Capacitative calcium entry: from concept to molecules

Rapid to moderately rapid changes in intracellular Ca2+ concentration, or Ca2+ signals, control a variety of critical cellular functions in the immune system. These signals are comprised of Ca2+ release from intracellular stores coordinated with Ca2+ influx across the plasma membrane. The most common mechanisms by which these two modes of signaling occur is through inositol 1,4,5-trisphosphate (IP3)-induced release of Ca2+ from the endoplasmic reticulum (ER) and store-operated Ca2+ entry across the plasma membrane. The latter process was postulated over 20 years ago, and in just the past few years, the key molecular players have been discovered: STIM proteins serve as sensors of Ca2+ within the ER which communicate with and activate plasma membrane store-operated channels composed of Orai subunits. The process of store-operated Ca2+ entry provides support for oscillating Ca2+ signals from the ER and also provides direct activator Ca2+ that signals to a variety of downstream effectors.