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

doi:10.1038/s41467-019-09593-0

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 journal › Article › peer-review

73 Scopus citations

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 language	English (US)
Article number	1971
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09593-0
State	Published - Dec 1 2019

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-019-09593-0

Cite this

Zhang, X., Pathak, T., Yoast, R., Emrich, S., Xin, P., Nwokonko, R. M., Johnson, M., Wu, S., Delierneux, C., Gueguinou, M., Hempel, N., Putney, J. W., Gill, D. L., & Trebak, M. (2019). A calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction. Nature communications, 10(1), Article 1971. https://doi.org/10.1038/s41467-019-09593-0

@article{79d987df5c594ecf97f1ce794e179943,

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

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",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-09593-0",

language = "English (US)",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - A calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction

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

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85065059599&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065059599&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-09593-0

DO - 10.1038/s41467-019-09593-0

M3 - Article

C2 - 31036819

AN - SCOPUS:85065059599

SN - 2041-1723

VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1971

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this