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The Endoplasmic Reticulum-Located TRPV1 Channel Is Not Thermal Sensitive
Elena O Petukhova1,2, Dmitry I Maltsev1,2,3, Daria Y Pechinko1,2
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia.
ACS Chemical Biology
|July 17, 2025
Summary
Heat-evoked calcium responses mediated by the capsaicin receptor (TRPV1) depend on extracellular calcium. This suggests distinct TRPV1 pools in the endoplasmic reticulum and plasma membrane sense different signals.
Area of Science:
- Physiology
- Molecular Biology
- Cell Biology
Background:
- Transient Receptor Potential Vanilloid subfamily member 1 (TRPV1), or capsaicin receptor, is crucial for detecting heat, maintaining thermal homeostasis, and mediating inflammation.
- TRPV1 functions as a nonselective cation channel, triggering calcium influx and depolarization upon activation.
- A significant portion of TRPV1 is located in the endoplasmic reticulum (ER), where its activation releases calcium, but its role in heat-evoked cytosolic calcium elevation is unclear.
Purpose of the Study:
- To investigate the role of endoplasmic reticulum-located TRPV1 in heat-evoked cytosolic calcium elevation.
- To determine if different TRPV1 pools exhibit differential sensitivity to heat and ligand activation.
Main Methods:
- Human TRPV1 was heterologously expressed in HEK293TN cells.
- Calcium changes were recorded in response to heat and capsaicin stimulation.
- Experiments were conducted with and without extracellular calcium to differentiate calcium sources.
Main Results:
- Heat-evoked calcium responses in hTRPV1-expressing cells were abolished when extracellular calcium was removed.
- Capsaicin still induced intracellular calcium elevation even without extracellular calcium.
- Restoring extracellular calcium recovered heat-evoked calcium responses.
Conclusions:
- Heat-evoked TRPV1 activation primarily relies on extracellular calcium influx, suggesting a plasma membrane pool is involved.
- Ligand-dependent TRPV1 activation (e.g., by capsaicin) can utilize intracellular calcium stores (ER).
- These findings support the hypothesis of functionally distinct TRPV1 pools with differential sensitivities to various stimuli, potentially elucidating the structural basis of temperature-dependent gating.
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