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Abstract
Background and Purpose: Ca2+ influx via TRPV4 channels triggers Ca2+ release from the IP3‐sensitive internal store to generate repetitive oscillations. Although 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 Results: TRPV4 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 PLC blocker U73122 and the inositol trisphosphate receptor 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.
Original language | English |
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Pages (from-to) | 1017-1032 |
Number of pages | 16 |
Journal | British Journal of Pharmacology |
Volume | 179 |
Issue number | 5 |
Early online date | 4 Oct 2021 |
DOIs | |
Publication status | Published - 31 Mar 2022 |
Keywords
- intercellular Ca2+ waves
- intercellular communication
- mitochondria
- pannexin
- purinergic receptors
- TRPV4
- vascular
- endothelium
- inositol 1,4,5-trisphosphate (IP3)
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A multicellular endothelial signalling web coordinates vascular function and is impaired in hypertension
McCarron, J. (Principal Investigator), Buckley, C. (Co-investigator) & Wilson, C. (Co-investigator)
19/01/21 → 18/01/26
Project: Research
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Mitochondrial amplification of local calcium entry and vascular contraction in hypertension
McCarron, J. (Principal Investigator), Buckley, C. (Co-investigator), Chalmers, S. (Co-investigator) & Wilson, C. (Co-investigator)
3/04/20 → 8/01/24
Project: Research
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Optical dissection of endothelial calcium signalling Sir Henry Wellcome Postdoctoral Fellowship
Wilson, C. (Fellow)
17/04/17 → 16/10/21
Project: Research Fellowship