Calcium signals mediated by STIM and Orai proteins-A new paradigm in inter-organelle communication

In all cells Ca²⁺ signals are key to controlling a spectrum of cellular responses. Ca²⁺ signals activated by phospholipase C-coupled receptors have two components-rapid Ca²⁺ release from ER stores followed by slower Ca²⁺ entry from outside the cell. The coupling process between ER and PM to mediate this "store-operated" Ca²⁺ entry process has remained a molecular and mechanistic mystery. Through a combination of high throughput screening and molecular physiological approaches, the machinery and mechanism of this process have been elucidated. Two proteins are key to the coupling process. STIM1, a single spanning membrane protein with an unpaired Ca²⁺ binding EF-hand functions as the sensor of ER luminal Ca²⁺ and through redistribution in the ER transduces information directly to the PM. Orai1, a tetra-spanning PM protein, functions as the highly Ca²⁺ selective channel in the PM that is gated through interactions with the store-activated ER Ca²⁺ sensor. This molecular pas-de-deux between ER and PM components represents not only a crucial signaling pathway, but also a new paradigm in inter-organelle communication.