Cytosolic Ca²⁺ has long been known to act as a key second messenger in many intracellular pathways including synaptic transmission, muscle contraction, hormonal secretion, and cell growth and proliferation.^1,2 The mechanism controlling the influx of intracellular Ca²⁺ either by calcium-release-activated Ca²⁺ channels (CRAC) or from intracellular stores has lately become of great interest.

Recently, several key players of the store-operated complex have been identified.³ The Orai family consists of three members, Orai1-3, and the STIM family, which consists of two members, STIM1 and STIM2. Orai1 (also known as CRACM1) acts as the store-operated calcium channel (SOC) and STIM1 as the endoplasmic reticulum (ER) Ca²⁺ sensor.^3,4 The majority of STIM1 appears to be localized intracellularly at the ER membrane while low expression of STIM1 has been detected on the cell surface of several cell types.⁵ STIM1 has an amino-terminal EF hand Ca²⁺ binding domain facing the lumen of the ER.⁶ Upon Ca²⁺ store depletion, STIM1 molecules are redistributed in punctae underneath the plasma membrane and activate SOCs.

Several possible interactions between STIM1 and Orai1 have been suggested. The most simple and cited is a dynamic interaction between the cytosolic C-terminus of STIM1 and the cytoplasmic domain of the Orai1 channel.^7-9 STIM1 is assumed to regulate the activity of all known SOCs, including native SOCs.⁵ Consistent with their important role as calcium sensors within the ER, STIM1 proteins are ubiquitously expressed.