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Mitochondria regulate TRPV4 mediated release of ATP
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  • Xun Zhang,
  • Matthew Lee,
  • Charlotte Buckley,
  • Calum Wilson,
  • John McCarron
Xun Zhang
University of Strathclyde

Corresponding Author:[email protected]

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Matthew Lee
University of Strathclyde
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Charlotte Buckley
University of Strathclyde
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Calum Wilson
University of Strathclyde
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John McCarron
University of Strathclyde
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Background and Purpose Ca2+ influx via TRPV4 triggers Ca2+ release from the IP3-sensitive internal store to generate repetitive oscillations. While mitochondria are acknowledged regulators of IP3-mediated Ca2+ release, how TRPV4-mediated Ca2+ signals are regulated by mitochondria is unknown. We show that depolarised mitochondria switch TRPV4 signalling from relying on Ca2+-induced Ca2+ release at IP3 receptors, to being independent of Ca2+ influx and instead mediated by ATP release via pannexins. Experimental Approach TRPV4 evoked Ca2+ signals were individually examined in hundreds of cells in the endothelium of rat mesenteric resistance arteries using the indicator Cal520. Key ResultsTRPV4 activation with GSK1016790A(GSK) generated repetitive Ca2+ oscillations that required Ca2+ influx. However, when the mitochondrial membrane potential was depolarised, by the uncoupler CCCP or complex I inhibitor rotenone, TRPV4 activation generated large propagating, multicellular, Ca2+ waves in the absence of external Ca2+. The ATP synthase inhibitor oligomycin did not potentiate TRPV4 mediated Ca2+ signals. GSK-evoked Ca2+ waves, when mitochondria were depolarised, were blocked by the TRPV4 channel blocker HC067047, the SERCA inhibitor cyclopiazonic acid, the phospholipase C (PLC) blocker U73122 and the inositol triphosphate receptor (IP3 R) blocker caffeine. The Ca2+ 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 Ca2+ signalling by facilitating ATP release. When mitochondria are depolarised, TRPV4-mediated release of ATP via pannexin channels activates plasma membrane purinergic receptors to trigger IP3 evoked Ca2+ release.
21 Apr 2021Submitted to British Journal of Pharmacology
21 Apr 2021Submission Checks Completed
21 Apr 2021Assigned to Editor
26 Apr 2021Reviewer(s) Assigned
12 May 2021Review(s) Completed, Editorial Evaluation Pending
13 May 2021Editorial Decision: Revise Minor
10 Aug 20211st Revision Received
10 Aug 2021Submission Checks Completed
10 Aug 2021Assigned to Editor
11 Aug 2021Reviewer(s) Assigned
02 Sep 2021Review(s) Completed, Editorial Evaluation Pending
02 Sep 2021Editorial Decision: Accept
Mar 2022Published in British Journal of Pharmacology volume 179 issue 5 on pages 1017-1032. 10.1111/bph.15687