Historical Overview of Store-Operated Ca(2+) Entry

Calcium influx is an essential mechanism for the activation of cellular functions both in excitable and non-excitable cells. In non-excitable cells, activation of phospholipase C by occupation of G protein-coupled receptors leads to the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which, in turn, initiate two Ca(2+) entry pathways: Ca(2+) release from intracellular Ca(2+) stores, signaled by IP3, leads to the activation of store-operated Ca(2+) entry (SOCE); on the other hand, DAG activates a distinct second messenger-operated pathway. SOCE is regulated by the filling state of the intracellular calcium stores. The search for the molecular components of SOCE has identified the stromal interaction molecule 1 (STIM1) as the Ca(2+) sensor in the endoplasmic reticulum and Orai1 as a store-operated channel (SOC) subunit. Furthermore, a number of reports have revealed that several members of the TRPC family of channels also take part of the SOC macromolecular complex. This introductory chapter summarizes the early pieces of evidence that led to the concept of SOCE and the components of the store-operated signaling pathway.