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

Cell Rep. 2021 Mar 2;34(9):108760. doi: 10.1016/j.celrep.2021.108760.


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.

Keywords: CRAC channels; IP(3)R; NFAT; Orai; SOCE; STIM; calcium entry; calcium oscillations; calcium signaling.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling* / drug effects
  • Carbachol / pharmacology
  • HEK293 Cells
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Membrane Potentials
  • Models, Biological
  • Muscarinic Agonists / pharmacology
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism
  • Neoplasm Proteins / agonists
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • ORAI1 Protein / genetics
  • ORAI1 Protein / metabolism*
  • ORAI2 Protein / genetics
  • ORAI2 Protein / metabolism*
  • Protein Binding
  • Receptor Cross-Talk
  • Stromal Interaction Molecule 1 / agonists
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism*
  • Stromal Interaction Molecule 2 / agonists
  • Stromal Interaction Molecule 2 / genetics
  • Stromal Interaction Molecule 2 / metabolism*
  • Time Factors


  • Calcium Channels
  • Inositol 1,4,5-Trisphosphate Receptors
  • Muscarinic Agonists
  • NFATC Transcription Factors
  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • ORAI2 Protein
  • ORAI2 protein, human
  • Orai3 protein, human
  • STIM1 protein, human
  • STIM2 protein, human
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2
  • Carbachol