Evidence that the TRPV1 S1-S4 membrane domain contributes to thermosensing

Minjoo Kim, Nicholas J. Sisco, Jacob K. Hilton, Camila M. Montano, Manuel A. Castro, Brian R. Cherry, Marcia Levitus and Wade D. Van Horn ()
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Minjoo Kim: School of Molecular Sciences, Arizona State University
Nicholas J. Sisco: School of Molecular Sciences, Arizona State University
Jacob K. Hilton: School of Molecular Sciences, Arizona State University
Camila M. Montano: The Biodesign Institute Virginia G. Piper Center for Personalized Diagnostics, Arizona State University
Manuel A. Castro: School of Molecular Sciences, Arizona State University
Brian R. Cherry: The Magnetic Resonance Research Center, Arizona State University
Marcia Levitus: School of Molecular Sciences, Arizona State University
Wade D. Van Horn: School of Molecular Sciences, Arizona State University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Sensing and responding to temperature is crucial in biology. The TRPV1 ion channel is a well-studied heat-sensing receptor that is also activated by vanilloid compounds, including capsaicin. Despite significant interest, the molecular underpinnings of thermosensing have remained elusive. The TRPV1 S1-S4 membrane domain couples chemical ligand binding to the pore domain during channel gating. Here we show that the S1-S4 domain also significantly contributes to thermosensing and couples to heat-activated gating. Evaluation of the isolated human TRPV1 S1-S4 domain by solution NMR, far-UV CD, and intrinsic fluorescence shows that this domain undergoes a non-denaturing temperature-dependent transition with a high thermosensitivity. Further NMR characterization of the temperature-dependent conformational changes suggests the contribution of the S1-S4 domain to thermosensing shares features with known coupling mechanisms between this domain with ligand and pH activation. Taken together, this study shows that the TRPV1 S1-S4 domain contributes to TRPV1 temperature-dependent activation.

Date: 2020
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DOI: 10.1038/s41467-020-18026-2

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