The Endoplasmic Reticulum–Plasma Membrane Junction: A Hub for Agonist Regulation of Ca2+ Entry

Stimulation of cell-surface receptors induces cytosolic Ca 2+ ([Ca 2+ ] i ) increases that are detected and transduced by effector proteins for regulation of cell function. Intracellular Ca 2+ release, via endoplasmic reticulum (ER) proteins inositol 1,4,5-trisphosphate receptors (IP 3 R) and ryanodine receptors (RyR), and Ca 2+ influx, via store-operated Ca 2+ entry (SOCE), contribute to the increase in [Ca 2+ ] i The amplitude, frequency, and spatial characteristics of the [Ca 2+ ] i increases are controlled by the compartmentalization of proteins into signaling complexes such as receptor-signaling complexes and SOCE complexes. Both complexes include protein and lipid components, located in the plasma membrane (PM) and ER. Receptor signaling initiates in the PM via phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP 2 ), and culminates with the activation of IP 3 R in the ER. Conversely, SOCE is initiated in the ER by Ca 2+ -sensing stromal interaction molecule (STIM) proteins, which then interact with PM channels Orai1 and TRPC1 to activate Ca 2+ entry. This review will address how ER-PM junctions serve a central role in agonist regulation of SOCE.