pH-dependent modulation of TRPV1 by modality-selective antagonists.

Autor: Daniluk J; Laboratory of Ion Channel Research (LICR), VIB-KU Leuven Centre for Brain & Disease Research, Leuven, Belgium.; Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Voets T; Laboratory of Ion Channel Research (LICR), VIB-KU Leuven Centre for Brain & Disease Research, Leuven, Belgium.; Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2023 Nov; Vol. 180 (21), pp. 2750-2761. Date of Electronic Publication: 2023 Jul 08.
DOI: 10.1111/bph.16173
Abstrakt: Background and Purpose: Antagonists of TRPV1 that inhibit all activation modes cause hyperthermia, hampering their medical use as novel analgesics. TRPV1 antagonists that do not (fully) inhibit responses to low pH do not cause hyperthermia, but it remains incompletely understood how such antagonists affect channel gating. We tested the hypothesis that pH-sparing antagonists act in a modality-selective manner on TRPV1, differentially affecting channel activation by protons and capsaicin.
Experimental Approach: Using whole-cell patch-clamp and calcium imaging to measure channel activity in cells expressing wild type human TRPV1 or the pH-insensitive mutant F660A. Responses to protons and capsaicin were measured at different pH values in the presence of antagonists that reportedly partially spare (A-1165442) or potentiate (AMG7905) acid-evoked channel activation.
Key Results: At pH 5.5, A-1165442 was equipotent at blocking acid- and capsaicin-evoked responses of wild type TRPV1. Its potency to inhibit acid-evoked responses was attenuated at pH ≤ 5.0. AMG7905, at a concentration (1 μM) that fully inhibits capsaicin-evoked responses, potentiated proton-evoked (pH 5.5) responses of wild type TRPV1. In the F660A mutant, the inhibitory efficacy of A-1165442 and AMG7905 towards capsaicin-evoked responses was reduced at lower pH values and AMG7905 acted as a partial agonist.
Conclusion and Implications: Our findings show that A-1165442 and AMG7905 interact in a pH-dependent manner with TRPV1, but this pH dependence is not strictly modality-selective. Reduced TRPV1 antagonism at acidic pH may limit analgesic efficacy in injured tissue and needs to be considered in models explaining the effects of antagonists on core body temperature.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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