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

Author

Listed:
  • Xuexin Zhang

    (The Pennsylvania State University College of Medicine)

  • Trayambak Pathak

    (The Pennsylvania State University College of Medicine)

  • Ryan Yoast

    (The Pennsylvania State University College of Medicine)

  • Scott Emrich

    (The Pennsylvania State University College of Medicine)

  • Ping Xin

    (The Pennsylvania State University College of Medicine)

  • Robert M. Nwokonko

    (The Pennsylvania State University College of Medicine)

  • Martin Johnson

    (The Pennsylvania State University College of Medicine)

  • Shilan Wu

    (National Institutes of Health)

  • Céline Delierneux

    (The Pennsylvania State University College of Medicine)

  • Maxime Gueguinou

    (The Pennsylvania State University College of Medicine)

  • Nadine Hempel

    (The Pennsylvania State University College of Medicine)

  • James W. Putney

    (National Institutes of Health)

  • Donald L. Gill

    (The Pennsylvania State University College of Medicine)

  • Mohamed Trebak

    (The Pennsylvania State University College of Medicine)

Abstract

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.

Suggested Citation

  • 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 & Dona, 2019. "A calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09593-0
    DOI: 10.1038/s41467-019-09593-0
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