STIM Proteins and the Endoplasmic Reticulum-Plasma Membrane Junctions

Eukaryotic organelles can interact with each other through stable junctions where the two membranes are kept in close apposition. The junction that connects the endoplasmic reticulum to the plasma membrane (ER-PM junction) is unique in providing a direct communication link between the ER and the PM. In a recently discovered signaling process, STIM (stromal-interacting molecule) proteins sense a drop in ER Ca²⁺ levels and directly activate Orai PM Ca²⁺ channels across the junction space. In an inverse process, a voltage-gated PM Ca²⁺ channel can directly open ER ryanodine-receptor Ca²⁺ channels in striated-muscle cells. Although ER-PM junctions were first described 50 years ago, their broad importance in Ca²⁺ signaling, as well as in the regulation of cholesterol and phosphatidylinositol lipid transfer, has only recently been realized. Here, we discuss research from different fields to provide a broad perspective on the structures and unique roles of ER-PM junctions in controlling signaling and metabolic processes.