Omnitemporal choreographies of all five STIM/Orai and IP3Rs underlie the complexity of mammalian Ca2+ signaling

Scott M. Emrich, Ryan E. Yoast, Ping Xin, Vikas Arige, Larry E. Wagner, Nadine Hempel, Donald L. Gill, James Sneyd, David I. Yule, Mohamed Trebak

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Stromal-interaction molecules (STIM1/2) sense endoplasmic reticulum (ER) Ca2+ depletion and activate Orai channels. However, the choreography of interactions between native STIM/Orai proteins under physiological agonist stimulation is unknown. We show that the five STIM1/2 and Orai1/2/3 proteins are non-redundant and function together to ensure the graded diversity of mammalian Ca2+ signaling. Physiological Ca2+ signaling requires functional interactions between STIM1/2, Orai1/2/3, and IP3Rs, ensuring that receptor-mediated Ca2+ release is tailored to Ca2+ entry and nuclear factor of activated T cells (NFAT) activation. The N-terminal Ca2+-binding ER-luminal domains of unactivated STIM1/2 inhibit IP3R-evoked Ca2+ release. A gradual increase in agonist intensity and STIM1/2 activation relieves IP3R inhibition. Concomitantly, activated STIM1/2 C termini differentially interact with Orai1/2/3 as agonist intensity increases. Thus, coordinated and omnitemporal functions of all five STIM/Orai and IP3Rs translate the strength of agonist stimulation to precise levels of Ca2+ signaling and NFAT induction, ensuring the fidelity of complex mammalian Ca2+ signaling. Ca2+ signals are crucial for cell function. Emrich et al. show that the five store-operated STIM/Orai proteins are non-redundant. Physiological store-operated channel activities are omnitemporal choreographies of all five STIM1/2 and Orai1/2/3 proteins and their functional interactions with IP3Rs, ensuring the fidelity and diversity of Ca2+ signaling and NFAT activation.

Original languageEnglish (US)
Article number108760
JournalCell Reports
Issue number9
StatePublished - Mar 2 2021

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology


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