A C. Elegans Nicotinic Receptor Subunit Allele, Unc-63(X26), Provides A Model For Human Congenital Myasthenia Syndrome

JONES A; D RAYES; HERNANDO G.; MAYNARD TPR; JONES R; MATTHEWS S; CECILIA BEATRIZ BOUZAT; SATTELLE D

San Diego

Congreso; Nicotinic Acetylcholine Receptors Meeting; 2007

Society for Neuroscience

Congenital myasthenia syndrome (CMS) is a group of genetically-determined heterogeneous disorders, and leads to a progressive deterioration in mobility. It is caused by various disorders at the neuromuscular junction, many of which are mutations in nicotinic acetylcholine receptor (nAChR) subunits. New drugs are needed to treat CMS. We have characterized the C. elegans nAChR gene family and shown that a mutant allele of one muscle nAChR subunit, (unc-63), mimics a mutation in a human nAChR subunit that underlies one form of congenital myasthenia syndrome. Single-channel recordings from cultured muscles from C. elegans L1 larvae reveal profound changes in activation of levamisole-sensitive nAChRs. The number of active patches is significantly reduced. In addition, the frequency of opening events is 100-fold lower than that of wild-type strains and openings are abnormally brief. Such changes will result in a dramatically reduced response to ACh during neuromuscular synaptic transmission. Two drugs used to treat CMS, the anticholinesterases pyridostigimine bromide and neostigimine bromide, partially rescue the reduced motility phenotype of the unc-63 mutant, validating this worm strain as a potential tool for high-throughput screening of novel candidate drugs.