INVESTIGADORES
BOUZAT Cecilia Beatriz
congresos y reuniones científicas
Título:
Functional roles of amino acids of nicotinic receptors are conserved between C. elegans and human.
Autor/es:
BERGÉ IGNACIO; G HERNANDO; ANDREOCCI, E; ROCCAMO, A.M.; BOUZAT C
Lugar:
Sierra de la Ventana
Reunión:
Congreso; XLIII Reunión Annual de la Sociedad Argentina de Biofísica (SAB).; 2014
Institución organizadora:
SAB
Resumen:
Mutations in ion channels may lead to genetic disorders named as channelopathies. Congenital myasthenic syndromes (CMS) are channelopathies produced by mutations in the muscle nicotinic receptor (AChR). Our goal is to generate models of these human neuromuscular disorders to be used for drug screening and development of therapeutic strategies. To this end, we use the free-living nematode C. elegans, whose muscle AChR (L-AChR) is essential for neuromuscular transmission and locomotion. We generated gain-of-function mutant L-AChRs by exchanging hydrophobic residues at 9' position of M2 segment, which have been shown to form the gate of the ion channel in vertebrates, by hydrophilic residues in two essential subunits of the L-AChR. Single-channel recordings from muscle cells of the mutant transgenic worms show a dramatic increase (11- to 14-fold) of the open duration of mutant L-AChR with respect to wild-type. Macroscopic currents elicited by ACh show a decrease in the desensitization rate. These functional changes are similar to those observed in vertebrate AChRs carrying the equivalent mutations, thus revealing a high degree of conservation of functional roles of AChR amino acids. Generation and analysis of a mutant strain carrying in the L-AChR a gain-of-function mutation (T12´M2P) that in human leads to a severe slow-channel CMS reveals that the functional changes in the worm mimic those of the patients. These results open doors for establishing C. elegans models for human myasthenic syndromes.