Ca²⁺ and lipid signals hold hands at endoplasmic reticulum-plasma membrane contact sites

Discovery of the STIM1 and Orai proteins as the principal components of store-operated Ca²⁺ entry has drawn attention to contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM). Such contacts between adjacent membranes of different cellular organelles, primarily between the mitochondria and the ER, had already been known as the sites where Ca²⁺ released from the ER can be efficiently channelled to the mitochondria and also where phosphatidylserine synthesis and transfer takes place. Recent studies have identified contact sites between virtually every organelle and the ER and the functional importance of these small specialized membrane domains is increasingly recognized. Most recent developments have highlighted the role of phosphatidylinositol 4-phosphate gradients as critical determinants of the non-vesicular transport of various lipids from the ER to other organelles such as the Golgi or PM. As we learn more about membrane contact sites it becomes apparent that Ca²⁺ is not only transported at these sites but also controls both the dynamics and the lipid transfer efficiency of these processes. Conversely, lipids are critical for regulating the Ca²⁺ entry process. This review will summarize some of the most exciting recent developments in this rapidly expanding research field.