A hidden thermal mechanism in inhibitory ligand-gated chloride channels

Abstract

Temperature profoundly shapes neural activity, with temperature-sensitive excitatory cation channels serving as key molecular components of thermosensation and neuronal excitability. Here we show that the glutamate-gated chloride channel AVR-14B, a Cys-loop receptor and principal molecular target of the antiparasitic drug ivermectin in the nematode Brugia malayi, exhibits temperature-dependent gating. Application of glutamate to AVR-14B evoked rapidly desensitizing transient currents; however, above approximately 24 {degrees}C, an additional non-desensitizing sustained current component emerged. Mechanistically, warming altered the gating behavior of the channel, thereby conferring intrinsic temperature sensitivity. Mutational and structural analyses revealed that ions permeate via lateral fenestrations distinct from the central axial pore, forming a noncanonical pathway for temperature-dependent gating. This temperature-dependent gating determines drug efficacy: ivermectin failed to activate AVR-14B below the thermal threshold at which the sustained current emerges. Finally, AVR-14B-null C. elegans showed enhanced heat tolerance, even though wild-type animals generally fail to thrive above 25 {degrees}C, confirming that this molecular mechanism governs organismal physiology. Similar temperature-dependent gating was observed in the human glycine receptor, indicating a conserved principle within this receptor class. Our findings identify inhibitory ligand-gated ion channels as intrinsic thermosensors and uncover a mechanism by which temperature can switch a single receptor between phasic and tonic inhibition, with implications for neural function and temperature-mediated therapeutics.