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bioRxiv · 10.1101/2023.01.22.525118

Antithetic effects of agonists and antagonists on the structural fluctuations of TRPV1 channel

Sumino, A.·Zhao, Y.·Mukai, D.·Sumikama, T.·Puppulin, L.·Hattori, M.·Shibata, M.
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Abstract

Transient receptor potential vanilloid member 1 (TRPV1) is a heat and capsaicin receptor that allows cations to permeate and cause pain. As the molecular basis for temperature sensing, the heat capacity ({Delta}Cp) model (D. E. Clapham, C. Miller, Proc. Natl. Acad. Sci. U. S. A. 108, 19492-19497 (2011).) has been proposed and experimentally supported. Theoretically, heat capacity is proportional to a variance in enthalpy, presumably related to structural fluctuation; however, the fluctuation of TRPV1 has not been directly visualized. In this study, we directly visualized single-molecule structural fluctuations of the TRPV1 channels in a lipid bilayer with the ligands resiniferatoxin (RTX: agonist, 1000 times hotter than capsaicin) and capsazepine (CPZ: antagonist) by high-speed atomic force microscopy (HS-AFM). We observed the structural fluctuations of TRPV1 in an apo state and found that RTX binding enhances structural fluctuations, while CPZ binding suppresses fluctuations. These ligand-dependent differences in structural fluctuation would play a key role in the gating of TRPV1.

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Sumino, A., Zhao, Y., Mukai, D., Sumikama, T., Puppulin, L., Hattori, M., Shibata, M.. 2023-01-23. Antithetic effects of agonists and antagonists on the structural fluctuations of TRPV1 channel. https://doi.org/10.1101/2023.01.22.525118

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