A mutation in the Caenorhabditis elegans nicotinic receptor alpha subunit, unc-63, provides a model for fast channel congenital myasthenia?

JONES AK; RAYES D; HERNANDO G; MAYNARD T; JONES R; MATTHEWS S; BOUZAT C; SATTELLE D

Hinxton, Reino Unido

Congreso; Nicotinic Acetylcholine Receptors 2008. Wellcome Trust.; 2008

Wellcome Trust.

The  nematode Caenorhabditis elegans is an established model organism for studying neurobiology since many synaptic molecular components are conserved both in the worm and humans. The unc-63 alpha subunit of the C.elegans nicotinic acetylcholine receptor (nAChR) plays an important role in fast cholinergic synaptic transmission at the nematode neuromuscular junction. Here we show that worms with the unc-63(x26) allele, with alphaC151Y mutation that disrupts the Cys-Lloop, have deficient muscle function as displayed by impaired thrashing locomotion compared to wild type worms. Single-channel recordings from muscle cells of the mutant starin show reduced number of active patches, a 100-fold reduced  frequency of opening events, and abnormally reduced duration of channel openings. These observations can be explained by a decrease in nAChR expression at the cell surface together with impaired opening and fast channel closing, similar to that observed in patients with fast-channel congenital myasthenia syndromes (FCCMS). Interestingly, a mutation in the equivalent position of the alpha subunit of the human muscle nAChR (alphaC128S) is associated qith a FCCMS due to nAChR deficiency at the endplate. Therefore, disruption of the Cys-loop results in qualitatively similar actions on both nematode and human receptors. Therapy for FCCMS is limited in variety and success with 3,4 diaminopyridine (3,4 DAP) and anticholinesterase drugs such as pyridostigmine bromide (PB). We show that PB and 3,4-DAP can partially rescue the motility defec seen in unc-63(x26), making this the first candidate C.elegans model for screening for drugs aimed at ameliorating the consequences of mutations in nAChRs associated with FCCMS.