Close functional coupling between Ca2+ release-activated Ca2+ channels, arachidonic acid release, and leukotriene C4 secretion.
In non-excitable cells, one major route for Ca2+ influx is through store-operated Ca2+ channels in the plasma membrane. These channels are activated by the emptying of intracellular Ca2+ stores, and in some cell types, particularly of hemopoietic origin, store-operated influx occurs through Ca2+ release-activated Ca2+ (CRAC) channels. However, little is known about the downstream consequences of CRAC channel activation. Here, we report that Ca2+ entry through CRAC channels stimulates arachidonic acid production, whereas Ca2+ release from the stores is ineffective even though the latter evokes a robust intracellular Ca2+ signal. We find that arachidonic acid released by Ca2+ entering through CRAC channels is used to synthesize the potent paracrine proinflammatory signal leukotriene C4 (LTC4). Both pharmacological inhibitors of CRAC channels and mitochondrial depolarization, which impairs CRAC channel activity, suppress arachidonic acid release and LTC4 secretion. Thus, arachidonic acid release is preferentially stimulated by elevated subplasmalemmal Ca2+ levels due to open CRAC channels, suggesting that the enzyme is located close to the CRAC channels. Our results also identify a novel role for CRAC channels, namely the activation of a downstream signal transduction pathway resulting in the secretion of LTC4. Finally, mitochondria are key determinants of the generation of both intracellular (arachidonic acid) and paracrine (LTC4) signals through their effects on CRAC channel activity.
Chang
Wei-Chiao
WC
Laboratory of Cellular and Molecular Signalling, Department of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.
Parekh
Anant B
AB
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D015153:Blotting, Western; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D045744:Cell Line, Tumor; D005682:Gadolinium / Q000494:pharmacology; D017997:Leukotriene C4 / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019284:Thapsigargin / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors
D001896:Boron Compounds; D015220:Calcium Channels; D016718:Arachidonic Acid; D017997:Leukotriene C4; D019284:Thapsigargin; D005682:Gadolinium; C109986:2-aminoethoxydiphenyl borate; D001094:Arachidonate 5-Lipoxygenase; D002118:Calcium