A Cold-Sensing Receptor Encoded by a Glutamate Receptor Gene

In search of the molecular identities of cold-sensing receptors, we carried out an unbiased genetic screen for cold-sensing mutants in C. elegans and isolated a mutant allele of glr-3 gene that encodes a kainate-type glutamate receptor. While glutamate receptors are best known to transmit chemical synaptic signals in the CNS, we show that GLR-3 senses cold in the peripheral sensory neuron ASER to trigger cold-avoidance behavior. GLR-3 transmits cold signals via G protein signaling independently of its glutamate-gated channel function, suggesting GLR-3 as a metabotropic cold receptor. The vertebrate GLR-3 homolog GluK2 from zebrafish, mouse, and human can all function as a cold receptor in heterologous systems. Mouse DRG sensory neurons express GluK2, and GluK2 knockdown in these neurons suppresses their sensitivity to cold but not cool temperatures. Our study identifies an evolutionarily conserved cold receptor, revealing that a central chemical receptor unexpectedly functions as a thermal receptor in the periphery. [Display omitted] •C. elegans genetic screen identifies the glutamate receptor GLR-3 as a cold receptor•GLR-3 senses cold in a peripheral sensory neuron to trigger cold-avoidance behavior•GLR-3 is a metabotropic cold receptor requiring G proteins to transmit cold signals•The mouse GLR-3 homolog GluK2 acts in DRG sensory neurons to mediate cold sensation An evolutionarily conserved cold sensor, which is encoded by a glutamate receptor gene, transmits cold signals through G-protein signaling, independent of its channel function.