ORAI1 constitutes the store-operated Ca release-activated Ca (CRAC) channel crucial for life. Whereas ORAI1 activation by Ca-sensing STIM proteins is known, still obscure is how ORAI1 is turned off through Ca-dependent inactivation (CDI), protecting against Ca toxicity. Here we identify a spatially-restricted Ca/cAMP signaling crosstalk critical for mediating CDI. Binding of Ca-activated adenylyl cyclase 8 (AC8) to the N-terminus of ORAI1 positions AC8 near the mouth of ORAI1 for sensing Ca. Ca 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 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 signals and NFAT activation.
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| http://dx.doi.org/10.1038/s41467-019-09593-0 | DOI Listing |
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