Regulation of Store-Operated Ca(2+) Entry by SARAF

Calcium (Ca(2+)) signaling plays a dichotomous role in cellular biology, controlling cell survival and proliferation on the one hand and cellular toxicity and cell death on the other. Store-operated Ca(2+) entry (SOCE) by CRAC channels represents a major pathway for Ca(2+) entry in non-excitable cells. The CRAC channel has two key components, the endoplasmic reticulum Ca(2+) sensor stromal interaction molecule (STIM) and the plasma-membrane Ca(2+) channel Orai. Physical coupling between STIM and Orai opens the CRAC channel and the resulting Ca(2+) flux is regulated by a negative feedback mechanism of slow Ca(2+) dependent inactivation (SCDI). The identification of the SOCE-associated regulatory factor (SARAF) and investigations of its role in SCDI have led to new functional and molecular insights into how SOCE is controlled. In this review, we provide an overview of the functional and molecular mechanisms underlying SCDI and discuss how the interaction between SARAF, STIM1, and Orai1 shapes Ca(2+) signaling in cells.