Nicotinic AChR in Congenital Myasthenic Syndromes

About 20 % of the identified cases of congenital myasthenic syndromes are due to defects causing overstimulation of endplate ACh receptors, with consequent excessive Ca2+ entry, endplate structural damage, and impairment of the neuromuscular transmission. Overstimulation arises from extended dwelling of ACh in the synaptic cleft because of absence of acetylcholine esterase or from prolonged activation of “slow-channel” mutant ACh receptors. The high Ca2+ permeability of human endplate ACh receptor, recently described likely predisposes to excitotoxic damage. The good knowledge of ACh receptor function has allowed molecular understanding of the defects introduced in channel kinetics and Ca2+ permeability by slow-channel mutations and the design of efficient therapeutic strategies. These forms of congenital myasthenic syndrome are treated by limiting ACh-induced cation entry, thus preventing endplate degeneration. Several molecules of wide clinical use, such as fluoxetine and quinidine, but also verapamil and salbutamol modulate AChR kinetics and ion selectivity and may be used to lower ACh-evoked responses in these patients. In this contribution we summarize the main findings in the field.