Capacitative Ca2+ entry links the emptying of intracellular Ca2+ stores to the activation of store-operated Ca2+ channels in the plasma membrane. In the twenty years since the inception of the concept of capacitative Ca2+ entry, a number of activation mechanisms have been proposed, and there has been considerable interest in the possibility that TRP channels function as store-operated channels. However, in the past two years, two major players in both the signaling and permeation mechanisms for store-operated channels have been discovered: Stim1 and the Orai proteins. Stim1 is an endoplasmic reticulum Ca2+ sensor. It appears to act by redistributing within a small component of the endoplasmic reticulum, approaching the plasma membrane, but does not seem to translocate into the plasma membrane. Stim1 signals to plasma membrane Orai proteins, which constitute pore-forming subunits of store-operated channels.

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A major mechanism whereby calcium entry into cells is regulated is the store-operated or capacitative calcium entry pathway. In this article, two basic issues are discussed: (i) the methods investigators use to measure store-operated entry, and (ii) the role played by the store-operated pathway in responses to hormones and neurotransmitters under physiological conditions. The two topics are considered together because they are closely interrelated; as we begin to ask questions about calcium movements at low concentrations of agonists, the technology to measure these movements becomes increasing challenging.