Unravelling the physiological and molecular function of the betainesensitive receptor in Caenorhabditis elegans: a new target for anthelmintic drugs.

TURANI, O.; HERNANDO, G.; BOUZAT, C.

Ciudad Autónoma de Buenos Aires

Congreso; XLIX Reunión Anual SAB; 2021

Sociedad Argentina de Biofísica (SAB)

The free-living nematode Caenorhabditis elegans is a model of parasitic nematodes. Thisworm has the most extensive family of Cys-loop receptors, which are pentameric ligandgated ion channels that include nicotinic receptors (nAChRs). C. elegans contains anextended family of nAChRs but the functional properties and roles of many of thesenAChRs remain unknown. ACR-23 is a nAChR present in neuronal and muscle cells ofnematodes and is not conserved in vertebrates. It is a cation-selective channel activatedby betaine (BE) and sensitive to monepantel (MNP), a new anthelmintic drug. Given thelimited information about its functional role in nematodes, we explored ACR-23 from apharmacological, physiological, and molecular perspective. Locomotion assays of adultworm showed that BE significantly increased motility. This effect was not observed inacr-23 mutants, indicating that BE acts through ACR-23. MNP decreased worm motility inthe adult stage in a concentration-dependent manner with an EC50 of about 30 µM. Theacr-23 mutant showed different MNP sensitivity compared to the wild-type strain,indicating that, in addition to ACR-23, other receptors may be targeted by MNP. By using aprimary culture of C. elegans muscle cells, we described for the first time the properties ofBE-elicited single-channel currents. Opening events showed a mean duration of 0.3 msand amplitude of about 2.4 pA at a holding potential of 100 mV. The identification andfunctional characterization of receptors for BE and MNP provides insights into themolecular basis of anthelmintic action, which pave the way for anthelmintic drug design.