Abstract
Calcium (Ca2+) 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 Ca2+ entry (SOCE) by CRAC channels represents a major pathway for Ca2+ entry in non-excitable cells. The CRAC channel has two key components, the endoplasmic reticulum Ca2+ sensor stromal interaction molecule (STIM) and the plasma-membrane Ca2+ channel Orai. Physical coupling between STIM and Orai opens the CRAC channel and the resulting Ca2+ flux is regulated by a negative feedback mechanism of slow Ca2+ 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 Ca2+ signaling in cells.
Highlights
The results showed that when STIM1 was targeted to PtdIns(4,5)P2-rich domains, it interacted with SOCE-associated regulatory factor (SARAF) and was sensitive to slow Ca2+ dependent inactivation (SCDI) but not when it was targeted to domains poor with PtdIns(4,5)P2
The discovery of SARAF and its role in regulation of calcium release-activated calcium (CRAC) channel function constitutes a step forward in this direction. It enabled a first examination of the role of SCDI in vivo and confirmed that SCDI plays a protective role against Ca2+ -induced cellular toxicity [76] or pathological tissue remodeling [117,137]
In some tissues, the role of SARAF appears to extend beyond its contribution to SCDI [77,120], calling for further examination of the function of SARAF in additional tissues and under different physiological and pathophysiological states
Summary
The cytosolic-facing part of STIM1 contains multiple functional and regulatory domains, including the STIM1-Orai activation region (SOAR [35], referred to as CAD [36]), a short segment that is both necessary and sufficient for binding and gating the Orai channel. These conformational changes liberate a lipid-binding region at the C-terminus, allowing STIM1 multimers to interact with plasma membrane phospholipids and accumulate at ER-PM contact sites [6,23,39,40,41] At these active sites, STIM1 binds to and gates Orai channels to elicit Ca2+ influx into cells.
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