Figure 15. A diagrammatic scheme for the role of mitochondria in controlling I_CRAC under physiological conditions of weak intracellular Ca²⁺ buffering.

A, the resting state, where I_CRAC is not functioning, is shown. Stores are largely full and any Ca²⁺ that leaks from the stores is taken back up by the SERCA pumps. B, increasing InsP₃ levels in the absence of active mitochondrial Ca²⁺ uptake, releases Ca²⁺ from the stores. However, the SERCA pumps are able to resequester sufficient Ca²⁺ so only a very small fraction of CRAC channels are activated (undetectable in whole cell mode). Furthermore, the rise in cytosolic Ca²⁺ results in Ca²⁺-dependent slow inactivation of CRAC channels, and possibly InsP₃ receptors as well. C, in the presence of respiring mitochondria, InsP₃ activates macroscopic I_CRAC. Ca²⁺ released from the stores by InsP₃ is taken up by mitochondria. This reduces the amount of Ca²⁺ available to the SERCA pumps and in the vicinity of open InsP₃ receptors such that the stores are depleted sufficiently for macroscopic I_CRAC to activate (less refilling by SERCA pumps and less inactivation of InsP₃ receptors). Some refilling does occur because inclusion of thapsigargin enhances the size of the current. Furthermore, mitochondrial Ca²⁺ buffering reduces the rate and extent of Ca²⁺-dependent slow inactivation, thereby increasing the size and duration of the current. D, a simplified gating scheme for CRAC channels summarising the role of mitochondrial Ca²⁺ buffering. Mitochondria facilitate opening (Closed to Open transition) whilst, simultaneously, reducing inactivation (Open to Inactivated transition). In this way, mitochondria have a much larger impact on I_CRAC than through either transition alone.