Subpopulation of Store-operated Ca²⁺ Channels Regulate Ca ²⁺-induced Ca²⁺ Release in Non-excitable Cells

Ca²⁺-induced Ca²⁺ release (CICR) is a well characterized activity in skeletal and cardiac muscles mediated by the ryanodine receptors. The present study demonstrates CICR in the non-excitable parotid acinar cells, which resembles the mechanism described in cardiac myocytes. Partial depletion of internal Ca²⁺ stores leads to a minimal activation of Ca²⁺ influx. Ca²⁺ influx through this pathway results in an explosive mobilization of Ca²⁺ from the majority of the stores by CICR. Thus, stimulation of parotid acinar cells in Ca²⁺-free medium with 0.5 μM carbachol releases ∼5% of the Ca²⁺ mobilizable by 1 mM carbachol. Addition of external Ca ²⁺ induced the same Ca²⁺ release observed in maximally stimulated cells. Similar results were obtained by a short treatment with 2. 5-10 μM cyclopiazonic acid, an inhibitor of the sarco/endoplasmic reticulum Ca²⁺ ATPase pump. The Ca²⁺ release induced by the addition of external Ca²⁺ was largely independent of IP ₃Rs because it was reduced by only ∼30% by the inhibition of the inositol 1,4,5-trisphosphate receptors with caffeine or heparin. Measurements of Ca²⁺-activated outward current and [Ca²⁺]_i suggested that most CICR triggered by Ca²⁺ influx occurred away from the plasma membrane. Measurement of the response to several concentrations of cyclopiazonic acid revealed that Ca²⁺ influx that regulates CICR is associated with a selective portion of the internal Ca²⁺ pool. The minimal activation of Ca²⁺ influx by partial store depletion was confirmed by the measurement of Mn²⁺ influx. Inhibition of Ca ²⁺ influx with SKF96365 or 2-aminoethoxydiphenyl borate prevented activation of CICR observed on addition of external Ca²⁺. These findings provide evidence for activation of CICR by Ca²⁺ influx in non-excitable cells, demonstrate a previously unrecognized role for Ca ²⁺ influx in triggering CICR, and indicate that CICR in non-excitable cells resembles CICR in cardiac myocytes with the exception that in cardiac cells Ca²⁺ influx is mediated by voltage-regulated Ca ²⁺ channels whereas in non-excitable cells Ca²⁺ influx is mediated by store-operated channels.