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BS22 TRPV4 is a phospholipase C coupled receptor when mitochondria are depolarised in intact endothelial cells
  2. Calum Wilson,
  3. John McCarron
  1. University of Strathclyde, Glasgow, UK


Mitochondria are significant regulators of intracellular Ca2+ signalling in the vascular endothelium. Depolarization of the mitochondrial membrane potential (Δψm) inhibits IP3-mediated Ca2+ release and may regulate Ca2+ influx across the plasma membrane. However, precisely how Ca2+ influx is regulated by mitochondria in the endothelium is unknown. To examine mitochondrial regulation of Ca2+ influx, the interaction of TRPV4-mediated Ca2+ influx with mitochondria was examined in the endothelium in intact blood vessels. In controls, TRPV4 activation with GSK1016790A(GSK) generated repetitive Ca2+ oscillations that required Ca2+ influx. When the Δψm was depolarised, by the uncoupler carbonyl cyanide m-chlorophenyl hydrazine (CCCP) or the complex I inhibitor rotenone, TRPV4 activation generated a much larger Ca2+ rise and propagating multicellular Ca2+ waves. The ATP synthase inhibitor oligomycin did not potentiate TRPV4 mediated Ca2+ influx. GSK-evoked Ca2+ waves, that occurred when mitochondria were depolarised, persisted in a Ca2+ free extracellular solution i.e. were independent of Ca2+ influx. These signals were blocked by the TRPV4 channel blocker HC067047 (HC067), the SERCA inhibitor cyclopiazonic acid, the phospholipase C (PLC) blocker U73122 and the inositol triphosphate receptor (IP3R) blocker caffeine. These observations suggest that TRPV4 may directly activate Ca2+ release from the internal store. The large propagating waves were inhibited by the pannexin blocker probenecid and the extracellular ATP blockers suramin and apyrase. These results highlight a previously unknown role of mitochondria in shaping TRPV4 mediated Ca2+ signalling and show that TRPV4 may trigger ATP release via a pannexin hemichannel when mitochondria are depolarised.

Conflict of Interest n/a

  • Endothelium
  • Calcium
  • Mitochondria

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