A calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction

• Published in: Nature communications Vol. 10; no. 1; pp. 1971 - 13
• Main Authors: Zhang, Xuexin, Pathak, Trayambak, Yoast, Ryan, Emrich, Scott, Xin, Ping, Nwokonko, Robert M., Johnson, Martin, Wu, Shilan, Delierneux, Céline, Gueguinou, Maxime, Hempel, Nadine, Putney, James W., Gill, Donald L., Trebak, Mohamed
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.04.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/95; 14/19; 14/34; 631/57; 631/80/86/1999; 631/80/86/2372; 82/29; 82/80; 9/74; 96/1; 96/106; 96/109; 96/33; A Kinase Anchor Proteins - metabolism; Activation; Binding sites; Blotting, Western; Calcineurin; Calcium; Calcium - metabolism; Calcium channels; Calcium ions; Calcium signalling; Cellular Biology; Crosstalk; Cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Cytomegalovirus; Deactivation; HEK293 Cells; Humanities and Social Sciences; Humans; Inactivation; Kinases; Life Sciences; multidisciplinary; N-Terminus; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; NF-AT protein; Orai1 protein; ORAI1 Protein - genetics; ORAI1 Protein - metabolism; Phosphatase; Phosphorylation; Physiology; Protein kinase A; Proteins; Science; Science (multidisciplinary); Serine; Signal transduction; Stromal Interaction Molecule 1 - genetics; Stromal Interaction Molecule 1 - metabolism; Stromal Interaction Molecule 2 - genetics; Stromal Interaction Molecule 2 - metabolism; Toxicity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09593-0

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.