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

Minjoo Kim,Wade D Van Horn,Nicholas J Sisco,Jacob K Hilton,Manuel A Castro,Brian R Cherry,Marcia Levitus,Camila M Montano

doi:10.1038/s41467-020-18026-2

Minjoo Kim, Wade D Van Horn + Show 6 more

Open Access

https://doi.org/10.1038/s41467-020-18026-2

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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.

Highlights

Sensing and responding to temperature is crucial in biology
These structures have shown that Transient receptor potential (TRP) channels resemble the transmembrane topology of voltage-gated ion channels (VGICs), with two conserved transmembrane structural domains
The hV1-S1S4 membrane topology was determined from secondary structure derived from backbone chemical shift data (TALOS-N) and membrane accessibility from nuclear magnetic resonance (NMR)-detected deuteriumhydrogen (D/H) exchange factors (Fig. 1b, c)

Summary

Introduction

Sensing and responding to temperature is crucial in biology. The TRPV1 ion channel is a wellstudied heat-sensing receptor that is activated by vanilloid compounds, including capsaicin. 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. Cryo-electron microscopy (cryo-EM)-based structural biology has had a significant impact on understanding the molecular architecture that underlies TRP channel function[18]. These structures have shown that TRP channels resemble the transmembrane topology of voltage-gated ion channels (VGICs), with two conserved transmembrane structural domains. The temperature-induced activation of thermosensitive TRP channels generates large changes in enthalpy (ΔH) and significant compensating changes in entropy (ΔS), resulting in biologically accessible changes in free energy (ΔG) between closed and open states.

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