An Action Potential on the Presynaptic NeuronTriggers an Action Potential on the Muscle CeIIThrough the Release of Acetylcholine

The function of the neuromuscular junction is to transmit a chemical message unidirectionally between a motor neuron and a skeletal muscle cell (fiber) with a frequency established by the CNS.

An action potential on a motor neuron arises at its initial axon segment and then spreads along the entire axon, eventually arriving at the presynaptic terminal (see Chapter 4). As previously noted, the exchange of Na’ and K* ions, across axonal voltage-gated Na⁺ and K^, channels, is responsible for the generation of the action potential and its conduction to the terminal. However, as the action potential arrives at the presynaptic membrane, the wave of depolarization opens voltage-gated Ca²⁺ channels located in this region; as Ca²* flows toward equilibrium across the membrane, the Ca² ’ enters the presynaptic terminal. This increase in the intra­cellular Ca²⁺ level is critical for the release of neurotransmitter from the terminal.

Recall that the acetylcholine-containing synaptic vesicles are lined up at the active zones of the presynaptic terminal. They are docked there by the intertwining of binding proteins that respectively reside on the vesicle membrane and on the inner surface of the terminal membrane. This holds the vesicles near the location of Ca²⁺ entry because the voltage­gated Ca²⁺ channels are efficiently located in the vicinity of these active zones. When Ca²* flows into the terminal, the ion binds with yet another protein on the synaptic vesicle mem­brane.

After release, acetylcholine then diffuses across the synaptic cleft and binds with transmitter-specific receptors, the nicotinic acetylcholine receptors, in the postsynaptic muscle membrane. This specific subtype of acetylcholine receptor, found at the neuromuscular junction, is so named because it can also bind the alkaloid drug nicotine. The nicotinic acetylcholine receptor is actually a ligand-gated ion channel (see Chapter 1), per­meable to small cations, with two binding sites for the acetyl­choline molecule. As acetylcholine binds at these two loci, the channel opens and, among other ionic movements, Na^f ions diffuse into the muscle cell as they attempt to flow toward equilibrium. This contributes to a depolarization of the post­synaptic muscle cell membrane analogous to an excitatory postsynaptic potential (EPSP). However, at the neuro­muscular junction, the unitary postsynaptic potential is suf­ficient to open voltage-gated Na' channels deep within the junctional folds and leads to the generation of an action potential on the muscle cell membrane.

Acetylcholine binds with its receptor only briefly (~1 msec). Once free, it is destroyed by the enzyme acetylcholinesterase. This enzyme, anchored to the basal lamina of the synaptic cleft, inactivates acetylcholine by breaking it down into acetic acid and choline molecules (Eigure 5-3). The choline, a pre­cursor of acetylcholine synthesis, can then be transported back into the presynaptic terminal and recycled in acetylcholine synthesis. Chemicals that inhibit acetylcholinesterase, such as some organophosphate insecticides and nerve gases (e.g., sarin), can abnormally prolong the presence of acetylcholine at the synapse, often with disastrous physiological consequences. Because the neurotransmitter is normally destroyed soon after its binding with the muscle membrane receptor, and because more transmitter is not available to attach to the receptors in sufficient quantities until another motor neuron action potential occurs, there is approximately a 1:1 ratio between action potentials on the neuronal and muscle cell membranes.