Omnitemporal choreographies of all five STIM/Orai and IP ₃Rs underlie the complexity of mammalian Ca ²⁺ signaling

SUMMARY

Stromal-interaction molecules (STIM1/2) sense endoplasmic reticulum (ER) Ca ²⁺ 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 Ca ²⁺ signaling. Physiological Ca ²⁺ signaling requires functional interactions between STIM1/2, Orai1/2/3, and IP ₃Rs, ensuring that receptor-mediated Ca ²⁺ release is tailored to Ca ²⁺ entry and nuclear factor of activated T cells (NFAT) activation. The N-terminal Ca ²⁺-binding ER-luminal domains of unactivated STIM1/2 inhibit IP ₃R-evoked Ca ²⁺ release. A gradual increase in agonist intensity and STIM1/2 activation relieves IP ₃R 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 IP ₃Rs translate the strength of agonist stimulation to precise levels of Ca ²⁺ signaling and NFAT induction, ensuring the fidelity of complex mammalian Ca ²⁺ signaling.

Graphical Abstract

In brief

Ca ²⁺ 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 IP ₃Rs, ensuring the fidelity and diversity of Ca ²⁺ signaling and NFAT activation.