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Contributed by Ramón Latorre, June 18, 2020 (sent for review March 9, 2020; reviewed by Feng Qin and Thomas Voets)
Significance
Sensory and homeostatic responses in several organisms depend on the exquisite temperature dependence of ion channels of the transient receptor potential family (thermo-TRP). To date, this temperature dependence has been explained either in terms of the existence of a dedicated temperature sensor or by the increase in the molar heat capacity during channel gating. We found that the Carboxy Terminus Domain (CTD) is required for temperature-driven gating of the cold-activated TRPM8 channel and that this domain folds in response to cold. Here we propose that the CTD of the TRPM8 channel is a bona fide temperature sensor that drives channel gating due to an increase in the molar heat capacity during the folded-to-unfolded transition.
Abstract
In 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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: ignacio.diaz{at}unab.cl, or ramon.latorre{at}uv.cl.
↵2Present address: Institute of Plant Biochemistry and Photosynthesis, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville-41092, Spain
Author contributions: I.D.-F. and R.L. designed research; I.D.-F., N.R., and K.C. performed research; I.D.-F., N.R., K.C., F.G.-N., and R.L. analyzed data; and I.D.-F. and R.L. wrote the paper.
Reviewers: F.Q., State University of New York at Buffalo; and T.V., Katholieke Universiteit Leuven.
The authors declare no competing interest.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2004303117/-/DCSupplemental.
Data Availability.
All study data are included in the article and SI Appendix.
Published under the PNAS license.
References
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A folding reaction at the C-terminal domain drives temperature sensing in TRPM8 channels
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