Activation and Modulation of the Caenorhabditis elegans Serotonin-gated Chloride Channel

CORRADI JEREMÍAS; BOUZAT CECILIA; RODRIGUEZ ARAUJO NOELIA

Rosario

Congreso; Second Latin American Worm Meeting; 2020

Activation and Modulation of the Caenorhabditis elegans Serotonin-gatedChloride ChannelN Rodríguez Araujo, J Corradi and C BouzatInstituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB-UNS/CONICET)Serotonin-gated ion channels (5-HT3) belong to the family of Cys-loop receptors, whichare pentameric proteins that mediate fast synaptic transmission. In mammals, 5-HT3 arenon-selective cationic channels that can be found as homomers (5-HT3A) orheteromers. Caenorhabditis elegans is a model for the study of the nervous system andfor antiparasitic drug discovery. As parasitic nematodes, C. elegans contains ahomomeric serotonin-gated chloride channel, MOD-1, that modulates locomotorybehavior. The absence of this receptor in vertebrates, converts MOD-1 into a potentialantiparasitic drug target. We expressed MOD-1 in mammalian cells and explored bypatch-clamp recordings its activation and modulation properties. Dose-response curvesrevealed an EC50 for 5-HT activation of about 1 µM, which is in the same range as thatof human 5-HT3A receptors. The analysis of whole-cell currents determined that MOD-1channels do not show rectification, desensitize slowly in the presence of 5-HT, andrecover from desensitization with a time constant of about 1 s. In contrast to theiractions at mammalian 5-HT3 receptors, 5-hydroxyindol and thymol do not potentiateMOD-1 currents. Ivermectin, which acts as activator or potentiator of different Cys-loopreceptors, neither activates nor potentiates MOD-1 but pre-exposure to IVM inhibitsMOD-1 currents. The anthelmintic agent piperazine, which interacts with GABAreceptors, acts as a negative allosteric modulator. To gain further insights into themolecular function of the native MOD-1, we sought to identify serotonin-activatedchloride channels from C. elegans neurons expressing MOD-1 and compared to MOD-1channels heterologously expressed in mammalian cells. The understanding of themolecular pharmacology of MOD-1 contributes to our knowledge of the Cys-loopreceptor family and to its potential as a novel drug target for anthelmintic therapy.