STIM and Orai: the long-awaited constituents of store-operated calcium entry

Rapid changes in cytosolic Ca2+ concentrations [Ca2+]i are the most commonly used signals in biology to regulate a whole host of cellular functions including contraction, secretion and gene activation. A widely utilized form of Ca2+ influx is termed store-operated Ca2+ entry (SOCE) owing to its control by the Ca2+ content of the endoplasmic reticulum (ER). The underlying molecular mechanism of SOCE has eluded identification until recently when two groups of proteins, the ER Ca2+ sensors stromal interaction molecule (STIM)1 and STIM2 and the plasma-membrane channels Orai1, Orai2 and Orai3, have been identified. These landmark discoveries have enabled impressive progress in clarifying how these proteins work in concert and what developmental and cellular processes require their participation most. As we begin to better understand the biology of the STIM and Orai proteins, the attention to the pharmacological tools to influence their functions quickly follow suit. Here, we briefly summarize recent developments in this exciting area of Ca2+ signaling.