Store-Operated Ca²⁺ Entry (SOCE) Pathways

Nicolas Demaurex, Daniele Guido

Store-operated Ca(2+) entry (SOCE) is a cell signaling pathway essential for immune and muscle function controlled by dynamic interactions between Ca(2+)-sensing STIM proteins on the endoplasmic reticulum (ER) and Ca(2+)-permeable ORAI channels on the plasma membrane (PM). STIM-ORAI interactions occur at membrane contact sites (MCS), evolutionarily conserved cellular structures characterized by the close apposition (10-20 nm) between the ER and target membranes that facilitate the exchange of lipids by non-vesicular transport mechanisms. STIM-ORAI interactions were considered to be restricted to ER-PM MCS, but recent evidence indicates that productive interactions take place between ER-bound STIM1 and Ca(2+) channels located in intracellular organelles. Interactions between the ER and endosomes or lysosomes regulate the lipid homeostasis of these organelles and the propagation of Ca(2+) signals initiated by the release of Ca(2+) from acidic stores. Intracellular MCS also regulate the efficiency of phagocytosis, a fundamental cellular process essential for immunity and tissue homeostasis, by ensuring the coordinated opening of Ca(2+) channels on phagocytic vacuoles and of Ca(2+) release channels on juxtaposed ER stores. In this chapter, we review the current knowledge on the molecular composition and architecture of membrane contact sites that sustain Ca(2+) signals at the plasma membrane and in intracellular organelles.