Unravelling the physiological role and molecular function of Caenorhabditis elegans betaine sensitive nicotinic receptors

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

Congreso; Third Latin American Worm Meeting; 2023

Latin American Worm Meetingturan

Parasitic nematodes have acquired resistance to anthelmintic drugs, generating important problems in human and 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. There is a great diversity of nAChRs in nematodes and the role and molecular function remain poorly understood for many of them. The broad-spectrum nematocidal drug monepantel (MNP), which belongs to a new class of compounds, targets ACR-23 nAChR. ACR-23, whose endogenous agonist is betaine (BE), is present in muscle and neuronal cells of nematodes and since it is not 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 novel drug 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.