The ER/PM microdomain, PI(4,5)P₂ and the regulation of STIM1-Orai1 channel function

All forms of cell signaling occur in discreet cellular microdomains in which the ER is the main participant and include microdomains formed by the ER with lysosomes, endosomes, the nucleus, mitochondria and the plasma membrane. In the microdomains the two opposing organelles transfer and exchange constituents including lipids and ions. As is the case for other forms of signaling pathways, many components of the receptor-evoked Ca²⁺ signal are clustered at the ER/PM microdomain, including the Orai1-STIM1 complex. This review discusses recent advances in understanding the molecular components that tether the ER and plasma membrane to form the ER/PM microdomains in which PI(4,5)P₂ is enriched, and how dynamic targeting of the Orai1-STIM1 complex to PI(4,5)P₂-poor and PI(4,5)P₂-rich microdomains controls the activity of Orai1 and its regulation by Ca²⁺ that is mediated by SARAF.