Close functional coupling between Ca²⁺ release-activated Ca ²⁺ 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.