Mimicking Human Myasthenic Syndromes in C. elegans:Evaluation of Function and Drug Modulation of Nicotinic Receptors

BERGÉ IGNACIO; HERNANDO GUILLERMINA; ANDREOCCI EMANUEL; ROCCAMO ANA MARÍA; BOUZAT CECILIA

Congreso; XXX Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2015

In humans, gain-of-function mutations in the muscle nicotinic receptor (AChR) lead to slowchannelcongenital myasthenic syndromes (SCCMS), characterized by slow decay ofendplate currents, destabilization of the closed channel and prolonged activation episodesof AChR. Our goal is to use the free-living nematode C. elegans to generate models of thesehuman syndromes. To this end, we first generated transgenic worms expressing mutant LAChRsat 9´ position of the M2 segment, which has been shown to form the gate of the ionchannel in vertebrates. Electrophysiological recordings of L-AChRs from muscle cells ofthese transgenic worms show an increase of 11- to 14-fold of the open-channel lifetimeand decreased desensitization rate with respect to wild-type, as expected for a gain-offunctionmutation. We found that quinidine sulfate, a long-lived open-channel blocker ofthe human AChR used for the treatment of SCCMS, also reduces the open duration of themutant C. elegans L-AChR. These results show that it is possible to mimic in C. elegans themolecular and functional changes observed in human AChRs as well as their responses totherapeutic drugs. We next generated mutant strains with L-AChRs mimicking gain-offunctionmutations that lead to severe slow-channel CMS to be used as models of thesehuman neuromuscular disorders for drug screening and development of therapeuticstrategies.