Redox dependence of endoplasmic reticulum (ER) Ca2+ signaling

Abstract

The endoplasmic reticulum (ER) is a multifunctional organelle that accommodates a large array of functions. Recent publications have shown that many of these functions are influenced by the ongoing oxidative folding of secretory and membrane proteins. Conversely, successful ER protein folding critically depends on the cellular redox state, but also the availability of Ca2+. These findings suggest the existence of regulatory mechanisms that steer ER Ca2+ homeostasis according to the cellular redox state. Indeed, accumulating evidence demonstrates that ER Ca2+ uptake and release by sarco-endoplasmic reticulum Ca2+ transport ATPases (SERCAs), stromal interaction molecule 1 (STIM1), Orai1, inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) and ryanodine receptors (RyR) depends on redox modifications of these channels and pumps. In addition, ER chaperones and oxidoreductases moonlight as regulators of ER Ca2+ channels and pumps. Discrete redox conditions of channels, pumps and oxidoreductases exist that allow for opening and closing. Through these functions, redox regulation of ER Ca2+ influences signaling mechanisms governing cell growth and migration, apoptosis and mitochondrial energy production. Therefore, pharmacological intervention based on ER redox or on ER redox-sensitive chaperones and oxidoreductases is a promising strategy to influence all metabolic syndromes including cancer and neurodegeneration.