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 journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1971
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Calcium Signaling
mouth
deactivation
Mouth
calcium
induction
Chemical activation
Calcium
activation
Crosstalk
Serine
Toxicity
Protein Isoforms
permeating
phosphatases
crosstalk
toxicity
adenylyl cyclase 8
Proteins
signatures

All Science Journal Classification (ASJC) codes

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

Cite this

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. / A calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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.",
author = "Xuexin Zhang and Trayambak Pathak and Ryan Yoast and Scott Emrich and Ping Xin and Nwokonko, {Robert M.} and Martin Johnson and Shilan Wu and C{\'e}line Delierneux and Maxime Gueguinou and Nadine Hempel and Putney, {James W.} and Gill, {Donald L.} and Mohamed Trebak",
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Zhang, X, Pathak, T, Yoast, R, Emrich, S, Xin, P, Nwokonko, RM, Johnson, M, Wu, S, Delierneux, C, Gueguinou, M, Hempel, N, Putney, JW, Gill, DL & Trebak, M 2019, 'A calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction', Nature communications, vol. 10, no. 1, 1971. https://doi.org/10.1038/s41467-019-09593-0

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

In: Nature communications, Vol. 10, No. 1, 1971, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Zhang, Xuexin

AU - Pathak, Trayambak

AU - Yoast, Ryan

AU - Emrich, Scott

AU - Xin, Ping

AU - Nwokonko, Robert M.

AU - Johnson, Martin

AU - Wu, Shilan

AU - Delierneux, Céline

AU - Gueguinou, Maxime

AU - Hempel, Nadine

AU - Putney, James W.

AU - Gill, Donald L.

AU - Trebak, Mohamed

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