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Store-operated CRAC channels: function in health and disease

Nature Reviews Drug Discovery volume 9, pages 399–410 (2010)Cite this article

Subjects

Key Points

  • A rise in cytoplasmic Ca2+ concentration acts as a universal intracellular messenger that drives numerous cellular responses.

  • In many cell types, a major route for Ca2+ influx is through store-operated Ca2+ release-activated Ca2+ (CRAC) channels in the plasma membrane. These ion channels are activated by the process of emptying the intracellular Ca2+ stores.

  • The molecular basis of this ubiquitous Ca2+ entry mechanism has recently been unravelled with the discoveries of stromal interaction molecule 1 (STIM1), a protein that senses the Ca2+ content of the stores, and ORAI1 (also known as CRACM1), which forms the CRAC channel pore.

  • Ca2+ entry through CRAC channels activates various temporally distinct responses, ranging from exocytosis to cell growth and proliferation.

  • Aberrant CRAC channel activity has been linked to several debilitating human diseases, including certain types of immunodeficiency and autoimmunity disorders, allergy, and inflammatory bowel disease.

  • Although in its early stages, drugs targeting the CRAC channel pathway are now being developed and should prove useful in treating a range of immune and non-immune disorders.

Abstract

Elevation of cytosolic Ca2+ levels through the activation of store-operated Ca2+ release-activated Ca2+ (CRAC) channels is involved in mediating a disparate array of cellular responses. These include secretion, metabolism and gene expression, as well as cell growth and proliferation. Moreover, emerging evidence points to the involvement of aberrant CRAC channel activity in human diseases, such as certain types of immunodeficiency and autoimmunity disorders, allergy, and inflammatory bowel disease. This article summarizes recent advances in understanding the gating and function of CRAC channels, their links to human disease and key issues for the development of channel blockers.

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Figure 1: Schematic of store-operated calcium entry.
Figure 2: Gating of Ca2+ release-activated Ca2+ (CRAC) channels.
Figure 3: Short-term and long-term responses activated by Ca2+ microdomains near Ca2+ release-activated Ca2+ (CRAC) channels.

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References

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

    CAS  Google Scholar 

  2. Clapham, D. E. Calcium Signaling. Cell 131, 1047–1058 (2008).

    Google Scholar 

  3. Rizzuto, R. et al. Calcium and apoptosis: facts and hypotheses. Oncogene 22, 8619–8627 (2003).

    CAS  PubMed  Google Scholar 

  4. Neher, E. Vesicle pools and Ca2+ microdomains: new tools for understanding their roles in neurotransmitter release. Neuron 20, 389–399 (1998). This is an authoritative description of how local Ca2+ signals arise and how they can be investigated.

    CAS  PubMed  Google Scholar 

  5. Rizzuto, R. & Pozzan, T. Microdomains of intracellular calcium: molecular determinants and functional consequences. Physiol. Rev. 86, 369–408 (2006). This provides an excellent overview of microdomains and their impact on physiological processes.

    CAS  PubMed  Google Scholar 

  6. Hille, B. Ionic Channels of Excitable Membranes 1–814 (Sinauer Associates, Sunderlan, Massachusetts, 2001).

    Google Scholar 

  7. Berridge, M. J. Inositol trisphosphate and calcium signalling. Nature 361, 315–325 (1993).

    CAS  PubMed  Google Scholar 

  8. Putney, J. W. J. A model for receptor-regulated calcium entry. Cell Calcium 7, 1–12 (1986). This visionary paper proposes the concept of store-operated Ca2+ entry.

    CAS  PubMed  Google Scholar 

  9. Hoth, M. & Penner, R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355, 353–356 (1992). This is the first description of the store-operated CRAC current.

    CAS  PubMed  Google Scholar 

  10. Zweifach, A. & Lewis, R. S. Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc. Natl Acad. Sci. USA 90, 6295–6299 (1993). This paper shows that CRAC channels have a tiny conductance and are activated by a physiological agonist.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Zweifach, A. & Lewis, R. S. Calcium-dependent potentiation of store-operated calcium channels in T lymphocytes. J. Gen. Physiol. 107, 597–610 (1996).

    CAS  PubMed  Google Scholar 

  13. Hoth, M. Calcium and barium permeation through calcium release-activated (CRAC) channels. Pflugers Arch. 430, 315–322 (1995).

    CAS  PubMed  Google Scholar 

  14. Fierro, L. & Parekh, A. B. Substantial depletion of the intracellular Ca2+ stores is required for macroscopic activation of the Ca2+ release-activated Ca2+ current in rat basophilic leukaemia cells. J. Physiol. 522, 247–257 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Bakowski, D. & Parekh, A. B. Monovalent cation permeability and Ca2+ block of the store-operated calcium current ICRAC in rat basophilic leukaemia cells. Pflugers Arch. 443, 892–902 (2002).

    CAS  PubMed  Google Scholar 

  16. Bakowski, D. & Parekh, A. B. Permeation through store-operated CRAC channels in divalent-free solution: potential problems and implications for putative CRAC channel genes. Cell Calcium 32, 379–391 (2002).

    CAS  PubMed  Google Scholar 

  17. Prakriya, M. & Lewis, R. S. Regulation of CRAC channel activity by recruitment of silent channels to a high open-probability gating mode. J. Gen. Physiol. 128, 373–386 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Yeromin, A. V., Roos, J., Stauderman, K. A. & D., C. M. A store-operated calcium channel in Drosophila S2 cells. J. Gen. Physiol. 123, 167–182 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Parekh, A. B. & Putney, J. W. J. Store-operated calcium channels. Physiol. Rev. 85, 757–810 (2005).

    CAS  PubMed  Google Scholar 

  21. Nilius, B., Owsianik, G., Voets, T. & Peters, J. A. Transient receptor potential cation channels in disease. Physiol. Rev. 87, 165–217 (2007).

    CAS  PubMed  Google Scholar 

  22. Clapham, D. E., Runnels, L. W. & Struebing, C. The TRP ion channel family. Nature Rev. Neurosci. 2, 387–396 (2002).

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Liou, J. et al. STIM is a calcium sensor essential for calcium-store-depletion-triggered calcium infux. Curr. Biol. 15, 1235–1241 (2005). References 23 and 24 identified the importance of STIM1 in store-operated Ca2+ entry.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cahalan, M. D. STIMulating store-operated Ca2+ entry. Nature Cell Biol. 11, 669–676 (2009).

    CAS  PubMed  Google Scholar 

  26. Dziadek, M. A. & Johnstone, L. S. Biochemical properties and cellular localisation of STIM1 proteins. Cell Calcium 42, 123–132 (2007).

    CAS  PubMed  Google Scholar 

  27. Spassova, M. A., Soboloff, J., He, L.-P., Dziadek, M. A. & Gill, D. L. STIM1 has a plasma membrane role in activation of store-operated calcium channels. Proc. Natl Acad. Sci. USA 103, 4040–4045 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    CAS  PubMed  Google Scholar 

  29. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 110, 110–122 (2008).

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Feske, S., Prakriya, M., Rao, A. & Lewis, R. S. A severe defect in CRAC calcium channel activation and altered potassium channel gating in T cells from immunodeficient patients. J. Exp. Med. 202, 651–662 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 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). References 33–35 show that ORAI1 is central for CRAC channel function.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang, J., Ellinor, P. T., Sather, W. A., Zhang, J. F. & Tsien, R. W. Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels. Nature 366, 158–161 (1993).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  38. Vig, M. et al. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr. Biol. 16, 2073–2079 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 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). References 37–39 demonstrated that ORAI1 forms the CRAC channel pore.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Parekh, A. B. A CRAC current tango. Nature Cell Biol. 8, 655–656 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  43. Akabas, M. H., Stauffer, D. A., Xu, M. & Karlin, A. Acetylcholine receptor channel structure probed in cysteine-substitution mutants. Science 258, 307–310 (1992).

    CAS  PubMed  Google Scholar 

  44. McNally, B. A., Yamashita, M., Engh, A. & Prakriya, M. Structural determinants of ion permeation in CRAC channels. Proc. Natl Acad. Sci. USA 106, 22516–22521 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Long, S. B., Tao, X., Campbell, E. B. & MacKinnon, R. Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450, 376–382 (2007).

    CAS  PubMed  Google Scholar 

  46. Gwack, Y. et al. Biochemical and functional characterization of Orai proteins. J. Biol. Chem. 282, 16232–16243 (2007).

    CAS  PubMed  Google Scholar 

  47. Lis, A. et al. CRACM1, CRACM2 and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr. Biol. 17, 794–800 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. DeHaven, W. I., Smyth, J. T., Boyles, R. R. & Putney, J. W. J. Calcium inhibition and calcium potentiation of Orai1, Orai2 and Orai3 calcium release-activated calcium channels. J. Biol. Chem. 282, 17548–17556 (2007).

    CAS  PubMed  Google Scholar 

  49. Gross, S. A. et al. Murine Orai2 splice variants form functional Ca2+ release-activated Ca2+ (CRAC) channels. J. Biol. Chem. 282, 19375–19384 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Bird, G. S. et al. STIM1 is a calcium sensor specialised for digital signalling. Curr. Biol. 19, 1724–1729 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 calcium store depletion. Proc. Natl Acad. Sci. USA 104, 9301–9306 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Varnai, P., Toth, B., Toth, D. J., Hunyady, L. & Balla, T. Visualization and manipulation of plasma membrane–endoplasmic reticulum contact sites indicates the presence of additional molecular components within the STIM1–Orai1 complex. J. Biol. Chem. 282, 29678–29689 (2007).

    CAS  PubMed  Google Scholar 

  55. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Park, C. Y. et al. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain of Orai1. Cell 136, 1–15 (2009).

    CAS  Google Scholar 

  57. Xu, P. et al. Aggregation of STIM1 underneath the plasma membrane induces clustering of Orai1. Biochem. Biophys. Res. Comm. 350, 969–976 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Yuan, J. P. et al. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nature Cell Biol. 11, 337–343 (2009).

    CAS  PubMed  Google Scholar 

  60. Kawasaki, T., Lange, I. & Feske, S. A minimal regulatory domain in the C terminus of STIM1 binds to and activates ORAi1 CRAC channels. Biochem. Biophys. Res. Comm. 385, 49–54 (2009). References 56 and 58–60 provide a molecular mechanism for CRAC channel gating.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Mignen, O., Thompson, J. L. & Shuttleworth, T. J. Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J. Physiol. 586, 419–425 (2008).

    CAS  PubMed  Google Scholar 

  63. Ji, W. et al. Functional stoichiometry of the unitary calcium release-activated calcium channel. Proc. Natl Acad. Sci. USA 105, 13668–13673 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Carafoli, E. Calcium signalling: a tale for all seasons. Proc. Natl Acad. Sci. USA 99, 1115–1122 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Michalak, M., Robert Parker, J. M. & Opas, M. Ca2+ signalling and calcium binding chaperones of the endoplasmic reticulum. Cell Calcium 32, 269–278 (2002).

    CAS  PubMed  Google Scholar 

  66. Parekh, A. B. Functional consequences of activating store-operated CRAC channels. Cell Calcium 42, 111–121 (2007).

    CAS  PubMed  Google Scholar 

  67. Parekh, A. B. Ca2+ microdomains near plasma membrane Ca2+ channels: impact on cell function. J. Physiol. 586, 3043–3054 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 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).

    CAS  PubMed  Google Scholar 

  69. Dolmetsch, R. E., Xu, K. & Lewis, R. S. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392, 933–936 (1998).

    CAS  PubMed  Google Scholar 

  70. Mogami, H., Nakano, K., Tepikin, A. V. & Petersen, O. H. Ca2+ flow via tunnels in polarized cells: recharging of apical Ca2+ stores by focal Ca2+ entry through basal membrane patch. Cell 88, 49–55 (1997).

    CAS  PubMed  Google Scholar 

  71. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Willoughby, D. & Cooper, D. M. F. Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Physiol. Rev. 87, 965–1010 (2007).

    CAS  PubMed  Google Scholar 

  73. Chang, W.-C., Nelson, C. & Parekh, A. B. Ca2+ influx through CRAC channels activates cytosolic phospholipase A2, leukotriene C4 secretion and expression of c-fos through ERK-dependent and independent pathways in mast cells. FASEB J. 20, E1681–E1693 (2006).

    Google Scholar 

  74. Peters-Golden, M., Gleason, M. M. & Togias, A. Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis. Clin. Exp. Allergy 36, 689–703 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Steinke, J. W. & Borish, L. Leukotriene receptors in rhinitis and sinusitis. Curr. Allergy Asthma Rep. 4, 217–223 (2004).

    PubMed  Google Scholar 

  76. Chang, W. C. & Parekh, A. B. Close functional coupling between CRAC channels, arachidonic acid release and leukotriene secretion. J. Biol. Chem. 279, 29994–29999 (2004).

    CAS  PubMed  Google Scholar 

  77. Chang, W. C. et al. Local calcium influx through calcium release-activated calcium (CRAC) channels stimulates production of an intracellular messenger and an intercellular pro-inflammatory signal. J. Biol. Chem. 283, 4622–4631 (2008).

    CAS  PubMed  Google Scholar 

  78. DiCapite, J. L., Shirley, A., Nelson, C., Bates, G. & Parekh, A. B. Intercellular calcium wave propagation involving positive feedback between CRAC channels and cysteinyl leukotrienes. FASEB J. 23, 894–905 (2009).

    CAS  Google Scholar 

  79. Gallo, E. M., Cante-Barrett, K. & Crabtree, G. R. Lymphocyte calcium signaling from membrane to nucleus. Nature Immunol. 7, 25–32 (2006).

    CAS  Google Scholar 

  80. Ng, S.-W., Nelson, C. & Parekh, A. B. Coupling of Ca2+ microdomains to spatially and temporally distinct cellular responses by the tyrosine kinase Syk. J. Biol. Chem. 284, 24767–24772 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 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). This paper shows that local Ca2+ entry through CRAC channels and not cytosolic Ca2+ oscillations drives gene expression.

    CAS  PubMed  Google Scholar 

  82. 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 (2008).

    CAS  Google Scholar 

  83. Baba, Y., Nishida, K., Fujii, Y., Hikida, M. & Kurosaki, T. Essential function for the calcium sensor STIM1 in mast cell activation and anaphylatic responses. Nature Immunol. 9, 81–88 (2008). References 82 and 83 show that CRAC channels are essential for mast-cell function.

    CAS  Google Scholar 

  84. Gwack, Y. et al. Hair loss and defective T- and B-cell function in mice lacking ORAI1. Mol. Cell. Biol. 28, 5209–5222 (2008). A detailed characterization of the ORAI1 -knockout mouse.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 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).

    CAS  PubMed  Google Scholar 

  86. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 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).

    CAS  PubMed  Google Scholar 

  88. Le Deist, F. et al. A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood 85, 1053–1062 (1995).

    CAS  PubMed  Google Scholar 

  89. Feske, S. et al. Severe combined immunodeficiency due to defective binding of nuclear factor of activated T cells in T lymphocytes of two male siblings. Eur. J. Immunol. 26, 2119–2126 (1996).

    CAS  PubMed  Google Scholar 

  90. Feske, S. Orai1 and STIM1 deficiency in human and mice: roles of store-operated calcium entry in immune cells and beyond. Immunol. Rev. 231, 189–209 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Picard, C. et al. STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N. Engl. J. Med. 360, 1971–1980 (2009). This paper describes mutations in STIM1 that are linked to immunodeficiencies.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Radenne, F. et al. Quality of life in nasal polyposis. J. Allergy Clin. Immunol. 103, 79–84 (1999).

    Google Scholar 

  94. Bateman, N. D., Fahy, C. & Woolford, T. J. Nasal polyps: still more questions than answers. J. Larynol. Otol. 117, 1–9 (2003).

    Google Scholar 

  95. Pawankar, R. Nasal polyposis: an update. Curr. Opin. Allergy Clin. Immunol. 3, 1–6 (2003).

    CAS  PubMed  Google Scholar 

  96. Di Capite, J., Nelson, C., Bates, G. & Parekh, A. B. Targeting Ca2+ release-activated Ca2+ channel channels and leukotriene receptors provides a novel combination strategy for treating nasal polyposis. J. Allergy Clin. Immunol. 124, 1014–1021 (2009).

    CAS  PubMed  Google Scholar 

  97. Ishikawa, J. et al. A pyrazole derivative, YM-58483, potently inhibits store-operated sustained calcium influx and IL-2 production in T lymphocytes. J. Immunol. 170, 4441–4449 (2003).

    CAS  PubMed  Google Scholar 

  98. Ohga, K. et al. The suppressive effects of YM-58483/BTP2, a store-oeprated Ca2+ entry blocker, on inflammatory mediator release in vitro and airway responses in vivo. Pulm. Pharmacol. Ther. 21, 360–369 (2008).

    CAS  PubMed  Google Scholar 

  99. Yoshino, T. et al. YM-58483, a selective CRAC channel inhibitor prevents antigen-induced airway eosinophilia and late phase asthmatic responses via Th2 cytokine inhibition in animal models. Eur. J. Pharmacol. 560, 225–233 (2007).

    CAS  PubMed  Google Scholar 

  100. Peel, S. E., Liu, B. & Hall, I. P. Orai and store-operated calcium influx in human airway smooth muscle cells. Am. J. Resp. Cell Mol. Biol. 38, 744–749 (2008).

    CAS  Google Scholar 

  101. Pirzer, U., Schoenhaar, A., Fleischer, B., Hermann, E. & Meyer zum Bueschenfelde, K. H. Reactivity of infiltrating T lymphocytes with microbial antigens in Crohn's disease. Lancet 338, 1238–1239 (1991).

    CAS  PubMed  Google Scholar 

  102. Fiocchi, C. Inflammatory bowel disease:etilogy and pathogenesis. Gastroenterology 115, 182–205 (1998).

    CAS  PubMed  Google Scholar 

  103. Schwarz, A. et al. Ca2+ signalling in identified T-lymphocytes from human intestinal mucosa. J. Biol. Chem. 279, 5641–5647 (2004).

    CAS  PubMed  Google Scholar 

  104. Ng, S.-W., DiCapite, J. L., Singaravelu, K. & Parekh, A. B. Sustained activation of the tyrosine kinase Syk by antigen in mast cells requires local Ca2+ influx through Ca2+ release-activated Ca2+ channels. J. Biol. Chem. 283, 31348–31355 (2008).

    CAS  PubMed  Google Scholar 

  105. Di Sabatino, A. et al. Targeting gut T cell Ca2+ release-activated Ca2+ channels inhibits T cell cytokine production and T-Box transcription factor T-Bet in inflammatory bowel disease. J. Immunol. 183, 3454–3462 (2009).

    CAS  PubMed  Google Scholar 

  106. 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). This study implicates a major role for CRAC channels in the development of breast cancer.

    CAS  PubMed  Google Scholar 

  107. Vanden Abeele, F. et al. Bcl-2-dependent modulation of Ca2+ homeostasis and store-operated channels in prostate cancer cells. Cancer Cell 1, 169–179 (2002).

    CAS  PubMed  Google Scholar 

  108. Prevarskaya, N., Skryma, R., Bidaux, G., Flourakis, M. & Shuba, Y. Ion channels in death and differentiation of prostate cancer cells. Cell Death Differ. 14, 1295–1304 (2007).

    CAS  PubMed  Google Scholar 

  109. Franzius, D., Hoth, M. & Penner, R. Non-specific effects of calcium entry antagonists in mast cells. Pflugers Arch. 428, 433–438 (1994).

    CAS  PubMed  Google Scholar 

  110. Putney, J. W. Pharmacology of capacitative calcium entry. Mol. Interv. 1, 84–94 (2001).

    CAS  PubMed  Google Scholar 

  111. Djuric, S. W. et al. 3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator. J. Med. Chem. 43, 2975–2981 (2000).

    CAS  PubMed  Google Scholar 

  112. Trevillyan, J. M. et al. Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. J. Biol. Chem. 276, 48118–48126 (2001).

    CAS  PubMed  Google Scholar 

  113. Zitt, C. et al. Potent inhibition of Ca2+ release-activated Ca2+ channels and T-lymphocyte activation by the pyrazole derivative BTP2. J. Biol. Chem. 279, 12427–12437 (2004).

    CAS  PubMed  Google Scholar 

  114. Takezawa, R. et al. A pyrazole derivative potently inhibits lymphocyte Ca2+ influx and cytokine production by facilitating transient receptor potential melastatin 4 channel activity. Mol. Pharmacol. 69, 1413–1420 (2006).

    CAS  PubMed  Google Scholar 

  115. He, L. P., Hewavitharana, T., Soboloff, J., Spassova, M. A. & Gill, D. L. Functional link between store-operated and TRPC channels revealed by the 3,5-bis (trifluoromethyl)pyrazole derivative, BTP2. J. Biol. Chem. 280, 10997–11006 (2005).

    CAS  PubMed  Google Scholar 

  116. Zakharov, S. I. et al. Diethylstilbestrol is a potent inhibitor of store-operated channels and capacitative Ca2+ influx. Mol. Pharmacol. 66, 702–707 (2004).

    CAS  PubMed  Google Scholar 

  117. Ohana, L., Stanley, E. F. & Schlichter, L. C. The Ca2+ release-activated Ca2+ current (ICRAC) mediates store-operated Ca2+ entry in rat microglia. Channels 3, 129–139 (2009).

    CAS  PubMed  Google Scholar 

  118. Rodland, K. D., Wersto, R. P., Hobson, S. & Kohn, E. C. Thapsigargin-induced gene expression in nonexcitable cells is dependent on calcium influx. Mol. Endocrinol. 11, 281–291 (1997).

    CAS  PubMed  Google Scholar 

  119. Kohn, E. C. et al. A phase 1 trial of carboxyamido-triazole and paclitaxel for relapsed solid tumours: potential efficacy of the combination and demonstration of pharmacokinetic interaction. Clin. Cancer Res. 7, 1600–1609 (2001).

    CAS  PubMed  Google Scholar 

  120. Hussain, M. M. et al. Phase II trial of carboxyamidotriazole in patients with relapsed epithelial ovarian cancer. J. Clin. Oncol. 21, 4356–4363 (2003).

    CAS  PubMed  Google Scholar 

  121. Mignen, O. et al. Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells. J. Cell Sci. 118, 5615–5623 (2005).

    CAS  PubMed  Google Scholar 

  122. Glitsch, M. D., Bakowski, D. & Parekh, A. B. Store-operated Ca2+ entry depends on mitochondrial Ca2+ uptake. EMBO J. 21, 6744–6754 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Gilabert, J.-A. & Parekh, A. B. Respiring mitochondria determine the pattern of activation and inactivation of the store-operated Ca2+ current ICRAC . EMBO J. 19, 6401–6407 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Hoth, M., Button, D. & Lewis, R. S. Mitochondrial control of calcium channel gating: a mechanism for sustained signaling and transcriptional activation in T lymphocytes. Proc. Natl Acad. Sci. USA 97, 10607–10612 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Parekh, A. B. Mitochondrial regulation of store-operated CRAC channels. Cell Calcium 44, 6–13 (2008).

    CAS  PubMed  Google Scholar 

  126. DeHaven, W. I., Smyth, J. T., Boyles, R. R., Bird, G. S. & Putney, J. W. Complex actions of 2-aminoethyldiphenyl borate (2-APB) on store-operated calcium entry. J. Biol. Chem. 283, 19265–19273 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Peinelt, C., Lis, A., Beck, A., Fleig, A. & Penner, R. 2-aminoethoxydiphenyl borate directly facilitates and indirectly inhibits STIM1-dependent gating of CRAC channels. J. Physiol. 586, 3061–3073 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Zhang, S. L. et al. Store-dependent and independent modes of regulating Ca2+ release-activated Ca2+ channel activity of human Orai1 and Orai3. J. Biol. Chem. 283, 17662–17671 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Schindl, R. et al. 2-aminoethoxydiphenyl borate alters selectivity of Orai3 channels by increasing their pore size. J. Biol. Chem. 283, 20261–20267 (2008).

    CAS  PubMed  Google Scholar 

  130. Navarro-Borelly, L. et al. STIM1–Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. J. Physiol. 586, 5383–5401 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  132. 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).

    CAS  Google Scholar 

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Acknowledgements

Work in my laboratory is supported by the Medical Research Council and the British Heart Foundation. I thank D. Bakowski for comments on the manuscript.

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  1. Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK

    Anant B. Parekh

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Glossary

SERCA

Sarco/endoplasmic reticulum Ca2+ ATPase pump, which transports Ca2+ from the cytosol into the endoplasmic reticulum.

Fluctuation analysis

A method that extracts information concerning the nature of individual channel events from statistical descriptions of the current noise.

Transient receptor potential (TRP) ion channel family

A broad family of largely non-selective cation channels permeable to Na+ and Ca2+. TRP channels were first discovered in the trp mutant strain of Drosophila melanogaster.

EF-hand domain

A highly conserved Ca2+ binding site found in many Ca2+-binding proteins.

Sterile α-motif domain

A putative protein–protein interaction module that helps drive homo-oligomerization and hetero-oligomerization.

Ezrin-radixin-moesin

A group of actin-binding proteins that link actin with plasma membrane proteins and are involved in signal transduction.

ICRAC

The current that flows through Ca2+ release-activated Ca2+ (CRAC) channels.

Muscular hypotonia

Decreased muscle tone.

Ectodermal dysplasia

Abnormalities of ectodermal structures including hair, nails, sweat glands and teeth. These abnormalities can lead to reduced sweat production and reduced dental enamel formation.

Puncta

Hot-spots or clusters of stromal interaction molecule 1 (STIM1) at endoplasmic reticulum–plasma membrane regions just below the plasma membrane.

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Parekh, A. Store-operated CRAC channels: function in health and disease. Nat Rev Drug Discov 9, 399–410 (2010). https://doi.org/10.1038/nrd3136

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