Figure 5. Cartoon summary of interaction between leak and reuptake.

Top panel shows that Ca²⁺ efflux from the stores can be balanced by SERCA-mediated reuptake at a cytoplasmic Ca²⁺ binding ratio < = 3300 (corresponding to an EGTA concentration of < = 0.5 mm). Although the Ca²⁺ content of the stores may have fallen, I_CRAC has not activated. Following exposure to moderate cytoplasmic buffers (0.5 to 2.5 mm, Ca²⁺ binding ratio 3300 to 16 700), SERCA pump activity decreases somewhat (depicted by the thinner arrow) and cannot fully compensate the continuous Ca²⁺ leakage from the stores. I_CRAC activates to a submaximal extent and this is manifested as the typical monophasic current (middle panel). In the presence of high concentrations of chelators (> = 2.5 mm), pumps are initially operational, but then cease to function (dashed arrow). This results in full and uncompensated efflux of Ca²⁺ from the stores. Under these conditions, the majority of cells generate the biphasic I_CRAC which develops to reach the maximal amplitude possible (bottom panel). In this model, we are considering only the effects of introducing Ca²⁺ chelators in their free form into the cytosol. Our analysis does not extend to the situation where mixtures of Ca²⁺-bound and free chelators are added simultaneously to clamp cytosolic Ca²⁺ at a predetermined value.