Modulation of Orai1 and STIM1 by Cellular Factors

This chapter focuses on the identified molecules regulating the function of Orai1 and STIM1. α-SNAP was identified as a cytosolic factor that interacts with both Orai1 and STIM1. Depletion of SARAF increased intracellular Ca²⁺ concentration and enhanced SOCE after store depletion, whereas its overexpression showed an opposite effect. As demonstrated by STIM1, protein interactions broadly regulate gating, Ca²⁺ selectivity, intracellular localization, and clustering of Orai1. Protein interactions are not only important for CRAC channel regulation but also essential for activation of signaling pathways downstream of Orai1. Machaca and colleagues used Xenopus oocyte as a model and showed that during meiosis, SOCE is inactivated due to internalization of Orai1 into an intracellular vesicular compartment and inhibition of STIM1 clustering. An isoform of the secretory pathway Ca²⁺ ATPase, SPCA2, was shown to enhance mammary tumor cell growth by raising [Ca²⁺]i via a direct interaction with the N and C termini of Orai1 in a STIM1 and store-independent manner.