The mechanism of neuromuscular transmission at the motor end plate is similar to that described for preganglionic cholinergic nerves in Chapter 6. The arrival of an action potential at the motor nerve terminal causes an influx of calcium and release of the neurotransmitter acetylcholine. Acetylcholine then diffuses across the synaptic cleft to activate nicotinic receptors located on the motor end plate, present at a density of 10,000/μm2 in some species. As noted in Chapter 7, the adult NM receptor is composed of five peptides: two alpha peptides, one beta, one gamma, and one delta peptide (Figure 27–1). The binding of two acetylcholine molecules to receptors on the α-β and δ-α subunits causes opening of the channel. The subsequent movement of sodium and potassium through the channel is associated with a graded depolarization of the end plate membrane (see Figure 7–4, panel B). This change in voltage is termed the motor end plate potential. The magnitude of the end plate potential is directly related to the amount of acetylcholine released. If the potential is small, the permeability and the end plate potential return to normal without an impulse being propagated from the end plate region to the rest of the muscle membrane. However, if the end plate potential is large, the adjacent muscle membrane is depolarized, and an action potential will be propagated along the entire muscle fiber. Muscle contraction is then initiated by excitation-contraction coupling. The released acetylcholine is quickly removed from the end plate region by both diffusion and enzymatic destruction by the local acetylcholinesterase enzyme.
At least two additional types of acetylcholine receptors are found within the neuromuscular apparatus. One type is located on the presynaptic motor axon terminal, and activation of these receptors mobilizes additional transmitter for subsequent release by moving more acetylcholine vesicles toward the synaptic membrane. The second type of receptor is found on extrajunctional cells and is not normally involved in neuromuscular transmission. However, under certain conditions (eg, prolonged immobilization, thermal burns), these receptors may proliferate sufficiently to affect subsequent neuromuscular transmission. This proliferation of extrajunctional acetylcholine receptors may be clinically relevant when using depolarizing or nondepolarizing skeletal muscle relaxant drugs and is described later.
Skeletal muscle relaxation and paralysis can occur from interruption of function at several sites along the pathway from the CNS to myelinated somatic nerves, unmyelinated motor nerve terminals, nicotinic acetylcholine receptors, the motor end plate, the muscle membrane, and the intracellular muscular contractile apparatus itself.
Blockade of end plate function can be accomplished by two basic mechanisms. First, pharmacologic blockade of the physiologic agonist acetylcholine is characteristic of the antagonist neuromuscular blocking drugs (ie, nondepolarizing neuromuscular blocking drugs). These drugs prevent access of the transmitter to its receptor and thereby prevent depolarization. The prototype of this nondepolarizing subgroup is d-tubocurarine. The second mechanism of blockade can be produced by an excess of a depolarizing agonist, such as acetylcholine. This seemingly paradoxical effect of acetylcholine also occurs at the ganglionic nicotinic acetylcholine receptor. The prototypical depolarizing blocking drug is succinylcholine. A similar depolarizing block can be produced by acetylcholine itself when high local concentrations are achieved in the synaptic cleft (eg, by cholinesterase inhibitor intoxication) and by nicotine and other nicotinic agonists. However, the neuromuscular block produced by depolarizing drugs other than succinylcholine cannot be precisely controlled and is of no clinical value.
FIGURE 27–1 The adult nicotinic acetylcholine receptor (nAChR) is an intrinsic membrane protein with five distinct subunits (α2 βδγ).