The Wellcome Prize Lecture: Store‐operated Ca2+ Entry: Dynamic Interplay between Endoplasmic Reticulum, Mitochondria and Plasma Membrane

Abstract

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 and is required for controlling a host of Ca 2+‐dependent processes ranging from exocytosis to cell growth and proliferation. In many cell types, store‐operated Ca 2+ entry is manifest as a non‐voltage‐gated Ca 2+ current called ICRAC (Ca 2+ release‐activated Ca 2+ current). Just how store emptying activates CRAC channels remains unclear, and some of our recent experiments that address this issue will be described. No less important from a physiological perspective is the weak Ca 2+ buffer paradox: whereas macroscopic (whole cell) ICRAC can be measured routinely in the presence of strong intracellular Ca 2+ buffer, the current is generally not detectable under physiological conditions of weak buffering following store emptying with the second messenger Ins P3. In this review, I describe some of our experiments aimed at understanding just why Ins P3 is ineffective under these conditions and which lead us to conclude that respiring mitochondria are essential for the activation of ICRAC in weak intracellular Ca 2+ buffer. Mitochondrial Ca 2+ uptake also increases the dynamic range over which Ins P3 functions as the second messenger that controls Ca 2+ influx. Finally, we find that Ca 2+‐dependent slow inactivation of Ca 2+ influx, a widespread but poorly understood phenomenon that helps shape the profile of an intracellular Ca 2+ signal, is regulated by mitochondrial Ca 2+ buffering. 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 therefore a dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane.