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ORAI1 constitutes the store-operated Ca
2+
release-activated Ca
2+
(CRAC) channel crucial for life. Whereas ORAI1 activation by Ca
2+
-sensing STIM proteins is known, still obscure is how ORAI1 is turned off through Ca
2+
-dependent inactivation (CDI), protecting against Ca
2+
toxicity. Here we identify a spatially-restricted Ca
2+
/cAMP signaling crosstalk critical for mediating CDI. Binding of Ca
2+
-activated adenylyl cyclase 8 (AC8) to the N-terminus of ORAI1 positions AC8 near the mouth of ORAI1 for sensing Ca
2+
. Ca
2+
permeating ORAI1 activates AC8 to generate cAMP and activate PKA. PKA, positioned by AKAP79 near ORAI1, phosphorylates serine-34 in ORAI1 pore extension to induce CDI whereas recruitment of the phosphatase calcineurin antagonizes the effect of PKA. Notably, CDI shapes ORAI1 cytosolic Ca
2+
signature to determine the isoform and degree of NFAT activation. Thus, we uncover a mechanism of ORAI1 inactivation, and reveal a hitherto unappreciated role for inactivation in shaping cellular Ca
2+
signals and NFAT activation.
ORAI1 constitutes the store-operated Ca
2+
release-activated Ca
2+
(CRAC) channel, but how this channel is turned off through Ca
2+
-dependent inactivation (CDI) remained unclear. Here the authors identify a spatially-restricted Ca
2+
/cAMP signaling crosstalk critical for mediating CDI which in turn regulates cellular Ca
2+
signals and NFAT activation.