https://orcid.org/0000-0003-3464-160X
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ABSTRACT
TRPV1 is a polymodal receptor ion channel that is best known to function as a molecular thermometer. It is activated in diverse ways, including by heat, protons (low pH), and vanilloid compounds, such as capsaicin. In this review, we summarize molecular studies of TRPV1 thermosensing, focusing on the cross-talk between heat and other activation modes. Additional insights from TRPV1 isoforms and non-rodent/non-human TRPV1 ortholog studies are also discussed in this context. While the molecular mechanism of heat activation is still emerging, it is clear that TRPV1 thermosensing is modulated allosterically, i.e., at a distance, with contributions from many distinct regions of the channel. Similarly, current studies identify cross-talk between heat and other TRPV1 activation modes, such as protons and capsaicin, and that these modes can generally be selectively disentangled. In aggregate, this suggests that future TRPV1 molecular studies should define allosteric pathways and provide mechanistic insight, thereby enabling mode-selective manipulation of the polymodal receptor. These advances are anticipated to have significant implications in both basic and applied biomedical sciences.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Abbreviations
| TRP | = | Transient Receptor Potential |
| TRPV1 | = | Transient Receptor Potential Vanilloid 1 |
| TRPV2 | = | Transient Receptor Potential Vanilloid 2 |
| TRPV3 | = | Transient Receptor Potential Vanilloid 3 |
| TRPV4 | = | Transient Receptor Potential Vanilloid 4 |
| TRPM8 | = | Transient Receptor Potential Melastatin 8 |
| TRPA1 | = | Transient Receptor Potential Ankyrin 1 |
| VGIC | = | Voltage-Gated Ion Channel |
| HEK293 | = | Human Embryonic Kidney 293 |
| ARD | = | Ankyrin Repeat Domain |
| TMD | = | S1-S6 α-helical Transmembrane Domain |
| S1-S4 Domain | = | S1-S4 α-helical Transmembrane Domain |
| S4-S5L | = | S4-S5 Linker Domain |
| Pore Domain | = | S5-S6 α-helical Transmembrane Domain |
| PD | = | Pore Domain |
| PH | = | Pore Helix |
| MPD | = | Membrane Proximal Domain |
| DRG | = | Dorsal Root Ganglia |
| ATP | = | Adenosine Triphosphate |
| rTRPV1 | = | Rat TRPV1 |
| mTRPV1 | = | Mouse TRPV1 |
| hTRPV1 | = | Human TRPV1 |
| cTRPV1 | = | Chicken TRPV1 |
| oTRPV1 | = | Rabbit TRPV1 |
| CfTRPV1 | = | Camel TRPV1 |
| ItTRPV1 | = | Ground Squirrel TRPV1 |
| DrTRPV1 | = | Zebrafish TRPV1 |
| CbTRPV1 | = | Carollia brevicauda Bat TRPV1 |
| XlTRPV1 | = | Xenopus laevis clawed frog TRPV1 |
| XtTRPV1 | = | Xenopus tropicalis clawed frog TRPV1 |
| OaTRPV1 | = | Platypus TRPV1 |
| Cryo-EM | = | Cryo-Electron Microscopy |
| WT | = | Wild Type |
| = | Open Probability | |
| PI | = | Phosphatidylinositol |
| PI4P | = | Phosphatidylinositol 4-phosphate |
| PI(4,5)P2 | = | Phosphatidylinositol 4,5-bisphosphate |
| CAP | = | Capsaicin |
| RTx | = | Resiniferatoxin |
| I-RTx | = | Iodoresiniferatoxin |
| 2-APB | = | 2-Aminophenylborate |
| = | Potency, Mid-Point of Activation | |
| = | Mid-Point of pH Activation/Proton Sensitivity | |
| = | Mid-Point Temperature/Heat Activation | |
| = | Temperature Threshold | |
| = | Melting Temperature | |
| = | Temperature Coefficient | |
| pKa | = | Negative Log of the Acid Dissociation Constant |
| = | Equilibrium constants | |
| = | Change in Free Energy | |
| = | Change in Enthalpy | |
| = | Change in Entropy | |
| T | = | Temperature |
| NMR | = | Nuclear Magnetic Resonance |
| FRET | = | Fluorescence Resonance Energy Transfer |
| Kv | = | Voltage-gated Potassium Channel |
| ΔN-TRPV1 | = | N-terminal Deletion TRPV1 Isoform |
| SIC | = | Stretch Inactivated Channel TRPV1 Isoform |
| VR.5ʹsv | = | Vanilloid Receptor 5ʹ-Isoform of TRPV1 |
| VR1L2 | = | Vanilloid Receptor 1 Like 2 |
| TRPV1VAR | = | TRPV1 Variant |
| TRPV1-S | = | Short Version of TRPV1 |
| TRPV1-XL | = | Extra Large Version of TRPV1 |
| TRPV1t | = | Amiloride-Insensitive Salt Taste Receptor TRPV1 |
| RT-PCR | = | Reverse Transcription Polymerase Chain Reaction |
| MWC | = | Monod–Wyman–Changeux |
| = | Hill Coefficient |
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.
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Notes on contributors
Dustin D. Luu
Dustin D. Luu is a Ph.D. candidate in the School of Molecular Sciences at Arizona State University. His research focuses on the molecular mechanism of TRP channel gating and modulation as well as membrane proteins in health and diseases.
Aerial M. Owens
Aerial M. Owens is a Ph.D. candidate in the School of Molecular Sciences at Arizona State University. Her research focuses on the TRPV1 channel with emphasis on how certain domains contribute to each mode of activation.
Mubark D. Mebrat
Mubark D. Mebrat is a Ph.D. candidate at Arizona State University in the School of Molecular Science. His research focuses on understanding the molecular mechanism for temperature activation in TRP channels, TRPV1 and TRPM8.
Wade D. Van Horn
Wade D. Van Horn is an Associate Professor in the School of Molecular Sciences and is affiliated with the Biodesign Institute Centers of Personalized Diagnostics and Mechanisms of Evolution at Arizona State University. His research interests include correlating protein dynamics, structure, and function to understand ion channel mechanisms that underlie polymodal regulation.