Díaz-Franulic, IgnacioRaddatz, NataliaCastillo, KarenGonzález-Nilo, Fernando D.Latorre, Ramon2023-05-042023-05-042020-08Proceedings of the National Academy of Sciences of the United States of America. Volume 117, Issue 33, Pages 20298 - 20304. August 20200027-8424https://repositorio.unab.cl/xmlui/handle/ria/49288Indexación: Scopus.ACKNOWLEDGMENTS.We thank Christopher Miller and John Ewer forcomments on the manuscript and Mrs. Luisa Soto, Mr. Patricio Farias, andMrs. Victoria Prado (Universidad de Valparaiso) for their excellent technicalassistance. This research was supported by the Fondo Nacional de DesarrolloCientífico y Tecnológico (FONDECYT) Regular 1190203 (to R.L.), 1170733 (toF.G.-N.), and 1180999 (to K.C.) and FONDECYT Postdoctorado 3170599 (toI.D.-F.), Proyecto PAI7719087 (to I.D.-F.); US Army Research Office Coopera-tive Agreement W911NF-17-2-0081 (to F.G.-N.); and US Air Force Office ofScientific Research grant under award FA9550-16-1-0384 (R.L.). The CentroInterdisciplinario de Neurociencias de Valparaiso (CINV) is a Millennium In-stitute supported by the Iniciativa Científica Milenio-Agencia Nacional deInvestigación y Desarrollo (ICM-ANID), Project P09-022-F, CINVIn mammals, temperature-sensitive TRP channels make membrane conductance of cells extremely temperature dependent, allowing the detection of temperature ranging from noxious cold to noxious heat. We progressively deleted the distal carboxyl terminus domain (CTD) of the cold-activated melastatin receptor channel, TRPM8. We found that the enthalpy change associated with channel gating is proportional to the length of the CTD. Deletion of the last 36 amino acids of the CTD transforms TRPM8 into a reduced temperature-sensitivity channel (Q10 ∼4). Exposing the intracellular domain to a denaturing agent increases the energy required to open the channel indicating that cold drives channel gating by stabilizing the folded state of the CTD. Experiments in the presence of an osmoticant agent suggest that channel gating involves a change in solute-inaccessible volume in the CTD of ∼1,900 Å3. This volume matches the void space inside the coiled coil according to the cryogenic electron microscopy structure of TRPM8. The results indicate that a folding–unfolding reaction of a specialized temperature-sensitive structure is coupled to TRPM8 gating.enTRPM8Temperature SensorHeat CapacitCoiled Coil|protein FoldingArtículoAtribution 4.0 International (CC BY 4.0)DOI: 10.1073/PNAS.2004303117