A Cold-Sensing Receptor Encoded by a Glutamate Receptor Gene

Cell. 2019 Sep 5;178(6):1375-1386.e11. doi: 10.1016/j.cell.2019.07.034.

Jianke Gong ¹, Jinzhi Liu ¹, Elizabeth A Ronan ², Feiteng He ¹, Wei Cai ², Mahar Fatima ³, Wenyuan Zhang ¹, Hankyu Lee ³, Zhaoyu Li ², Gun-Ho Kim ⁴, Kevin P Pipe ⁵, Bo Duan ³, Jianfeng Liu ⁶, X Z Shawn Xu ⁷

Affiliations

1 College of Life Science and Technology, Key Laboratory of Molecular Biophysics of MOE, and International Research Center for Sensory Biology and Technology of MOST, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
2 Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
3 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
4 Department of Mechanical Engineering, Ulsan National Institute of Science and Technology, 50 UNIST-gil, South Korea.
5 Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA.
6 College of Life Science and Technology, Key Laboratory of Molecular Biophysics of MOE, and International Research Center for Sensory Biology and Technology of MOST, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China. Electronic address: jfliu@mail.hust.edu.cn.
7 Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: shawnxu@umich.edu.

PMID: 31474366 DOI: 10.1016/j.cell.2019.07.034

Abstract

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.

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