Cys-loop receptors in Caenorhabditis elegans as pharmacological drug targets (Simposio)

Abstract

The free-living nematode Caenorhabditis elegans has emerged as a powerful model for the study of the nervous system and human diseases and as a model for antiparasitic drug discovery. This nematode has also shown promise in the pharmaceutical industry search for new therapeutic compounds by high-throughput screening. Pentameric ligand gated ion channels, which include Cys-loop receptors, mediate rapid synaptic transmission by converting the chemical signal given by the neurotransmitter into an electrical one. These receptors play key roles in physiological processes, such as neuromuscular transmission, cognition, memory, and are targets of pharmacological compounds of clinical relevance. C. elegans has one of the most extended families of Cys-loop receptors, which have multiple functions including neuromuscular transmission. In particular, nicotinic (nAChR) and GABA receptors are essential for worm locomotion and are of clinical importance as targets of antiparasitic drugs. We combined paralysis assays, locomotion measurements and electrophysiological recordings from C. elegans cultured cells to identify the subunit composition, molecular function and antiparasitic drug modulation of muscle nAChR and GABA receptors. We also identified plant terpenoids and novel synthetic compounds that emerge as potential antiparasitic compounds by inducing rapid paralysis of C. elegans and deciphered the main drug targets and mechanisms underlying their anthelmintic actions. In order to use C. elegans as a model of human neuromuscular diseases, we generated transgenic strains containing mutant nAChRs that mimic those found in congenital myasthenic syndromes. We found that it is possible to recapitulate the molecular functional changes observed in patients, thus validating C. elegans as a model for these disorders.