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Mitochondria regulate TRPV4‐mediated release of ATP
Author(s) -
Zhang Xun,
Lee Matthew D.,
Buckley Charlotte,
Wilson Calum,
McCarron John G.
Publication year - 2022
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15687
Subject(s) - pannexin , purinergic receptor , microbiology and biotechnology , channel blocker , mitochondrion , inositol trisphosphate receptor , thapsigargin , cyclopiazonic acid , biology , chemistry , receptor , biophysics , biochemistry , extracellular , endoplasmic reticulum , intracellular , inositol , gap junction , calcium , connexin , organic chemistry
Background and Purpose Ca 2+ influx via TRPV4 channels triggers Ca 2+ release from the IP 3 ‐sensitive internal store to generate repetitive oscillations. Although mitochondria are acknowledged regulators of IP 3 ‐mediated Ca 2+ release, how TRPV4‐mediated Ca 2+ signals are regulated by mitochondria is unknown. We show that depolarised mitochondria switch TRPV4 signalling from relying on Ca 2+ ‐induced Ca 2+ release at IP 3 receptors to being independent of Ca 2+ influx and instead mediated by ATP release via pannexins. Experimental Approach TRPV4‐evoked Ca 2+ signals were individually examined in hundreds of cells in the endothelium of rat mesenteric resistance arteries using the indicator Cal520. Key Results TRPV4 activation with GSK1016790A (GSK) generated repetitive Ca 2+ oscillations that required Ca 2+ influx. However, when the mitochondrial membrane potential was depolarised, by the uncoupler CCCP or complex I inhibitor rotenone, TRPV4 activation generated large propagating, multicellular, Ca 2+ waves in the absence of external Ca 2+ . The ATP synthase inhibitor oligomycin did not potentiate TRPV4‐mediated Ca 2+ signals. GSK‐evoked Ca 2+ waves, when mitochondria were depolarised, were blocked by the TRPV4 channel blocker HC067047, the SERCA inhibitor cyclopiazonic acid, the PLC blocker U73122 and the inositol trisphosphate receptor blocker caffeine. The Ca 2+ waves were also inhibited by the extracellular ATP blockers suramin and apyrase and the pannexin blocker probenecid. Conclusion and Implications These results highlight a previously unknown role of mitochondria in shaping TRPV4‐mediated Ca 2+ signalling by facilitating ATP release. When mitochondria are depolarised, TRPV4‐mediated release of ATP via pannexin channels activates plasma membrane purinergic receptors to trigger IP 3 ‐evoked Ca 2+ release.