Respiring mitochondria determine the pattern of activation and inactivation of the store‐operated Ca 2+ current I CRAC

In eukaryotic cells, hormones and neurotransmitters that engage the phosphoinositide pathway evoke a biphasic increase in intracellular free Ca 2+ concentration: an initial transient release of Ca 2+ from intracellular stores is followed by a sustained phase of Ca 2+ influx. This influx is generally store dependent. Most attention has focused on the link between the endoplasmic reticulum and store‐operated Ca 2+ channels in the plasma membrane. Here, we describe that respiring mitochondria are also essential for the activation of macroscopic store‐operated Ca 2+ currents under physiological conditions of weak intracellular Ca 2+ buffering. We further show that Ca 2+ ‐dependent slow inactivation of Ca 2+ influx, a widespread but poorly understood phenomenon, is regulated by mitochondrial buffering of cytosolic Ca 2+ . Thus, by enabling macroscopic store‐operated Ca 2+ current to activate, and then by controlling its extent and duration, mitochondria play a crucial role in all stages of store‐operated Ca 2+ influx. Store‐operated Ca 2+ entry reflects a dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane.