Transgenic C. elegans as a model of congenital myasthenic syndromes

BERGÉ I.; HERNANDO, G.; BOUZAT, C.

Huerta Grande, Córdoba, Arg

Congreso; XXVII Congreso anual de la Sociedad Argentina de Investigación en Neurociencias.; 2012

SAN

The free living nematode Caenorhabditis elegans is a model for the study of human neurological diseases and drug testing. Our goal is to establish C. elegans as a model of slow-channel congenital myasthenic syndromes, which are originated by gain-of-function mutations in nicotinic receptor subunits. We introduced a mutation in the 9? position of the M2 domain of UNC-38 (V9?S), an essential alpha-type subunit of muscle levamisole-sensitive nicotinic receptor (L-AChR), and generated transgenic worms that express the mutant subunit in muscle. Single-channel recordings from isolated muscle cells show a dramatic increase (about 10-fold) in the open duration of L-AChR channels. Single openings appear, in contrast to wild-type channels, grouped into long activation periods. Macroscopic currents are 3-fold smaller than wild-type currents and do not decay in the presence of ACh. The functional changes of L-AChR in the mutant worm mimic those observ ed in vertebrate AChRs carrying the equivalent mutation. Our results reveal a high degree of conservation of functional roles of amino acids between C. elegans and human AChRs, thus opening doors for studying other gain-of-function mutations associated to slow-channel syndromes.