcium channels, two seem to be important for transmitter release, the P channels and the slower L channels. The P channels, probably the type responsible for the normal release of transmitter, are found only in nerve terminals. ^{[10] [27]} In motor nerve endings, they are located immediately adjacent to the active zones (see Fig. 22-2 ).

863

Figure 22-2 The working of a chemical synapse, the motor nerve ending, including some of the apparatus for transmitter synthesis. The large, intracellular structures are mitochondria. Acetylcholine, synthesized from choline and acetate by acetylcoenzyme A, is transported into coated vesicles, which are moved to release sites. A presynaptic action potential, which triggers calcium influx through specialized proteins (Ca²⁺ channels), causes the vesicles to fuse with the membrane and discharge transmitter. Membrane from the vesicle is retracted from the nerve membrane and recycled. Each vesicle can undergo various degrees of release of contents—from incomplete to complete. The transmitter is inactivated by diffusion, catabolism, or reuptake. The inset provides a magnified view of a synaptic vesicle. Quanta of acetylcholine together with ATP are stored in the vesicle and covered by vesicle membrane proteins. Synaptophysin is a vesicle membrane component glycoprotein. Synaptotagmin is the vesicle's calcium sensor. Phosphorylation of another membrane protein, synapsin, facilitates vesicular trafficking to the release site. Synaptobrevin (VAMP) is a SNARE protein involved in attaching the vesicle to the release site (see Fig. 22-3 ). ACh, acetylcholine, acetyl CoA, acetyl coenzyme A; CAT, choline acetyltransferase.

Higher than normal concentrations of bivalent inorganic cations (e.g., magnesium, cadmium, manganese) can also block calcium entry through P channels and profoundly impair neuromuscular transmission. This is the mechanism for muscle weakness in the mother and fetus when magnesium sulfate is administered to treat preeclampsia. The P channels, however, are not affected by calcium entry-blocking drugs, such as verapamil, diltiazem, and nifedipine. These drugs have profound effects on the slower L channels present in the cardiovascular system. As a result, the L-type calcium channel blockers at therapeutic doses have no significant effect on the normal release of acetylcholine or on the strength of normal neuromuscular transmission. There have been a few reports, however, that calcium entry-blocking drugs may increase the block of neuromuscular transmission induced by nondepolarizing relaxants. The effect is small, and not all investigators have been able to observe it. The explanation may lie in the fact that nerve endings also contain L-type calcium channels.