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

Xuexin Zhang, Trayambak Pathak, Ryan Yoast, Scott Emrich, Ping Xin, Robert M. Nwokonko, Martin Johnson, Shilan Wu, Céline Delierneux, Maxime Gueguinou, Nadine Hempel, James W. Putney, Donald L. Gill, Mohamed Trebak

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


ORAI1 constitutes the store-operated Ca2+ release-activated Ca2+ (CRAC) channel crucial for life. Whereas ORAI1 activation by Ca2+-sensing STIM proteins is known, still obscure is how ORAI1 is turned off through Ca2+-dependent inactivation (CDI), protecting against Ca2+ toxicity. Here we identify a spatially-restricted Ca2+/cAMP signaling crosstalk critical for mediating CDI. Binding of Ca2+-activated adenylyl cyclase 8 (AC8) to the N-terminus of ORAI1 positions AC8 near the mouth of ORAI1 for sensing Ca2+. Ca2+ 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 Ca2+ 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 Ca2+ signals and NFAT activation.

Original languageEnglish (US)
Article number1971
JournalNature communications
Issue number1
StatePublished - Dec 1 2019

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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