Serum choline activates mutant acetylcholine receptors that cause slow channel congenital myasthenic syndromes

We have found that mutant acetylcholine receptor channels (AChRs) that caus e slow-channel congenital myasthenic syndromes are activated by serum and t hat the high frequency of openings in serum is reduced by treatment with ch oline oxidase. Thus, slow-channel congenital myasthenic syndrome AChRs at t he neuromuscular junction are likely to be activated both by steady exposur e to serum choline and by transient exposure to synaptically released trans mitter. Single-channel kinetic analyses indicate that the increased respons e to choline is caused by a reduced intrinsic stability of the closed chann el. The results suggest that a mutation that destabilizes the inactive conf ormation of the AChR, together with the sustained exposure of endplates to serum choline, results in continuous channel activity that contributes to t he pathophysiology of the disease.