NMJ: Cholinergic receptor anatomy

The neuromuscular junction is the connection point between motor nerve endings and post-junctional skeletal muscle. It consists of a pre-synaptic membrane, the synaptic space itself, and the post-synaptic skeletal muscle membrane; nicotinic acetylcholine receptors on both pre- and post-synaptic sites relay central signals to allow skeletal muscle function.

At the pre-synaptic motor nerve terminal, a protein called synapsin holds a vesicle with acetylcholine to the release site. When calcium ions enter the nerve through P channels, these large reserve vesicles are released into the synapse, and acetylcholine will travel to the post-synaptic membrane.

Post-synaptic acetylcholine receptors are five-subunit glycoproteins (α, α, β, ε, δ), arranged to form a channel allowing ion flow down concentration gradients. The two α subunits are the binding sites for acetylcholine; both sites must be bound for conformational change to occur in the membrane protein and ion flow to occur. Acetylcholine will bind to these ligand-gated ion channels, causing ions (principally sodium, calcium, and potassium) to flow down their concentration gradients. Transmembrane potential then decreases from -90 mV to the threshold potential of -45 mV, initiating a skeletal muscle action potential and ending in muscle contraction.

Of note, skeletal muscle membranes may also contain extra-junctional or immature receptors, similar in structure to the mature receptors above but with the ε subunit replaced with a γ subunit. These channels are arranged over skeletal muscle in general, and when bound are opened for extended periods of time and result in a low-conductance signal which does not aid in depolarization. Immature receptors have been shown to proliferate in denervation, burns, and sepsis, helping explain the dangerous response to succinylcholine in these patient populations.