SARAF Inactivates the Store Operated Calcium Entry Machinery to Prevent Excess Calcium Refilling

Abstract

Store operated calcium entry (SOCE) is a principal cellular process by which cells regulate basal calcium, refill intracellular Ca(2+) stores, and execute a wide range of specialized activities. STIM and Orai proteins have been identified as the essential components enabling the reconstitution of Ca(2+) release-activated Ca(2+) (CRAC) channels that mediate SOCE. Here, we report the molecular identification of SARAF as a negative regulator of SOCE. Using heterologous expression, RNAi-mediated silencing and site directed mutagenesis combined with electrophysiological, biochemical and imaging techniques we show that SARAF is an endoplasmic reticulum membrane resident protein that associates with STIM to facilitate slow Ca(2+)-dependent inactivation of SOCE. SARAF plays a key role in shaping cytosolic Ca(2+) signals and determining the content of the major intracellular Ca(2+) stores, a role that is likely to be important in protecting cells from Ca(2+) overfilling.

Calcium/calmodulin‐dependent protein kinase II regulates cyclooxygenase‐2 expression and prostaglandin E2 production by activating cAMP‐response element‐binding protein in rat peritoneal macrophages

“…In [40][41][42][43][44][45][46] In contrast to LPS, PMA induced the transient increase of [Ca 2+ ] i , which appeared after 10 min of treatment. So far, we still cannot fully explain this; it would be a good project to work on in the future.…”

Potentiation of the store-operated calcium entry (SOCE) induces phytohemagglutinin-activated Jurkat T cell apoptosis

“…TRPC1 [57], CRACR2A [58], SARAF [59] and junctate [60]. Thus, the SOCE channel molecular nature is not restricted only to Orai1 proteins, and SOCE studies should be performed with "complete" SOCE channels.…”

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

“…While Stim1 ΔEC mice displayed normal baseline characteristics up to 8 weeks, future studies are necessary to understand the role of STIM1 in aging, cardiovascular, and chronic lung diseases. Although Orai channels are the major STIM targets, new information reveals the additional STIM/Orai complex regulators including POST, junctate, SARAF, and CRACR2A (19,(63)(64)(65)(66) could also be considered as potential therapeutic targets. Importantly, therapeutic strategies targeting the Ca 2+ signaling machinery have great advantage over antioxidant-based strategies, since they do not interfere with the microbicidal role of ROS.…”