Too much of a good thing: The case of SOCE in cellular apoptosis

Intracellular calcium (Ca²⁺) is an essential second messenger in eukaryotic cells regulating numerous cellular functions such as contraction, secretion, immunity, growth, and metabolism. Ca²⁺ signaling is also a key signal transducer in the intrinsic apoptosis pathway. The store-operated Ca²⁺ entry pathway (SOCE) is ubiquitously expressed in eukaryotic cells, and is the primary Ca²⁺ influx pathway in non-excitable cells. SOCE is mediated by the endoplasmic reticulum Ca²⁺ sensing STIM proteins, and the plasma membrane Ca²⁺-selective Orai channels. A growing number of studies have implicated SOCE in regulating cell death primarily via the intrinsic apoptotic pathway in a variety of tissues and in response to physiological stressors such as traumatic brain injury, ischemia reperfusion injury, sepsis, and alcohol toxicity. Notably, the literature points to excessive cytosolic Ca²⁺ influx through SOCE in vulnerable cells as a key factor tipping the balance towards cellular apoptosis. While the literature primarily addresses the functions of STIM1 and Orai1, STIM2, Orai2 and Orai3 are also emerging as potential regulators of cell death. Here, we review the functions of STIM and Orai proteins in regulating cell death and the implications of this regulation to human pathologies.