Heat sensation of temperature sensitive TRPV1 channel supported by the transmembrane core domain

L. Ma,^1,2 F. Yang,² Y. Cui,^2,3 X. Cao,^2,3 K. Wang^3,4 and J. Zheng,² ¹Institute for Molecular Bioscience, The University of Queensland, Brisbane, St Lucia, QLD 4072, Australia, ²Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA, ³Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, China and ⁴4PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China.

Several transient receptor potential vanilloid (TRPV) channels serve as molecular temperature sensors. However, the structural basis for their high-sensitivity heat activation is strongly debated. Inspired by the recent finding of intrinsic high temperature sensitivity in homologous voltage-gated potassium channels (Kv), here we investigated this issue using two complementary strategies, unstructured peptide-insertion screening (UPS) and chimera screening. We showed that the transmembrane (TM) S1-S6 region of TRPV1 is sufficient to support heat activation, while both N and C termini contribute to this process. Furthermore, within the TM region, the pore domain plays a central role in determining the heat activation process; swapping the pore-forming region of TRPV1 with TRPV2 and TRPV3 could transfer distinct heat activation properties among these channels.