Unravelling the physiological role and molecular function of Caenorhabditis elegans betainesensitive nicotinic receptors.

TURANI, O.; HERNANDO, G.; RODRIGUEZ ARAUJO, N.; BOUZAT, C.

Valparaíso

Conferencia; THIRD LATIN AMERICAN WORM MEETING; 2023

Universidad de Valparaíso; Centro Interdisciplinario de Neurociencia de Valparaíso y EMBO

Parasitic nematodes have acquired resistance to anthelmintic drugs, generating problems in humanand animal health. The elucidation of function and drug selectivity of their targets is essential for the development of novel drugs. Nicotinic receptors (nAChRs) are involved in worm locomotion and are targets of anthelmintic drugs. The broad-spectrum nematocidal drug monepantel (MNP), whichbelongs to a new class of compounds, targets ACR-23 nAChR. ACR-23, whose endogenousagonist is betaine (BE), is present in muscle and neuronal cells of nematodes and since it isnot conserved in vertebrates it is an interesting pharmacological target. We use the free-living nematode Caenorhabditis elegans as a model of parasitic nematodes to explore ACR-23 as a noveldrug target. By performing locomotion assays with wild-type adult worms we showed that exogenous BE significantly increased worm motility. This effect was not observed in acr-23 mutants, indicating that the enhancement of ACR-23 activity causes worm hypermotility. The exposure of worms to MNP produced the opposite effect, resulting in reduced motility as a function of concentration (EC50 = 50 µM). MNP induced spastic paralysis and inhibited egg hatching, indicating important anthelmintic ability. Locomotion assays with mutant worms demonstrated that MNP-induced paralysis is mediated by ACR-23 and DEG-3/DES-2 nAChRs. By patch-clamp recordings from cultured C. elegans muscle cells, we described for the first time the properties of BE-elicited single-channel and macroscopic currents and the modulation by MNP. Our study provides insights into the molecular basis of anthelmintic action, which pave the way for the development of novel drugs.