Pentameric ligand-gated ion channels: Bridging molecular Insights and clinical promise

Abstract

Pentameric ligand-gated ion channels (pLGICs) are essential for translating neurotransmitter recognition into electrical signals in both vertebrates and invertebrates, contributing to fundamental processes such as movement, memory, cognition, and synaptic plasticity. These receptors are expressed not only in the nervous system but also in various non-neuronal cells, and are implicated in a wide spectrum of disorders, making them key pharmacological targets for clinically relevant drugs. In vertebrates, the pLGIC family includes cation-selective channels—nicotinic acetylcholine receptors (nAChRs) and serotonin type 3 receptors—as well as anion-selective channels such as glycine and GABAA_A receptors, whereas in invertebrates the repertoire is even more diverse. Remarkably, the free-living nematode Caenorhabditis elegans—a model for both human diseases and anthelmintic drug discovery—possesses one of the largest and most varied pLGIC families, making it an ideal system for investigating their function and therapeutic potential. Using a combination of experimental approaches, including high-resolution patch-clamp recordings primarily focused on nicotinic and serotonin receptors, we characterized their kinetic and functional properties and identified novel modulatory compounds, providing valuable insights into their potential as therapeutic targets. Extending this framework to C. elegans, we bridged molecular and organismal levels to uncover functional features of nematode pLGICs— some conserved and relevant to human diseases, others uniquely nematode-specific and emerging as anthelmintic targets. These findings highlight new molecular targets and lead compounds for the development of novel therapies. Our work offers insights into receptor function under both physiological and pathological conditions, paving the way for innovative therapeutic applications.