Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

STIM proteins: dynamic calcium signal transducers

Nature Reviews Molecular Cell Biology volume 13, pages 549–565 (2012)Cite this article

Subjects

Key Points

  • Stromal interaction molecule (STIM) proteins are dynamic sensors of Ca2+ stored within the endoplasmic reticulum (ER) and are triggered by Ca2+ store depletion to self-activate, aggregate and translocate to discrete ER-plasma membrane junctional domains. There STIM proteins attach to the plasma membrane and tether and activate the highly Ca2+ selective Orai family of plasma membrane Ca2+ entry channels.

  • The amino-terminal ER-luminal segments of STIM proteins are the Ca2+ sensing domains by virtue of specific EF-hand domain Ca2+ binding sites,which are highly tuned to detect small changes in luminal Ca2+ levels. The detection of decreased luminal Ca2+ concentrations triggers a conformational change that leads to aggregation and translocation of STIM proteins.

  • Cytoplasmic carboxy-terminal STIM protein domains contain a uniquely configured group of α-helical sequences that form an activating domain able to bind to and gate the Orai channel in the plasma membrane. The helical domains can both mediate and regulate the Orai channel-coupling process.

  • The STIM-induced ER-plasma membrane junctional domains contain a number of important regulatory proteins including CRAC regulatory protein 2A (CRACR2A), junctate, store-operated Ca2+ entry (SOCE)-associated regulatory factor (SARAF), golli and partner of STIM1 (POST). These proteins turn on and off the coupling between STIM proteins and the Ca2+ signalling target proteins that function within junctions.

  • New information reveals STIM proteins as sensors not only of decreased ER Ca2+ but also of oxidative stress, temperature increases, hypoxic stress and acidosis. STIM proteins also target proteins other than Orai channels, including voltage-operated CaV1.2 channels, transient receptor potential channels (TRPCs) and plasma membrane Ca2+ ATPase (PMCA) and SERCA Ca2+ pumps.

  • The function of STIM proteins is to generate long-term spatially discrete Ca2+ entry signals that specifically turn on transcriptional events. The triggered Ca2+ entry also replenishes stores, and this is required to maintain Ca2+ oscillations and to protect the integrity of the ER from potentially damaging decreases in ER Ca2+ levels that could compromise the protein trafficking and assembly functions of ER.

Abstract

Stromal interaction molecule (STIM) proteins function in cells as dynamic coordinators of cellular calcium (Ca2+) signals. Spanning the endoplasmic reticulum (ER) membrane, they sense tiny changes in the levels of Ca2+ stored within the ER lumen. As ER Ca2+ is released to generate primary Ca2+ signals, STIM proteins undergo an intricate activation reaction and rapidly translocate into junctions formed between the ER and the plasma membrane. There, STIM proteins tether and activate the highly Ca2+-selective Orai channels to mediate finely controlled Ca2+ signals and to homeostatically balance cellular Ca2+. Details are emerging on the remarkable organization within these STIM-induced junctional microdomains and the identification of new regulators and alternative target proteins for STIM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure and activation of STIM1.
Figure 2: STIM activation and organization of the Ca2+ signalling junction.
Figure 3: STIM proteins control gene expression by generating spatiotemporally controlled Ca2+ signals.

Similar content being viewed by others

References

  1. Roos, J. et al. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J. Cell Biol. 169, 435–445 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liou, J. et al. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 15, 1235–1241 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179–185 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang, S. L. et al. Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity. Proc. Natl Acad. Sci. USA 103, 9357–9362 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ringer, S. A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart. J. Physiol. 4, 29–42 (1883).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bohr, D. F. Vascular smooth muscle updated. Circ. Res. 32, 665–672 (1973).

    Article  CAS  PubMed  Google Scholar 

  8. Putney, J. W. A model for receptor-regulated calcium entry. Cell Calcium 7, 1–12 (1986).

    Article  CAS  PubMed  Google Scholar 

  9. Streb, H., Irvine, R. F., Berridge, M. J. & Schulz, I. Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 306, 67–69 (1983).

    Article  CAS  PubMed  Google Scholar 

  10. Takemura, H. & Putney, J. W. Jr. Capacitative calcium entry in parotid acinar cells. Biochem. J. 258, 409–412 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Muallem, S., Khademazad, M. & Sachs, G. The route of Ca2+ entry during reloading of the intracellular Ca2+ pool in pancreatic acini. J. Biol. Chem. 265, 2011–2016 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Takemura, H., Hughes, A. R., Thastrup, O. & Putney, J. W. Activation of calcium entry by the tumor promoter thapsigargin in parotid acinar cells. Evidence that an intracellular calcium pool and not an inositol phosphate regulates calcium fluxes at the plasma membrane. J. Biol. Chem. 264, 12266–12271 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Putney, J. W. Capacitative calcium entry revisited. Cell Calcium 11, 611–624 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Lewis, R. S. & Cahalan, M. D. Mitogen-induced oscillations of cytosolic Ca2+ and transmembrane Ca2+ current in human leukemic T cells. Cell Regul. 1, 99–112 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Penner, R., Matthews, G. & Neher, E. Regulation of calcium influx by second messengers in rat mast cells. Nature 334, 499–504 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Hoth, M. & Penner, R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355, 353–356 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Berridge, M. J. Capacitative calcium entry. Biochem. J. 312, 1–11 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Patterson, R. L., van Rossum, D. B. & Gill, D. L. Store operated Ca2+ entry: evidence for a secretion-like coupling model. Cell 98, 487–499 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Yao, Y., Ferrer-Montiel, A. V., Montal, M. & Tsien, R. Y. Activation of store-operated Ca2+ current in Xenopus oocytes requires SNAP-25 but not a diffusible messenger. Cell 98, 475–485 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. McCarl, C. A. et al. ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia. J. Allergy Clin. Immunol. 124, 1311–1318 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Picard, C. et al. STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N. Engl. J. Med. 360, 1971–1980 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Strange, K., Yan, X., Lorin-Nebel, C. & Xing, J. Physiological roles of STIM1 and Orai1 homologs and CRAC channels in the genetic model organism Caenorhabditis elegans. Cell Calcium 42, 193–203 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Collins, S. R. & Meyer, T. Evolutionary origins of STIM1 and STIM2 within ancient Ca2+ signaling systems. Trends Cell Biol. 21, 202–211 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Williams, R. T. et al. Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem. J. 357, 673–685 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Oh-Hora, M. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nature Immunol. 9, 432–443 (2008). An important study examining the roles of both STIM1 and STIM2 in mediating Ca2+ entry in T cells and fibroblasts and revealing the roles of STIM proteins in the development and function of regulatory T cells.

    Article  CAS  Google Scholar 

  26. Berna-Erro, A. et al. STIM2 regulates capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death. Sci. Signal. 2, ra67 (2009).

    Article  PubMed  Google Scholar 

  27. Bandyopadhyay, B. C., Pingle, S. C. & Ahern, G. P. Store-operated Ca2+ signaling in dendritic cells occurs independently of STIM1. J. Leukoc. Biol. 89, 57–62 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Deng, X., Wang, Y., Zhou, Y., Soboloff, J. & Gill, D. L. STIM and Orai-dynamic intermembrane coupling to control cellular calcium signals. J. Biol. Chem. 284, 22501–22505 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Manji, S. S. et al. STIM1: a novel phosphoprotein located at the cell surface. Biochim. Biophys. Acta 1481, 147–155 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Soboloff, J. et al. STIM2 is an inhibitor of STIM1-mediated store-operated Ca2+ entry. Curr. Biol. 16, 1465–1470 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Hewavitharana, T. et al. Location and function of STIM1 in the activation of Ca2+ entry signals. J. Biol. Chem. 283, 26252–26262 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lewis, R. S. The molecular choreography of a store-operated calcium channel. Nature 446, 284–287 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Liou, J., Fivaz, M., Inoue, T. & Meyer, T. Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc. Natl Acad. Sci. USA 104, 9301–9306 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wu, M. M., Buchanan, J., Luik, R. M. & Lewis, R. S. Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J. Cell Biol. 174, 803–813 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Baba, Y. et al. Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 103, 16704–16709 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Penna, A. et al. The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456, 116–120 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Covington, E. D., Wu, M. M. & Lewis, R. S. Essential role for the CRAC activation domain in store-dependent oligomerization of STIM1. Mol. Biol. Cell 21, 1897–1907 (2010). Reveals that the active domain within STIM1 that interacts with and triggers Orai channel opening is also involved in STIM1 oligomerization, which is the initial event promoted by store-depletion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li, Z. et al. Graded activation of CRAC channel by binding of different numbers of STIM1 to Orai1 subunits. Cell Res. 21, 305–315 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Hoover, P. J. & Lewis, R. S. Stoichiometric requirements for trapping and gating of Ca2+ release-activated Ca2+ (CRAC) channels by stromal interaction molecule 1 (STIM1). Proc. Natl Acad. Sci. USA 108, 13299–13304 (2011). Examines the stoichiometry of interaction between STIM and Orai proteins, indicating that eight STIM1 molecules interact with a single Orai channel comprising four Orai subunits.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang, X., Jin, H., Cai, X., Li, S. & Shen, Y. Structural and mechanistic insights into the activation of stromal interaction molecule 1 (STIM1). Proc. Natl Acad. Sci. USA 109, 5657–5662 (2012). The first atomic structure of SOAR, which is the active site within the C-terminal domain of STIM1, derived from X-ray analysis of a crystallized form of the STIM1 fragment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stathopulos, P. B., Li, G. Y., Plevin, M. J., Ames, J. B. & Ikura, M. Stored Ca2+ depletion-induced oligomerization of STIM1 via the EF-SAM region: an initiation mechanism for capacitive Ca2+ entry. J. Biol. Chem. 281, 35855–35862 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Stathopulos, P. B., Zheng, L., Li, G. Y., Plevin, M. J. & Ikura, M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 135, 110–122 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, S. L. et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437, 902–905 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Luik, R. M., Wang, B., Prakriya, M., Wu, M. M. & Lewis, R. S. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454, 538–542 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yuan, J. P. et al. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nature Cell Biol. 11, 337–343 (2009). Identifies SOAR as the active site of STIM1 that interacts with and triggers the opening of Orai channels.

    Article  CAS  PubMed  Google Scholar 

  46. Park, C. Y. et al. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136, 876–890 (2009). A detailed study revealing that the STIM1 segment CAD is the Orai coupling site and providing a detailed characterization of the molecular nature of the STIM–Orai interaction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Muik, M. et al. A cytosolic homomerization and a modulatory domain within STIM1 C-terminus determine coupling to ORAI1 channels. J. Biol. Chem. 284, 8421–8426 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Oritani, K. & Kincade, P. W. Identification of stromal cell products that interact with pre-B cells. J. Cell Biol. 134, 771–782 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Hauser, C. T. & Tsien, R. Y. A hexahistidine-Zn2+-dye label reveals STIM1 surface exposure. Proc. Natl Acad. Sci. USA 104, 3693–3697 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li, Z. et al. Mapping the interacting domains of STIM1 and Orai1 in CRAC channel activation. J. Biol. Chem. 282, 29448–29456 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Zheng, L., Stathopulos, P. B., Li, G. Y. & Ikura, M. Biophysical characterization of the EF-hand and SAM domain containing Ca2+ sensory region of STIM1 and STIM2. Biochem. Biophys. Res. Commun. 369, 240–246 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Stathopulos, P. B., Zheng, L. & Ikura, M. Stromal interaction molecule (STIM)1 and STIM2 EF-SAM regions exhibit distinct unfolding and oligomerization kinetics. J. Biol. Chem. 284, 728–732 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Zheng, L. et al. Auto-inhibitory role of the EF-SAM domain of STIM proteins in store-operated calcium entry. Proc. Natl Acad. Sci. USA 108, 1337–1342 (2011). Nuclear magnetic resonance (NMR)-based structural approaches revealing that the EF-hand–SAM domains of STIM1 and STIM2 may have distinct stabilization properties that could explain important differences in SOCE mediated by each protein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Williams, R. T. et al. Stromal interaction molecule 1 (STIM1), a transmembrane protein with growth suppressor activity, contains an extracellular SAM domain modified by N-linked glycosylation. Biochim. Biophys. Acta 1596, 131–137 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Smyth, J. T., Dehaven, W. I., Bird, G. S. & Putney, J. W. Jr Ca2+-store-dependent and -independent reversal of Stim1 localization and function. J. Cell Sci. 121, 762–772 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Muik, M. et al. Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J. Biol. Chem. 283, 8014–8022 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Brandman, O., Liou, J., Park, W. S. & Meyer, T. STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131, 1327–1339 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Carrasco, S. & Meyer, T. STIM proteins and the endoplasmic reticulum-plasma membrane junctions. Annu. Rev. Biochem. 80, 973–1000 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Spassova, M. A. et al. STIM1 has a plasma membrane role in the activation of store-operated Ca2+ channels. Proc. Natl Acad. Sci. USA 103, 4040–4045 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bird, G. S. et al. STIM1 is a calcium sensor specialized for digital signaling. Curr. Biol. 19, 1724–1729 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Soboloff, J., Spassova, M. A., Dziadek, M. A. & Gill, D. L. Calcium signals mediated by STIM and Orai proteins — a new paradigm in inter-organelle communication. Biochim. Biophys. Acta 1763, 1161–1168 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Saitoh, N. et al. Identification of functional domains and novel binding partners of STIM proteins. J. Cell Biochem. 112, 147–156 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Parvez, S. et al. STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. FASEB J. 22, 752–761 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Zhou, Y. et al. The short N-terminal domains of STIM1 and STIM2 control the activation kinetics of Orai1 channels. J. Biol. Chem. 284, 19164–19168 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Soboloff, J. et al. Orai1 and STIM reconstitute store-operated calcium channel function. J. Biol. Chem. 281, 20661–20665 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Wang, Y. et al. STIM protein coupling in the activation of Orai channels. Proc. Natl Acad. Sci. USA 106, 7391–7396 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kar, P., Bakowski, D., Di Capite, J., Nelson, C. & Parekh, A. B. Different agonists recruit different stromal interaction molecule proteins to support cytoplasmic Ca2+ oscillations and gene expression. Proc. Natl Acad. Sci. USA 109, 6969–6974 (2012). Reveals interesting differences in the ability of STIM1 and STIM2 to mediate Ca2+ entry in response to different PLC-coupled receptors and Ca2+ oscillations that lead to the activation of gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Korzeniowski, M. K., Manjarres, I. M., Varnai, P. & Balla, T. Activation of STIM1-Orai1 involves an intramolecular switching mechanism. Sci. Signal. 3, ra82 (2010). Provides information on the interactive sites in STIM1 and Orai1 that are involved in an electrostatic interaction and proposes an intramolecular switch to maintain STIM1 in an inactive state.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhou, Y. et al. STIM1 gates the store-operated calcium channel ORAI1 in vitro. Nature Struct. Mol. Biol. 17, 112–116 (2010).

    Article  CAS  Google Scholar 

  70. Calloway, N., Vig, M., Kinet, J. P., Holowka, D. & Baird, B. Molecular clustering of STIM1 with Orai1/CRACM1 at the plasma membrane depends dynamically on depletion of Ca2+ stores and on electrostatic interactions. Mol. Biol. Cell 20, 389–399 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Calloway, N., Holowka, D. & Baird, B. A basic sequence in STIM1 promotes Ca2+ influx by interacting with the C-terminal acidic coiled coil of Orai1. Biochemistry 49, 1067–1071 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Frischauf, I. et al. Molecular determinants of the coupling between STIM1 and Orai channels: differential activation of Orai1–3 channels by a STIM1 coiled-coil mutant. J. Biol. Chem. 284, 21696–21706 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lis, A., Zierler, S., Peinelt, C., Fleig, A. & Penner, R. A single lysine in the N-terminal region of store-operated channels is critical for STIM1-mediated gating. J. Gen. Physiol. 136, 673–686 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Muik, M. et al. STIM1 couples to ORAI1 via an intramolecular transition into an extended conformation. EMBO J. 30, 1678–1689 (2011). Reveals by using FRET technology that a segment of the STIM1 C-terminal domain containing the active site undergoes an important intramolecular transition into an extended conformation upon interaction with Orai.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Huang, G. N. et al. STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nature Cell Biol. 8, 1003–1010 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Kim, J. Y. & Muallem, S. Unlocking SOAR releases STIM. EMBO J. 30, 1673–1675 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yu, F., Sun, L., Courjaret, R. & Machaca, K. Role of the STIM1 C-terminal domain in STIM1 clustering. J. Biol. Chem. 286, 8375–8384 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. McNally, B. A., Somasundaram, A., Yamashita, M. & Prakriya, M. Gated regulation of CRAC channel ion selectivity by STIM1. Nature 482, 241–245 (2012). An important study revealing the intimate control mediated by STIM1on Orai1channels and revealing that STIM1 functions similar to a channel subunit controlling both gating and the pore properties of the Orai1 channel.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Korzeniowski, M. K. et al. Dependence of STIM1/Orai1-mediated calcium entry on plasma membrane phosphoinositides. J. Biol. Chem. 284, 21027–21035 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Luik, R. M., Wu, M. M., Buchanan, J. & Lewis, R. S. The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J. Cell Biol. 174, 815–825 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Treves, S. et al. Junctate is a key element in calcium entry induced by activation of InsP3 receptors and/or calcium store depletion. J. Cell Biol. 166, 537–548 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Treves, S. et al. Agonist-activated Ca2+ influx occurs at stable plasma membrane and endoplasmic reticulum junctions. J. Cell Sci. 123, 4170–4181 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Srikanth, S. et al. Junctate is a Ca2+-sensing structural component of Orai1 and stromal interaction molecule 1 (STIM1). Proc. Natl Acad. Sci. USA 109, 8682–8687 (2012). Identifies the ER protein junctate as a luminal Ca2+-sensing component within ER–plasma membrane junctions and shows that junctate mediates and controls recruitment of STIM1 into junctions to activate Orai channels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Edwards, J. N., Blackmore, D. G., Gilbert, D. F., Murphy, R. M. & Launikonis, B. S. Store-operated calcium entry remains fully functional in aged mouse skeletal muscle despite a decline in STIM1 protein expression. Aging Cell 10, 675–685 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Stiber, J. A. & Rosenberg, P. B. The role of store-operated calcium influx in skeletal muscle signaling. Cell Calcium 49, 341–349 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Darbellay, B., Arnaudeau, S., Bader, C. R., Konig, S. & Bernheim, L. STIM1L is a new actin-binding splice variant involved in fast repetitive Ca2+ release. J. Cell Biol. 194, 335–346 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Srikanth, S. et al. A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that stabilizes CRAC channels in T cells. Nature Cell Biol. 12, 436–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Palty, R., Raveh, A., Kamisky, I., Meller, R. & Reuveny, E. SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling. Cell 149, 425–438 (2012). Screening approaches that reveal the ER protein SARAF as a potentially important negative regulator of STIM protein function and indicate that SARAF may have an important function in limiting Ca2+ signals in cells.

    Article  CAS  PubMed  Google Scholar 

  89. Mullins, F. M., Park, C. Y., Dolmetsch, R. E. & Lewis, R. S. STIM1 and calmodulin interact with Orai1 to induce Ca2+-dependent inactivation of CRAC channels. Proc. Natl Acad. Sci. USA 106, 15495–15500 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hoth, M. & Penner, R. Calcium release-activated calcium current in rat mast cells. J. Physiol. 465, 359–386 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zweifach, A. & Lewis, R. S. Rapid inactivation of depletion-activated calcium current (ICRAC) due to local calcium feedback. J. Gen. Physiol. 105, 209–226 (1995).

    Article  CAS  PubMed  Google Scholar 

  92. Derler, I. et al. A Ca2+ release-activated Ca2+ (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca2+-dependent inactivation of ORAI1 channels. J. Biol. Chem. 284, 24933–24938 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee, K. P. et al. Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels. Proc. Natl Acad. Sci. USA 106, 14687–14692 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Litjens, T., Harland, M. L., Roberts, M. L., Barritt, G. J. & Rychkov, G. Y. Fast Ca2+-dependent inactivation of the store-operated Ca2+ current (ISOC) in liver cells: a role for calmodulin. J. Physiol. 558, 85–97 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Shen, W. W., Frieden, M. & Demaurex, N. Local cytosolic Ca2+ elevations are required for stromal interaction molecule 1 (STIM1) de-oligomerization and termination of store-operated Ca2+ entry. J. Biol. Chem. 286, 36448–36459 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Feng, J. M. et al. Golli protein negatively regulates store depletion-induced calcium influx in T cells. Immunity 24, 717–727 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Fulton, D. et al. Regulation of L-type Ca++ currents and process morphology in white matter oligodendrocyte precursor cells by golli-myelin proteins. Glia 58, 1292–1303 (2010).

    Article  PubMed  Google Scholar 

  98. Walsh, C. M., Doherty, M. K., Tepikin, A. V. & Burgoyne, R. D. Evidence for an interaction between Golli and STIM1 in store-operated calcium entry. Biochem. J. 430, 453–460 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. Soboloff, J., Madesh, M. & Gill, D. L. Sensing cellular stress through STIM proteins. Nature Chem. Biol. 7, 488–492 (2011). Provides current information on the role of STIM proteins in sensing and mediating responses to oxidative-, temperature- and hypoxic stress conditions.

    Article  CAS  Google Scholar 

  100. Hawkins, B. J. et al. S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. J. Cell Biol. 190, 391–405 (2010). Describes that STIM1 can sense ROS, couple to and activate Orai channels within ER–plasma membrane junctions without store deletion through glutathionylation of a specific N-terminal Cys residue.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Xiao, B., Coste, B., Mathur, J. & Patapoutian, A. Temperature-dependent STIM1 activation induces Ca2+ influx and modulates gene expression. Nature Chem. Biol. 7, 351–358 (2011). Interesting study indicating that STIM1 becomes activated by modest increases in temperature, but that coupling to Orai channels requires cooling. These findings suggest that STIM1 is an important temperature sensor.

    Article  CAS  Google Scholar 

  102. Mancarella, S., Wang, Y. & Gill, D. L. Signal transduction: STIM1 senses both Ca2+ and heat. Nature Chem. Biol. 7, 344–345 (2011).

    Article  CAS  Google Scholar 

  103. Mancarella, S. et al. Hypoxia-induced acidosis uncouples the STIM–Orai calcium signaling complex. J. Biol. Chem. 286, 44788–44798 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gillo, B. et al. Coexpression of Drosophila TRP and TRP-like proteins in Xenopus oocytes reconstitutes capacitative Ca2+ entry. Proc. Natl Acad. Sci. USA 93, 14146–14151 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Xu, X. Z., Li, H. S., Guggino, W. B. & Montell, C. Coassembly of TRP and TRPL produces a distinct store-operated conductance. Cell 89, 1155–1164 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Kiselyov, K. I. et al. Functional interaction between InsP3 receptors and store-operated Htrp3 channels. Nature 396, 478–482 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Yuan, J. P., Zeng, W., Huang, G. N., Worley, P. F. & Muallem, S. STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nature Cell Biol. 9, 636–645 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Zeng, W. et al. STIM1 gates TRPC channels but not Orai1 by electrostatic interaction. Mol.Cell 32, 439–448 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lee, K. P., Yuan, J. P., So, I., Worley, P. F. & Muallem, S. STIM1-dependent and STIM1-independent function of transient receptor potential canonical (TRPC) channels tunes their store-operated mode. J. Biol. Chem. 285, 38666–38673 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Varga-Szabo, D. et al. Store-operated Ca2+ entry in platelets occurs independently of transient receptor potential (TRP) C1. Pflügers. Arch. 457, 377–387 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Dehaven, W. et al. TRPC channels function independently of STIM1 and Orai1. J. Physiol. 587, 2275–2298 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wang, Y. et al. The calcium store-sensor, STIM1, reciprocally controls Orai and CaV1.2 channels. Science 330, 105–109 (2010). Describes how STIM proteins interact with and mediate control over the function of voltage-operated Ca V 1.2 channels within the same ER–plasma membrane junctional regions in which STIM proteins interact with Orai channels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cheng, K. T., Liu, X., Ong, H. L., Swaim, W. & Ambudkar, I. S. Local Ca2+ entry via Orai1 regulates plasma membrane recruitment of TRPC1 and controls cytosolic Ca2+ signals required for specific cell functions. PLoS Biol. 9, e1001025 (2011).

  114. Park, C. Y., Shcheglovitov, A. & Dolmetsch, R. The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels. Science 330, 101–105 (2010). Shows the molecular nature of the interactions between STIM1 and Ca V 1.2 channels and describes how these interactions lead to both inhibition of function and increased turnover and downregulation of Ca V 1.2 channels.

    Article  CAS  PubMed  Google Scholar 

  115. Woodard, G. E., Salido, G. M. & Rosado, J. A. Enhanced exocytotic-like insertion of Orai1 into the plasma membrane upon intracellular Ca2+ store depletion. Am. J. Physiol. Cell Physiol. 294, C1323–C1331 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Yu, F., Sun, L. & Machaca, K. Orai1 internalization and STIM1 clustering inhibition modulate SOCE inactivation during meiosis. Proc. Natl Acad. Sci. USA 106, 17401–17406 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mignen, O., Thompson, J. L. & Shuttleworth, T. J. STIM1 regulates Ca2+ entry via arachidonate-regulated Ca2+-selective (ARC) channels without store depletion or translocation to the plasma membrane. J. Physiol. 579, 703–715 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Mignen, O., Thompson, J. L. & Shuttleworth, T. J. Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels. J. Physiol. 586, 185–195 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Mignen, O., Thompson, J. L. & Shuttleworth, T. J. The molecular architecture of the arachidonate-regulated Ca2+-selective ARC channel is a pentameric assembly of Orai1 and Orai3 subunits. J. Physiol. 587, 4181–4197 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Jousset, H., Frieden, M. & Demaurex, N. STIM1 knockdown reveals that store-operated Ca2+ channels located close to SERCA pumps silently refill the endoplasmic reticulum. J. Biol. Chem. 282, 11456–11464 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Sampieri, A., Zepeda, A., Asanov, A. & Vaca, L. Visualizing the store-operated channel complex assembly in real time: dentification of SERCA2 as a new member. Cell Calcium 45, 439–146 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Manjarres, I. M., Rodriguez-Garcia, A., Alonso, M. T. & Garcia-Sancho, J. The sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) is the third element in capacitative calcium entry. Cell Calcium 47, 412–418 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Manjarres, I. M., Alonso, M. T. & Garcia-Sancho, J. Calcium entry-calcium refilling (CECR) coupling between store-operated Ca2+ entry and sarco/endoplasmic reticulum Ca2+-ATPase. Cell Calcium 49, 153–161 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Bautista, D. M. & Lewis, R. S. Modulation of plasma membrane calcium-ATPase activity by local calcium microdomains near CRAC channels in human T cells. J. Physiol. 556, 805–817 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Quintana, A. et al. Calcium microdomains at the immunological synapse: how ORAI channels, mitochondria and calcium pumps generate local calcium signals for efficient T-cell activation. EMBO J. 30, 3895–3912 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ritchie, M. F., Samakai, E. & Soboloff, J. STIM1 is required for attenuation of PMCA-mediated Ca2+ clearance during T-cell activation. EMBO J. 31, 1123–1133 (2012). Shows both functional and physical interactions between STIM1 and PMCA with important implications on the generation of Ca2+ signals in many cell types.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Krapivinsky, G., Krapivinsky, L., Stotz, S. C., Manasian, Y. & Clapham, D. E. POST, partner of stromal interaction molecule 1 (STIM1), targets STIM1 to multiple transporters. Proc. Natl Acad. Sci. USA 108, 19234–19239 (2011). The work identifies POST as a membrane protein present in both the ER and plasma membrane that moves with STIM1 into junctions upon store depletion and mediates interactions with important proteins including Ca2+ pumps.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Liu, B., Peel, S. E., Fox, J. & Hall, I. P. Reverse mode Na+/Ca2+ exchange mediated by STIM1 contributes to Ca2+ influx in airway smooth muscle following agonist stimulation. Respir. Res. 11, 168 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Prins, D., Groenendyk, J., Touret, N. & Michalak, M. Modulation of STIM1 and capacitative Ca2+ entry by the endoplasmic reticulum luminal oxidoreductase ERp57. EMBO Rep. 12, 1182–1188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lefkimmiatis, K. et al. Store-operated cyclic AMP signalling mediated by STIM1. Nature Cell Biol. 11, 433–442 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Berridge, M. J., Bootman, M. D. & Roderick, H. L. Calcium signalling: dynamics, homeostasis and remodelling. Nature Rev. Mol. Cell Biol. 4, 517–529 (2003).

    Article  CAS  Google Scholar 

  132. Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C. & Healy, J. I. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855–858 (1997).

    Article  CAS  PubMed  Google Scholar 

  133. Berridge, M. J. Inositol trisphosphate and calcium oscillations. Biochem. Soc. Symp. 74, 1–7 (2007).

    Article  CAS  Google Scholar 

  134. Putney, J. W. & Bird, G. S. Cytoplasmic calcium oscillations and store-operated calcium influx. J. Physiol. 586, 3055–3059 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Matsumoto, M. et al. The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. Immunity 34, 703–714 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Di Capite, J., Ng, S. W. & Parekh, A. B. Decoding of cytoplasmic Ca2+ oscillations through the spatial signature drives gene expression. Curr. Biol. 19, 853–858 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Mancarella, S., Wang, Y. & Gill, D. L. Calcium signals: STIM dynamics mediate spatially unique oscillations. Curr. Biol. 19, R950–R952 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bird, G. S. & Putney, J. W. Jr. Capacitative calcium entry supports calcium oscillations in human embryonic kidney cells. J. Physiol. 562, 697–706 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Kar, P., Nelson, C. & Parekh, A. B. Selective activation of the transcription factor NFAT1 by calcium microdomains near Ca2+ release-activated Ca2+ (CRAC) channels. J. Biol. Chem. 286, 14795–14803 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kar, P., Nelson, C. & Parekh, A. B. C. R.A. C. Channels drive digital activation and provide analog control and synergy to Ca2+-dependent gene regulation. Curr. Biol. 22, 242–247 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. Loh, C. et al. Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity. J. Biol. Chem. 271, 10884–10891 (1996).

    Article  CAS  PubMed  Google Scholar 

  142. Gwack, Y., Feske, S. Srikanth, S., Hogan, P. G. & Rao, A. Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. Cell Calcium 42, 145–156 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Li, H. et al. Balanced interactions of calcineurin with AKAP79 regulate Ca2+–calcineurin–NFAT signaling. Nature Struct. Mol. Biol. 19, 337–345 (2012).

    Article  CAS  Google Scholar 

  144. Wu, X. et al. Plasma membrane Ca2+-ATPase isoform 4 antagonizes cardiac hypertrophy in association with calcineurin inhibition in rodents. J. Clin. Invest. 119, 976–985 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Kiviluoto, S. et al. STIM1 as a key regulator for Ca2+ homeostasis in skeletal-muscle development and function. Skelet. Muscle 1, 16 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Seth, M. et al. Dynamic regulation of sarcoplasmic reticulum Ca(2+) stores by stromal interaction molecule 1 and sarcolipin during muscle differentiation. Dev. Dyn. 241, 639–647 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Hulot, J. S. et al. Critical role for stromal interaction molecule 1 in cardiac hypertrophy. Circulation 124, 796–805 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhang, W. et al. Orai1-mediated I (CRAC) is essential for neointima formation after vascular injury. Circ. Res. 109, 534–542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Berridge, M. J., Lipp, P. & Bootman, M. D. The versatility and universality of calcium signalling. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000).

    Article  CAS  Google Scholar 

  150. Zou, J. J., Gao, Y. D., Geng, S. & Yang, J. Role of STIM1/Orai1-mediated store-operated Ca2+ entry in airway smooth muscle cell proliferation. J. Appl. Physiol. 110, 1256–1263 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Mungai, P. T. et al. Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol. Cell. Biol. 31, 3531–3545 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Balghi, H. et al. Enhanced Ca2+ entry due to Orai1 plasma membrane insertion increases IL-8 secretion by cystic fibrosis airways. FASEB J. 25, 4274–4291 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Li, J. et al. Orai1 and CRAC channel dependence of VEGF-activated Ca2+ entry and endothelial tube formation. Circ. Res. 108, 1190–1198 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Ohba, T. et al. Essential role of STIM1 in the development of cardiomyocyte hypertrophy. Biochem. Biophys. Res. Commun. 389, 172–176 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. Voelkers, M. et al. Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes. J. Mol. Cell Cardiol 48, 1329–1334 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Jones, B. F., Boyles, R. R., Hwang, S. Y., Bird, G. S. & Putney, J. W. Calcium influx mechanisms underlying calcium oscillations in rat hepatocytes. Hepatology 48, 1273–1281 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Aromataris, E. C., Castro, J., Rychkov, G. Y. & Barritt, G. J. Store-operated Ca2+ channels and stromal interaction molecule 1 (STIM1) are targets for the actions of bile acids on liver cells. Biochim. Biophys. Acta 1783, 874–885 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Sours-Brothers, S., Ding, M., Graham, S. & Ma, R. Interaction between TRPC1/TRPC4 assembly and STIM1 contributes to store-operated Ca2+ entry in mesangial cells. Exp. Biol. Med. 234, 673–682 (2009).

    Article  CAS  Google Scholar 

  159. Yan, X. et al. Function of a STIM1 homologue in C. elegans: evidence that store-operated Ca2+ entry is not essential for oscillatory Ca2+ signaling and ER Ca2+ homeostasis. J. Gen. Physiol. 128, 443–459 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Gomez-Fernandez, C., Lopez-Guerrero, A. M., Pozo-Guisado, E., Alvarez, I. S. & Martin-Romero, F. J. Calcium signalling in mouse oocyte maturation: the roles of STIM1, ORAI1 and SOCE. Mol. Hum. Reprod. 18, 194–203 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Hwang, S. Y. & Putney, J. W. Orai1-mediated calcium entry plays a critical role in osteoclast differentiation and function by regulating activation of the transcription factor NFATc1. FASEB J. 26, 1484–1492 (2011).

    Article  PubMed  CAS  Google Scholar 

  162. Zhou, Y. et al. The role of calcium release activated calcium channels in osteoclast differentiation. J. Cell Physiol. 226, 1082–1089 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Robinson, L. J. et al. Gene disruption of the calcium channel Orai1 results in inhibition of osteoclast and osteoblast differentiation and impairs skeletal development. Lab. Invest. 92, 1071–1083 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lyfenko, A. D. & Dirksen, R. T. Differential dependence of store-operated and excitation-coupled Ca2+ entry in skeletal muscle on STIM1 and Orai1. J. Physiol. 586, 4815–4824 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Stiber, J. et al. STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle. Nature Cell Biol. 10, 688–697 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Darbellay, B. et al. Human muscle economy myoblast differentiation and excitation-contraction coupling use the same molecular partners, STIM1 and STIM2. J. Biol. Chem. 285, 22437–22447 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Venkiteswaran, G. & Hasan, G. Intracellular Ca2+ signaling and store-operated Ca2+ entry are required in Drosophila neurons for flight. Proc. Natl Acad. Sci. USA 106, 10326–10331 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. McAndrew, D. et al. ORAI1-mediated calcium influx in lactation and in breast cancer. Mol. Cancer Ther. 10, 448–460 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Yang, S., Zhang, J. J. & Huang, X. Y. Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell 15, 124–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  170. Feng, M. et al. Store-independent activation of Orai1 by SPCA2 in mammary tumors. Cell 143, 84–98 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Motiani, R. K., Abdullaev, I. F. & Trebak, M. A novel native store-operated calcium channel encoded by Orai3: selective requirement of Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells. J. Biol. Chem. 285, 19173–19183 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Faouzi, M. et al. Down-regulation of Orai3 arrests cell-cycle progression and induces apoptosis in breast cancer cells but not in normal breast epithelial cells. J. Cell Physiol. 226, 542–551 (2011).

    Article  CAS  PubMed  Google Scholar 

  173. Lur, G. et al. Ribosome-free terminals of rough ER allow formation of STIM1 puncta and segregation of STIM1 from IP3 receptors. Curr. Biol. 19, 1648–1653 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Lur, G. et al. InsP3 receptors and Orai channels in pancreatic acinar cells: co-localization and its consequences. Biochem. J. 436, 231–239 (2011).

    Article  CAS  PubMed  Google Scholar 

  175. Tamarina, N. A., Kuznetsov, A. & Philipson, L. H. Reversible translocation of EYFP-tagged STIM1 is coupled to calcium influx in insulin secreting β-cells. Cell Calcium 44, 533–544 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Roy, J., Lefkimmiatis, K., Moyer, M. P., Curci, S. & Hofer, A. M. The-ω3 fatty acid eicosapentaenoic acid elicits cAMP generation in colonic epithelial cells via a 'store-operated' mechanism. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G715–G722 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Ma, J., McCarl, C. A., Khalil, S., Luthy, K. & Feske, S. T-cell-specific deletion of STIM1 and STIM2 protects mice from EAE by impairing the effector functions of Th1 and Th17 cells. Eur. J. Immunol. 40, 3028–3042 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Limnander, A. et al. STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nature Immunol. 12, 425–433 (2011).

    Article  CAS  Google Scholar 

  179. Baba, Y. et al. Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses. Nature Immunol. 9, 81–88 (2008).

    Article  CAS  Google Scholar 

  180. Vig, M. et al. Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels. Nature Immunol. 9, 89–96 (2007).

    Article  CAS  Google Scholar 

  181. Grosse, J. et al. An. EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice. J. Clin. Invest. 117, 3540–3550 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Varga-Szabo, D. et al. The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J. Exp. Med. 205, 1583–1591 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Gilio, K. et al. Roles of platelet STIM1 and Orai1 in glycoprotein VI- and thrombin-dependent procoagulant activity and thrombus formation. J. Biol. Chem. 285, 23629–23638 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Braun, A. et al. Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation. Blood 26, 2056–2063 (2008).

    Google Scholar 

  185. Steinckwich, N., Schenten, V., Melchior, C., Brechard, S. & Tschirhart, E. J. An essential role of STIM1, Orai1, and S100A8-A9 proteins for Ca2+ signaling and FcγR-mediated phagosomal oxidative activity. J. Immunol. 186, 2182–2191 (2011).

    Article  CAS  PubMed  Google Scholar 

  186. Wang, Y., Lin, L. & Zheng, C. Downregulation of the expression of Orai1 in the airway alleviates murine allergic rhinitis. Exp. Mol. Med. 31, 177–190 (2011).

    Google Scholar 

  187. Braun, A. et al. STIM1 is essential for Fcγ receptor activation and autoimmune inflammation. Blood 21 Oct 2008 (doi:10.1182/blood-2008-05-158477).

    Article  PubMed  CAS  Google Scholar 

  188. Cole, C., Barber, J. D. & Barton, G. J. The Jpred 3 secondary structure prediction server. Nucleic Acids Res. 36, W197–W201 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Yue, C., Soboloff, J. & Gamero, A. M. Control of type I interferon-induced cell seath by Orai1-mediated calcium entry in T cells. J. Biol. Chem. 287, 3207–3216 (2012).

    Article  CAS  PubMed  Google Scholar 

  190. Ritchie, M. F., Zhou, Y. & Soboloff, J. Transcriptional mechanisms regulating Ca2+ homeostasis. Cell Calcium 49, 314–321 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. Ritchie, M. F., Yue, C., Zhou, Y., Houghton, P. J. & Soboloff, J. Wilms tumor suppressor 1 (WT1) and early growth response 1 (EGR1) are regulators of STIM1 expression. J. Biol. Chem. 285, 10591–10596 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Eylenstein, A. et al. Transcription factor NF-κB regulates expression of pore-forming Ca2+ channel unit, Orai1, and its activator, STIM1, to control Ca2+ entry and affect cellular functions. J. Biol. Chem. 287, 2719–2730 (2012).

    Article  CAS  PubMed  Google Scholar 

  193. Partiseti, M. et al. The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency. J. Biol. Chem. 269, 32327–32335 (1994).

    Article  CAS  PubMed  Google Scholar 

  194. Fanger, C. M., Hoth, M., Crabtree, G. R. & Lewis, R. S. Characterization of T cell mutants with defects in capacitative calcium entry: genetic evidence for the physiological roles of CRAC channels. J. Cell Biol. 131, 655–667 (1995).

    Article  CAS  PubMed  Google Scholar 

  195. Peinelt, C. et al. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nature Cell Biol. 8, 771–773 (2006).

    Article  CAS  PubMed  Google Scholar 

  196. Mercer, J. C. et al. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J. Biol. Chem. 281, 24979–24990 (2006).

    Article  CAS  PubMed  Google Scholar 

  197. Prakriya, M. et al. Orai1 is an essential pore subunit of the CRAC channel. Nature 443, 230–233 (2006).

    Article  CAS  PubMed  Google Scholar 

  198. Yeromin, A. V. et al. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443, 226–229 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Vig, M. et al. CRACM1 Multimers Form the Ion-Selective Pore of the CRAC Channel. Curr. Biol. 16, 2073–2079 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants AI058173 (to D.L.G.), GM097335 (to J.S.), HL109920 (to M.M. and J.S.), HL086699 (to M.M.) and GM068523(to B.S.R.).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, 19140, Pennsylvania, USA

    Jonathan Soboloff, Brad S. Rothberg, Muniswamy Madesh & Donald L. Gill

Authors
  1. Jonathan Soboloff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brad S. Rothberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muniswamy Madesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Donald L. Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Donald L. Gill.

Ethics declarations

Competing interests

Donald L. Gill has a collaborative research grant from Novartis Institutes for Biomedical Research. Jonathan Soboloff, Brad S. Rothberg and Muniswamy Madesh declare no competing financial interests.

Supplementary information

41580_2012_BFnrm3414_MOESM2_ESM.pdf

Supplementary information S1 (Figure) | Sequence alignment of stromal interaction molecule1 (STIM1) and STIM2. (PDF 502 kb)

Related links

Related links

FURTHER INFORMATION

Temple University School of Medicine Department of Biochemistry

Glossary

Ca2+ signalling

The process through which spatially and temporally controlled changes in Ca2+ levels are induced in response to external and/or internal cellular activation events.

Stromal interaction molecule

(STIM). The Ca2+ sensing endoplasmic reticulum (ER) transmembrane protein that becomes activated upon decrease of ER luminal Ca2+. Higher eukaryotes contain two similar proteins, STIM1 and STIM2. STIM2 is exclusively expressed in the ER, whereas ∼5–10% of STIM1 is located in the plasma membrane. Activated STIM proteins translocate into ER–plasma membrane junctions where they activate plasma membrane Orai Ca2+ channels.

Ca2+ homeostasis

The process of global Ca2+ maintenance within the entire cell and/or sub-compartments therein. The term refers to the regulation of Ca2+ within cells through the operation of all Ca2+ pumps, channels, binding proteins and other regulatory proteins within every cellular compartment, including the cytosol, endoplasmic reticulum, mitochondria, Golgi apparatus and endolysosomal system.

Endoplasmic reticulum

(ER). The extensive subcellular tubular network that has crucial roles in lipid and protein synthesis and serves also as the major Ca2+ storage organelle.

Orai channels

A family of plasma membrane Ca2+ entry channels comprising three mammalian homologues termed Orai1, Orai2 and Orai3. Orai proteins have four transmembrane domains and form tetrameric channels. Orai1 tetramers are the pore-forming units of Ca2+ release-activated Ca2+ (CRAC) channels, gated by stromal interaction molecule (STIM) proteins. Orai2 and Orai3 can also form STIM-responsive channels, although the physiological roles of these proteins are less clear.

Capacitative Ca2+ entry

This term was introduced to describe the activation of Ca2+ entry across the plasma membrane in response to the depletion of Ca2+ levels in the endoplasmic reticulum. Currently known as store-operated Ca2+ entry (SOCE).

Inositol-1,4,5-trisphosphate

(Ins(1,4,5)P3). A product derived from breakdown of phosphatidylinositol-4,5-bisphosphate by phospholipase C. It functions as a cytosolic second messenger by binding to Ins(1,4,5)P3 receptors, which are located on the endoplasmic reticulum membrane and operate as ER Ca2+ release channels.

Store-operated Ca2+ entry

(SOCE). The activation of a Ca2+ channel in the plasma membrane in response to the depletion of Ca2+ levels in the endoplasmic reticulum. Formerly known as capacitative Ca2+ entry.

Ca2+ release-activated Ca2+ current

(CRAC current or ICRAC). The electrophysiologically defined current mediated by the Orai family of channels.

Mast cells

Leukocyte cells with large secretory granules that contain histamine and various protein mediators. Mast cells contain an unusually high density of Ca2+ release-activated Ca2+ (CRAC) channels, which function to mediate mast cell activation.

EF-hand domains

Highly conserved Ca2+-binding domains comprising two helices (E and F after the 5th and 6th helices of parvalbumin) that are linked by a short acidic Ca2+-binding loop.

STIM–Orai activating region

(SOAR). A ∼100 amino acid segment within the cytosolic domain of stromal interaction molecule 1 (STIM1) that is the minimal sequence for mediating interaction with and activation of Orai channels.

Pre-B cells

Cells in a stage of B cell development in the bone marrow that are characterized by complete immunoglobulin heavy-chain rearrangement in the absence of immunoglobulin light-chain rearrangement. They express the pre-B cell receptor, which comprises a pseudo light chain and a heavy chain. Cells are phenotypically CD19+ cytoplasmic immunoglulin M+ (IgM+) or are sometimes defined as B220+ CD43− cell surface IgM− (which is known as the Hardy classification).

Hill coefficient

Quantifies the cooperativity of ligand binding by an allosteric protein and indicates the minimal number of interacting binding sites. A Hill coefficient of 1 indicates independent binding even when ligands are bound to different binding sites, and a coefficient of >1 reflects positive cooperativity.

Junctate

A Ca2+-binding, integral endoplasmic reticulum (ER) membrane protein that induces and/or stabilizes peripheral coupling between the ER and the plasma membrane.

Ca2+-dependent inactivation

(CDI). The process whereby an increase in cytosolic Ca2+ levels leads to inactivation of the Ca2+ release-activated Ca2+ (CRAC) current. CDI is mediated by residues located in stromal interaction molecule 1 (STIM1) (in the cytosolic domain) and Orai1 (within the amino terminus).

Inhibitory domain region

(ID region). A short sequence in the carboxy-terminal region of stromal interaction molecule 1 (STIM1) containing acidic residues that is important for mediating Ca2+-dependent inactivation of Orai channels.

Calmodulin

A highly conserved cytosolic Ca2+-binding protein that mediates several Ca2+-dependent responses in cells by interaction with and modification of calmodulin-binding target proteins. Calmodulin is expressed in all eukaryotic cell types.

CRAC regulatory protein 2A

(CRACR2A). A recently described stromal interaction molecule (STIM)–Orai-binding protein shown to regulate the stability of the Ca2+ signalling junction.

Golli

A member of the myelin basic protein (MBP) family that interacts with stromal interaction molecule 1 (STIM1) and regulates store operated Ca2+ entry (SOCE)

SOCE-associated regulatory factor

(SARAF). A recently defined stromal interaction molecule (STIM)-binding protein that mediates the dissociation of STIM proteins from Ca2+ signalling junctions.

Transient receptor potential channels

(TRPCs). A family of seven non-selective cation channels defined on the basis of homology with the Drosophila melanogaster TRP channel. TRPCs have been extensively investigated as potential mediators of store-operated Ca2+ entry (SOCE). However, this notion is highly controversial mainly because they are activated downstream of phospholipase C and mediate non-selective cation currents easily distinguishable from Ca2+ release-activated Ca2+(CRAC).

Phospholipase C

(PLC). A signalling enzyme that breaks down phosphatidylinositol-4,5-bisphosphate into inositol-1,4,5-trisphosphate and diacylglycerol in response to the activation of both G protein-coupled receptor and Tyr kinase-coupled receptor.

Diacylglycerol

(DAG). Lipid product of phospholipase C that activates and modulates the function of several proteins including various ion channels.

Phosphatidylinositol-4,5-bisphosphate

(PtdIns(4,5)P2). A negatively charged phospholipid found primarily in the inner leaflet of the plasma membrane. As the substrate for phospholipase C, PtdIns(4,5)P2 breakdown leads to the release of Ins(1,4,5)P3 and diacylglycerol.

ARC channel

An arachidonic acid-responsive channel activity comprising a unique combination of Orai1 and Orai3 subunits.

Sarcoendoplasmic reticulum Ca2+ ATPase

(SERCA). A family of Ca2+ pumps comprising three members, all of which pump Ca2+ from the cytosol into the endoplasmic reticulum (ER) or the sacroeplamic reticulum lumen. Each family member has several splice variants. Due to the leakiness of the ER to Ca2+, SERCA is constitutively active.

Aequorins

Ca2+-sensitive photoproteins isolated from luminescent jellyfish that are used to detect the Ca2+ content in different subcellular compartments.

Plasma membrane Ca2+ ATPase

(PMCA). A family of Ca2+ pumps comprising four members that pump Ca2+ from the cytosol to the extracellular milieu. Each family member has at least two splice variants. PMCA pumps primarily function to maintain cytosolic Ca2+ levels.

Immunological synapse

A region that can form between two cells of the immune system that are in close proximity. The name derives from similarities to the synapse that is found in the nervous system. The immunological synapse refers to the interaction between a T cell or natural killer cell and an antigen-presenting cell.

Partner of STIM1

(POST). A 12-transmembrane spanning protein found mostly in the endoplasmic reticulum membrane, but also in the plasma membrane. POST binds activated stromal interaction molecule 1 (STIM1) and modulates the function of multiple target proteins.

Calnexin

Ca2+-binding transmembrane endoplasmic reticulum chaperone protein that functions to support correct folding of new proteins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Soboloff, J., Rothberg, B., Madesh, M. et al. STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol 13, 549–565 (2012). https://doi.org/10.1038/nrm3414

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3414

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing