Caenorhabditis elegans betaine-sensitive nicotinic receptors: a potential target for antiparasitic drugs

Abstract

Parasitic nematodes have developed resistance to most anthelmintic drugs, generating problems in human and animal health. Consequently, there is an urgent need to identify novel drugs and targets. Caenorhabditis elegans, with its extensive and diverse family of nicotinic acetylcholine receptors (nAChRs), offers a valuable model for this purpose. Many of these receptors, which are critical for worm locomotion, remain uncharacterized, making them potential targets for novel anthelmintic drugs. ACR-23, whose endogenous agonist is betaine (BE) and is modulated by the nematocidal drug monepantel (MNP), is a poorly characterized nAChR present in body-wall muscle and mechanosensory neurons of nematodes. Since it is not conserved in vertebrates, ACR-23 is an interesting pharmacological target for anthelmintic drugs. Our goal is to elucidate the molecular function and pharmacology of ACR-23 to investigate its potential as a novel anthelmintic drug target. By performing locomotion assays with wild-type worms we showed that exogenous BE significantly increased worm motility. This effect was not observed in acr-23 mutants, indicating that the hypermotility is mediated by ACR-23. Exposure to MNP produced the opposite effect, as motility was reduced in a concentration-dependent manner. Additionally, MNP produced spastic paralysis and inhibited egg hatching. Locomotion assays with mutant worms demonstrated that MNP-induced paralysis is mediated by ACR-23 and DEG-3/DES-2, a nAChR present in sensory neurons involved in nociception and chemotaxis. By patch-clamp recordings from cultured C. elegans L1 muscle cells, we described for the first time BE-elicited single channels and macroscopic currents. Our study provides novel insights into the molecular function and pharmacology of the nAChR family and contributes to the understanding of the molecular basis of anthelmintic action. This paves the way for the development of novel drugs