In electrically non-excitable cells, calcium entry is required for regulating a variety of key processes including enzyme activity, exocytosis, gene transcription and cell growth, and proliferation. The major calcium influx pathway in these cells is the store-operated one, in which the process of emptying intracellular inositol 1,4,5-trisphosphate (InsP₃)-sensitive calcium stores results in the activation of calcium channels in the plasma membrane. The best characterised and most widely distributed store-operated current is the calcium release-activated calcium current I_CRAC, which can be measured directly and unambiguously using the patch-clamp technique.

Under physiological conditions of weak intracellular calcium buffering (0.1 mM EGTA or BAPTA), receptor stimulation or simply including InsP₃ in the recording patch pipette fails to activate any I_CRAC, in spite of reducing the calcium content of the stores in rat basophilic leukaemia (RBL-1) cells. Only when the Ca²⁺ ATPase pumps on the endoplasmic reticulum (called SERCA pumps) are blocked can InsP₃ activate I_CRAC under physiological conditions. SERCA pumps are very powerful in RBL-1 cells and are able to re-sequestrate sufficient calcium back into the stores so that I_CRAC cannot activate. We have recently found that calcium uptake by respiring mitochondria is essential for I_CRAC to activate in weak buffer even when SERCA pumps are active. Removal of cytosolic calcium by mitochondria seems to compete effectively with store refilling by SERCA pumps as well as possibly reducing calcium-dependent inactivation of InsP₃ receptors. This enables InsP₃ to deplete the stores sufficiently for macroscopic I_CRAC to activate. Furthermore, mitochondrial calcium buffering reduces both the rate and extent of slow calcium-dependent inactivation of CRAC channels, Finally, mitochondrial calcium uptake reduces the levels of InsP₃ required to activate the current. By sensitising cells to lower InsP₃, mitochondria may determine whether relatively weak stimuli are capable of evoking store-operated calcium influx or not.

A.B.P. is a Lister Institute Senior Research Fellow.