Review of Medical Physiology - William F. Ganong 2002

Physiology of Nerve and Muscle Cells
Synaptic and Junctional Transmission
Neuromuscular Transmission - The Neuromuscular Junction

Structure

An axon innervating Skeletal Muscle terminates in branching endings. Here, it loses its myelin sheath and forms numerous endings known as synaptic boutons (Fig. 4-35). A synaptic bouton contains numerous small, clear vesicles filled with acetylcholine, the neurotransmitter of these junctions. The nerve endings lie within depressions of the motor end-plate, which is a thickening of the muscle membrane at the junction site. Beneath the nerve ending, the muscle membrane of the end-plate forms folds. The cleft between the nerve ending and the thickened muscle membrane corresponds to the synaptic cleft of other synapses. This entire structure is referred to as the Neuromuscular Junction, or myoneural junction, as well as the neuromuscular or myoneural synapse. Each end-plate is innervated by only a single nerve fiber ending in a synaptic bouton; consequently, convergence of nerve impulses does not occur here.

Sequence of Transmission Processes

The processes occurring during impulse transmission from a motor nerve to a muscle (see Table 3-2) partially correspond to those taking place in other synapses. Upon arrival of an impulse at the motor neuron terminal, the permeability of the nerve endings to Ca²⁺ is activated. Ca²⁺ cations enter the endings and trigger a marked enhancement of exocytosis of acetylcholine vesicles. Acetylcholine diffuses to muscle-type nicotinic cholinergic receptors (see Fig. 4-18) clustered at the crests of the membrane folds of the motor end-plate. The binding of acetylcholine to these receptors increases the membrane permeability to Na⁺ and K⁺, and the influx of Na⁺ leads to the generation of a depolarizing potential—the end-plate potential. This local potential depolarizes adjacent Regions of the muscle membrane and reaches the critical firing level. Acetylcholine is rapidly hydrolyzed within the synaptic cleft by acetylcholinesterase, which is present in high concentrations at the neuromuscular synapse. Action potentials are generated on both sides of the end-plate and propagated in both directions along the muscle fiber. The muscle Action Potential subsequently initiates Muscle contraction, as described in Chapter 3.

End-Plate Potential

The human end-plate contains an average of 15–40 million acetylcholine receptors. Each Nerve Impulse triggers the release of acetylcholine from approximately 60 vesicles, with each vesicle containing about 10,000 neurotransmitter molecules. This quantity is sufficient to activate approximately 10 times more acetylcholine receptors than are strictly necessary to produce a full-sized end-plate potential. Consequently, the muscle consistently responds with a contraction, and this response masks the true potential. The end-plate potential can be measured by applying a factor that reduces it tenfold, making it insufficient to trigger depolarization of the adjacent muscle membrane. For this purpose, small doses of curare are used—a substance that competes with acetylcholine for binding to nicotinic cholinergic receptors. Under these conditions, the response can be recorded only in the region of the end-plate, beyond which it decays exponentially. Furthermore, temporal summation of end-plate potentials can be observed under these conditions.

Quantum Release of Transmitter

Small quanta ("packets") of acetylcholine are randomly released across the axon membrane even at rest, each causing a minor depolarization of the postsynaptic membrane with an amplitude of about 0.5 mV, known as the miniature end-plate potential. The number of acetylcholine quanta released in this manner is directly proportional to the concentration of Ca²⁺ and inversely proportional to the concentration of Mg²⁺ at the end-plate. When a nerve impulse reaches the nerve ending, the number of released acetylcholine quanta increases by orders of magnitude, resulting in a substantial end-plate potential that triggers the critical level of muscle fiber depolarization.

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Fig. 4-34. Induction of long-term potentiation (LTP) in CA1 hippocampal dendrites. Glutamate (Glu) released from the presynaptic neuron binds to AMPA and NMDA receptors on the dendritic membrane. Depolarization caused by the activation of AMPA receptors relieves the magnesium block of NMDA receptor channels, allowing Ca²⁺ and Na⁺ to enter the neuron. The increase in intracellular Ca²⁺ concentration activates calmodulin (CaM), which in turn activates Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). The kinase phosphorylates the AMPA receptor (P), increasing its conductance and likely promoting the translocation of more AMPA receptors to the synaptic region of The Cell membrane. Additionally, a chemical signal (CS) may be sent back to the presynaptic neuron, inducing a long-lasting increase in the quantum release of glutamate.

The quantal release of acetylcholine observed at the neuromuscular synapse is also characteristic of other cholinergic synapses. Similar processes presumably occur in noradrenergic and other synaptic contacts.

Myasthenia Gravis and Lambert-Eaton Syndrome

Myasthenia gravis is a serious, sometimes fatal autoimmune disorder characterized by weakness and rapid fatigability of skeletal Muscles. The disease results from The production of circulating Antibodies against nicotinic cholinergic receptors. These antibodies either destroy certain receptors or cross-link adjacent receptors, leading to their removal via endocytosis (see Chapter 1). The underlying cause of autoimmunity against acetylcholine receptors remains unclear.

Another disorder similar to myasthenia gravis is Lambert-Eaton syndrome. In this condition, muscle weakness is caused by antibodies directed against voltage-gated Ca²⁺ channels in the nerve terminals of the neuromuscular junction. This leads to a reduced influx of Ca²⁺ and, consequently, a decreased release of neurotransmitter. However, during sustained contractions, the increased accumulation of Ca²⁺ leads to an incremental improvement in muscle strength.