Caenorhabditis elegans serotonin-gated chloride channel MOD-1 as a novel drug target for anthelmintic therapy

CORRADI, J.; RODRÍGUEZ ARAUJO, N.; BOUZAT, C.

MODALIDAD VIRTUAL

Jornada; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica SAB 2020/Biofísica en Tiempos de COVID-19; 2020

Sociedad Argentina de Biofísica (SAB)

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 homomeric (5-HT3A) or heteromeric.Caenorhabditis elegans is a model for the study of the nervous system and forantiparasitic drug discovery. As parasitic nematodes, C. elegans contains a homomeric5HT-gated chloride channel, MOD-1, that modulates locomotory behavior. Due to itsabsence in vertebrates, MOD-1 emerges as a potential antiparasitic drug target. Wedeciphered its pharmacological properties and searched for novel ligands by patch clamprecordings from mammalian cells heterologously expressing MOD-1. Macroscopiccurrents activated by 5-HT showed that MOD-1 does not rectify, desensitizes slowly, andrecovers from desensitization with a time constant of 1 s. Dose-response curves revealedan EC50 for 5-HT of about 1 μM, similar to that of human 5-HT3A receptors. However,compared to their actions as partial agonists of human 5-HT3A receptors, tryptamineshowed markedly increased efficacy and 2-Me-5HT showed insignificant agonist activityat MOD-1. The typical anthelmintic drugs ivermectin (IVM), levamisole, and piperazine,which are agonists of GluCl, L-AChR and GABA receptors, respectively, did not activateMOD-1. However, IVM produced a slight and piperazine a profound inhibition of 5-HTactivated MOD-1 currents. The analysis revealed that piperazine is a noncompetitiveantagonist of MOD-1. To gain further insights into the molecular function of the nativeMOD-1, we also recorded 5HT-activated chloride channels from C. elegans neuronsexpressing MOD-1 and compared to those heterologously expressed in mammalian cells.The elucidation of the molecular pharmacology of MOD-1 contributes to our knowledgeof the function and drug selectivity of Cys-loop receptors and to its potential as a noveltarget for anthelmintic therapy.