An unexpected role of glutamate receptors in the peripheral nervous system

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The ability to sense environmental temperature is essential for life. Molecular thermal sensors are a central player in thermosensation. These thermal receptors are expressed in cold-sensitive neurons/cells in the periphery. Work in the past two decades has identified a large number of TRP family channels as heat receptors that sense a full range of warm and hot temperatures, spanning from 33°C to over 53°C. This has led to a fairly clear understanding of how animals sense heat. By contrast, little is known about cold sensation. Thus far, only one cold receptor (TRPM8) has been identified. TRPM8 senses cool temperatures with an activation threshold at ~26°C and mediates cool sensation. As animals and humans are clearly capable of sensing temperatures below 26°C, and TRPM8 knockout mice show robust responses to noxious cold, unknown cold receptors, particularly those sensing noxious cold, must exist but remain to be identified. The nematode C. elegans is a popular genetic model organism for sensory biology research. Like mammals, C. elegans senses a full range of temperature cues. Importantly, sensory receptors and channels tend to be evolutionarily conserved in C. elegans. This, together with its short generation time (~3 days) and facile and rich genetic tools, makes C. elegans an ideal system for identifying novel cold receptors. We therefore designed and conducted an unbiased, activity-based genetic screen for cold-sensing mutants in C. elegans, using a real-time PCR thermocycler. We identified GLR-3, a kainate-type glutamate receptor homolog, as a novel type of cold receptor that mediates cold sensation in C. elegans. Strikingly, the GLR-3 homolog GluK2 from fish, mouse and human can all function as a cold receptor in heterologous systems. We also found that mouse GluK2 is expressed in the peripheral DRG sensory neurons. The activation threshold of GluK2 is below 20°C, suggesting that it mainly senses noxious cold rather than cool temperatures. As glutamate receptors are best known to transmit chemical signals across synapses in the central nervous system, these results present a striking case where a central chemical receptor, surprisingly, functions as a thermal receptor in the periphery. Despite these exciting observations, many unanswered questions remain, particularly regarding the role of mammalian GluK2 in cold sensation. For example, does GluK2 mediate cold sensation in mice? If so, how? Here, we propose to address these questions by testing several hypotheses. To do so, we will leverage the expertise from two research groups using a multidisciplinary approach combining molecular genetics, behavioral analysis, calcium imaging, and electrophysiology. The proposed research will not only provide novel insights into the mechanisms of cold sensation, but also unveil an unexpected role of glutamate receptors in the periphery. .