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

Yin, Ying; Zhang, Feng; Feng, Shasha; Butay, Kevin John; Borgnia, Mario J.; Im, Wonpil; Lee, Seok-Yong

doi:10.1126/science.add1268

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

Journal Article · 14 October 2022 · Science

DOI:https://doi.org/10.1126/science.add1268· OSTI ID:2424141

^[1]; Zhang, Feng ^[1]; ^[2]; ^[3]; ^[4]; ^[2]; ^[1]

Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
Departments of Biological Sciences, Chemistry, and Bioengineering, Lehigh University, Bethlehem, PA 18015, USA.
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.

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 (PIP₂). 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 PIP₂-dependent TRPM8 activation. We present cryo–electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP₂-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.

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Organization:: USDOE

DOE Contract Number:: AC05-76RL01830

OSTI ID:: 2424141

Journal Information:: Science, Journal Name: Science Journal Issue: 6616 Vol. 378; ISSN 0036-8075

Publisher:: AAAS

Country of Publication:: United States

Language:: English

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