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Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP 2

Year: 2022
Type: article
Abstract: The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is controlled by cooling compounds together with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Our knowledge of cold sensation and the therapeutic potential of TRPM8 for neuroinflammatory diseases and pain will be enhanced by understanding the structural basis of cooling agonist- and PIP 2 -dependent TRPM8 activation. We present cryo–electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP 2 -dependent gating pathway. Our results uncover two discrete agonist sites, state-dependent rearrangements in the gate positions, and a disordered-to-ordered transition of the gate-forming S6—elucidating the molecular basis of chemically induced cool sensation in mammals.
Source: Science
DOI: 10.1126/science.add1268
Authors: Ying Yin, Feng Zhang, Shasha Feng, Kevin John Butay, Mario J. Borgnia, Wonpil Im, Seok-Yong Lee
Language: English
Subfield: Sensory Systems
Open Access status: green
Funders: National Institutes of Health, National Eye Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Awards: G192318385, G3144446506, G4689185066, G6221506569, NCCAT: National Center for CryoEM Access and Training, TRPM8 in eye health and disease, NIEHS Cryo-EM Core Facility, Cancer Center Support Grant
OpenAlex ID: W4305040308
FWCI: 9.869
Cites: 73
Cited by: 102
Related to: 10