The human adult subtype ACh receptor channel has high Ca²⁺ permeability and predisposes to endplate Ca²⁺

Slow-channel congenital myasthenic syndrome, caused by mutations in subunits of the endplate ACh receptor (AChR), results in prolonged synaptic currents and excitotoxic injury of the postsynaptic region by Ca²⁺ overloading. The Ca²⁺ overloading could be due entirely to the prolonged openings of the AChR channel or could be abetted by enhanced Ca²⁺ permeability of the mutant channels. We therefore measured the fractional Ca²⁺ current, defined as the percentage of the total ACh-evoked current carried by Ca²⁺ ions (P_f), for AChRs harbouring the αG153S or the αV249F slow-channel mutation, and for wild-type human AChRs in which P_f has not yet been determined. Experiments were performed in transiently t]ransfected GH4C1 cells and human myotubes with simultaneous recording of ACh-evoked whole-cell currents and fura-2 fluorescence signals. We found that the P_f of the wild-type human endplate AChR was unexpectedly high (P_f ∼7%), but neither the αV249F nor the αG153S mutation altered P_f. Fetal human AChRs containing either the wild-type or the mutated α subunit had a much lower P_f (2-3%). We conclude that the Ca²⁺ permeability of human endplate AChRs is higher than that reported for any other human nicotinic AChR, with the exception of α7-containing AChRs (P_f > 10%); and that neither the αG153S nor the αV249F mutations affect the P_f of fetal or adult endplate AChRs. However, the intrinsically high Ca²⁺ permeability of human AChRs probably predisposes to development of the endplate myopathy when opening events of the AChR channel are prolonged by altered AChR-channel kinetics.