Pharmacology of nicotinic receptors from C. elegans muscle

Abstract

Caenorhabditis elegans has emerged as a model organism useful for drug screening. It expresses two types of muscle nicotinic receptors (AChRs): levamisole-sensitive (L-AChR) and nicotine-sensitive (N-AChR). L-AChRs are targets of anthelmintic drugs, which act as specific and potent agonists. We here explore activation of both AChR types by the nematocide drug oxantel. Single-channel recordings from C. elegans muscle cultured cells show that oxantel elicits openings with amplitudes similar to those of L-AChRs. However, the frequency of opening is significantly reduced with respect to that observed in the presence of ACh, indicating reduced activation. In whole-cell recordings from cells expressing N-AChRs, peak currents elicited by oxantel are 45% of those elicited by ACh. Molecular docking studies show binding of oxantel to both types of AChRs, with similar binding energies but different orientations at the binding pocket. We conclude that oxantel behaves as a partial and non selective agonist of both L- and N-muscle AChRs, thus showing a different pharmacological profile compared to that of typical anthelmintic agents. These results contribute to the understanding of the pharmacology related to neuromuscular transmission in the model organism.