Extrajunctional ACh receptors

The neuromuscular junction (NMJ) is a synapse between a presynaptic motor neuron terminal and a postsynaptic skeletal muscle fiber. Acetylcholine is released by the presynaptic neuron, diffuses across the synaptic cleft, and binds nicotinic acetylcholine receptors (nAChR) on the postsynaptic fiber. The adult nAChR is a pentameric protein consisting of following subunits: 2 alpha, 1 beta, 1 delta, and 1 epsilon. In contrast, the fetal/immature type nAChR has a gamma subunit instead of an epsilon subunit; this change allows the receptor to stay open longer and permit more ions to flow.

In a healthy mature adult, the highest concentration of nAChRs on the muscle fiber is directly across from the presynaptic neuron. Nicotinic acetylcholine receptors can also exist outside the NMJ, but in much lower concentrations (up to 1000 times lower); these are termed “extrajunctional receptors” and are typically the fetal type of nAChR. Extrajunctional receptor synthesis is normally suppressed by neural activity, but certain pathologic states can result in their proliferation: upper and lower motor neuron lesions, trauma, burns, sepsis, and prolonged immobility (such as found in prolonged ICU stays). Upregulation of extrajunctional receptors has usually occurred by about 48 hours after injury, and may persist for up to 6 months.

The clinical significance of extrajunctional nAChR proliferation is that if depolarizing neuromuscular blockers (e.g. succinylcholine) are given, these receptors’ tendency to stay open longer and allow more ion passage can result in life-threatening hyperkalemia. Succinylcholine administration normally causes a transient increase in serum potassium levels by about 0.5 mEq/L, but with extrajunctional receptor proliferation, serum potassium levels can rise 10 times greater than expected leading to serum levels as high as 10 mEq/L. Proliferation of these receptors also accounts for the resistance or tolerance to nondepolarizing neuromuscular blockers.