Mitochondria regulate TRPV4-mediated release of ATP

Area of Science:

• Cellular Biology
• Physiology
• Biochemistry

Background:

• Calcium (Ca2+) influx via TRPV4 channels typically triggers intracellular Ca2+ release, causing oscillations.
• Mitochondria are known regulators of inositol trisphosphate (IP3)-mediated Ca2+ release.
• The precise role of mitochondria in regulating TRPV4-mediated Ca2+ signaling remained unclear.

Purpose of the Study:

• To investigate the role of mitochondria in modulating TRPV4-mediated Ca2+ signaling.
• To elucidate the mechanisms by which mitochondria influence Ca2+ dynamics initiated by TRPV4 channels.

Main Methods:

• Examined TRPV4-evoked Ca2+ signals in rat mesenteric artery endothelial cells using the indicator Cal520.
• Utilized mitochondrial membrane potential depolarizers (CCCP, rotenone) and inhibitors (oligomycin, HC067047, cyclopiazonic acid, U73122, caffeine, suramin, apyrase, probenecid).

Main Results:

• TRPV4 activation normally requires Ca2+ influx for repetitive Ca2+ oscillations.
• Depolarized mitochondria shifted TRPV4 signaling to rely on ATP release via pannexin channels, generating Ca2+ waves independent of external Ca2+.
• These Ca2+ waves were blocked by inhibitors of TRPV4, SERCA, PLC, IP3 receptors, extracellular ATP, and pannexin channels.

Conclusions:

• Mitochondria play a critical role in shaping TRPV4-mediated Ca2+ signaling by facilitating ATP release.
• Upon mitochondrial depolarization, TRPV4 channels mediate ATP release through pannexin channels, activating purinergic receptors and IP3-evoked Ca2+ release.