Journal Article

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

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

2020

Overview

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. The TRPV1 ion channel is a heat-sensing receptor that is also activated by vanilloid compounds, but the molecular underpinnings of thermosensing have remained elusive. Here authors use in solution NMR on the isolated human TRPV1 S1-S4 domain and show that this domain undergoes a non-denaturing temperature-dependent transition with a high thermosensitivity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/6 / 140/131 / 631/45/269/1153 / 631/535/878/1263 / 631/57/2270/1140 / 9/74 / Activation / Binding Sites - genetics / Capsaicin / Capsaicin - chemistry / Capsaicin - metabolism / Capsaicin receptors / Channel gating / Circular Dichroism / Couples / Coupling (molecular) / Detection / Domains / Fluorescence / Heat / Hot Temperature / Humanities and Social Sciences / Humans / Ion Channel Gating - genetics / Ion Channel Gating - physiology / Ion channels / Ligands / Magnetic Resonance Spectroscopy / Membranes / Models, Molecular / multidisciplinary / NMR / Nuclear magnetic resonance / Protein Binding / Protein Domains / Receptors / Science / Science (multidisciplinary) / Temperature dependence / Thermosensing - genetics / Thermosensing - physiology / TRPV Cation Channels - chemistry / TRPV Cation Channels - genetics / TRPV Cation Channels - metabolism