CRAC channelopathies

  • Stefan FeskeEmail author
Ion Channels, Receptors and Transporters


Store-operated Ca2+ entry (SOCE) is an important Ca2+ influx pathway in many non-excitable and some excitable cells. It is regulated by the filling state of intracellular Ca2+ stores, notably the endoplasmic reticulum (ER). Reduction in [Ca2+]ER results in activation of plasma membrane Ca2+ channels that mediate sustained Ca2+ influx which is required for many cell functions as well as refilling of Ca2+ stores. The Ca2+ release activated Ca2+ (CRAC) channel is the best characterized SOC channel with well-defined electrophysiological properties. In recent years, the molecular components of the CRAC channel, long mysterious, have been defined. ORAI1 (or CRACM1) acts as the pore-forming subunit of the CRAC channel in the plasma membrane. Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca2+]ER, and activates the CRAC channel upon store depletion by binding to ORAI1. Both proteins are widely expressed in many tissues in both human and mouse consistent with the widespread prevalence of SOCE and CRAC channel currents in many cells types. CRAC channelopathies in human patients with mutations in STIM1 and ORAI1 are characterized by abolished CRAC channel currents, lack of SOCE and—clinically—immunodeficiency, congenital myopathy, and anhydrotic ectodermal dysplasia. This article reviews the role of ORAI and STIM proteins for SOCE and CRAC channel function in a variety of cell types and tissues and compares the phenotypes of ORAI1 and STIM1-deficient human patients and mice with targeted deletion of Orai and Stim genes.


ORAI1 STIM1 CRAC SOCE Store-operated calcium entry Ca2+ T cells B cells Mast cells Lymphocytes Immunodeficiency SCID Signal transduction Myopathy Muscle Ectodermal dysplasia Amelogenesis Platelets Gene-targeting Mice 



Calcium release activated calcium (channel)


Anhydrotic ectodermal dysplasia


Severe combined immunodeficiency


Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase


Store-operated calcium entry


Stromal interaction molecule 1


Vascular smooth muscle cells



This work was supported by NIH grant AI066128 and a March of Dimes Foundation grant. I thank Dr. M. Prakriya for the critical reading of the manuscript and helpful suggestions.

Conflicts of interest

The author is a scientific co-founder and advisor of CalciMedica, a biotechnology company that seeks to develop CRAC channel inhibitors.


  1. 1.
    Abdullaev I, Bisaillon J, Potier M, Gonzalez J, Motiani R, Trebak M (2008) Stim1 and orai1 mediate CRAC currents and store-operated calcium entry important for endothelial cell proliferation. Circ Res 103:1289–1299PubMedCrossRefGoogle Scholar
  2. 2.
    Ahmmed GU, Mehta D, Vogel S, Holinstat M, Paria BC, Tiruppathi C, Malik AB (2004) Protein kinase Calpha phosphorylates the TRPC1 channel and regulates store-operated Ca2+ entry in endothelial cells. J Biol Chem 279:20941–20949PubMedCrossRefGoogle Scholar
  3. 3.
    Albert AP, Large WA (2002) A Ca2+-permeable non-selective cation channel activated by depletion of internal Ca2+ stores in single rabbit portal vein myocytes. J Physiol 538:717–728PubMedCrossRefGoogle Scholar
  4. 4.
    Albert AP, Large WA (2003) Store-operated Ca2+-permeable non-selective cation channels in smooth muscle cells. Cell Calcium 33:345–356PubMedCrossRefGoogle Scholar
  5. 5.
    Alicia S, Angelica Z, Carlos S, Alfonso S, Vaca L (2008) STIM1 converts TRPC1 from a receptor-operated to a store-operated channel: moving TRPC1 in and out of lipid rafts. Cell Calcium 44:479–491PubMedCrossRefGoogle Scholar
  6. 6.
    Aubart FC, Sassi Y, Coulombe A, Mougenot N, Vrignaud C, Leprince P, Lechat P, Lompre AM, Hulot JS (2009) RNA interference targeting STIM1 suppresses vascular smooth muscle cell proliferation and neointima formation in the rat. Mol Ther 17:455–462PubMedCrossRefGoogle Scholar
  7. 7.
    Baba Y, Nishida K, Fujii Y, Hirano T, Hikida M, Kurosaki T (2008) Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses. Nat Immunol 9:81–88PubMedCrossRefGoogle Scholar
  8. 8.
    Baba A, Yasui T, Fujisawa S, Yamada RX, Yamada MK, Nishiyama N, Matsuki N, Ikegaya Y (2003) Activity-evoked capacitative Ca2+ entry: implications in synaptic plasticity. J Neurosci 23:7737–7741PubMedGoogle Scholar
  9. 9.
    Barritt GJ, Litjens TL, Castro J, Aromataris E, Rychkov GY (2009) Store-operated Ca2+ channels and microdomains of Ca2+ in liver cells. Clin Exp Pharmacol Physiol 36:77–83PubMedCrossRefGoogle Scholar
  10. 10.
    Beech DJ (2009) Harmony and discord in endothelial calcium entry. Circ Res 104:e22–e23PubMedCrossRefGoogle Scholar
  11. 11.
    Bergmeier W, Oh-Hora M, McCarl CA, Roden RC, Bray PF, Feske S (2009) R93W mutation in Orai1 causes impaired calcium influx in platelets. Blood 113:675–678PubMedCrossRefGoogle Scholar
  12. 12.
    Berna-Erro A, Braun A, Kraft R, Kleinschnitz C, Schuhmann MK, Stegner D, Wultsch T, Eilers J, Meuth SG, Stoll G, Nieswandt B (2009) STIM2 regulates capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death. Sci Signal 2:ra67PubMedCrossRefGoogle Scholar
  13. 13.
    Beyersdorf N, Braun A, Vogtle T, Varga-Szabo D, Galdos R, Kissler S, Kerkau T, Nieswandt B (2009) STIM1-independent T cell development and effector function in vivo. J Immunol 182:3390–3397PubMedCrossRefGoogle Scholar
  14. 14.
    Bolotina VM, Csutora P (2005) CIF and other mysteries of the store-operated Ca2+-entry pathway. Trends Biochem Sci 30:378–387PubMedCrossRefGoogle Scholar
  15. 15.
    Brandman O, Liou J, Park WS, Meyer T (2007) STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131:1327–1339PubMedCrossRefGoogle Scholar
  16. 16.
    Braun A, Gessner J, Varga-Szabo D, Syed S, Konrad S, Stegner D, Vogtle T, Schmidt R, Nieswandt B (2008) STIM1 is essential for Fc receptor activation and autoimmune inflammation. Blood 113:1097–1104PubMedCrossRefGoogle Scholar
  17. 17.
    Braun A, Varga-Szabo D, Kleinschnitz C, Pleines I, Bender M, Austinat M, Bosl M, Stoll G, Nieswandt B (2009) Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation. Blood 113:2056–2063PubMedCrossRefGoogle Scholar
  18. 18.
    Brough GH, Wu S, Cioffi D, Moore TM, Li M, Dean N, Stevens T (2001) Contribution of endogenously expressed Trp1 to a Ca2+-selective, store-operated Ca2+ entry pathway. FASEB J 15:1727–1738PubMedCrossRefGoogle Scholar
  19. 19.
    Brueggemann LI, Markun DR, Henderson KK, Cribbs LL, Byron KL (2006) Pharmacological and electrophysiological characterization of store-operated currents and capacitative Ca2+ entry in vascular smooth muscle cells. J Pharmacol Exp Ther 317:488–499PubMedCrossRefGoogle Scholar
  20. 20.
    Cahalan MD (2009) STIMulating store-operated Ca2+ entry. Nat Cell Biol 11:669–677PubMedCrossRefGoogle Scholar
  21. 21.
    Calloway N, Vig M, Kinet JP, Holowka D, Baird B (2009) 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 20:389–399PubMedCrossRefGoogle Scholar
  22. 22.
    Casteels R, Raeymaekers L, Suzuki H, Van Eldere J (1981) Tension response and 45Ca release in vascular smooth muscle incubated in Ca-free solution. Pflugers Arch 392:139–145PubMedCrossRefGoogle Scholar
  23. 23.
    Courtois G, Smahi A, Reichenbach J, Doffinger R, Cancrini C, Bonnet M, Puel A, Chable-Bessia C, Yamaoka S, Feinberg J, Dupuis-Girod S, Bodemer C, Livadiotti S, Novelli F, Rossi P, Fischer A, Israel A, Munnich A, Le Deist F, Casanova JL (2003) A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest 112:1108–1115PubMedGoogle Scholar
  24. 24.
    Darbellay B, Arnaudeau S, Konig S, Jousset H, Bader C, Demaurex N, Bernheim L (2008) STIM1- and orai1-dependent store-operated calcium entry regulates human myoblast differentiation. J Biol Chem 284:5370–5380PubMedCrossRefGoogle Scholar
  25. 25.
    DeHaven WI, Jones BF, Petranka JG, Smyth JT, Tomita T, Bird GS, Putney JW Jr (2009) TRPC channels function independently of STIM1 and Orai1. J Physiol 587:2275–2298PubMedCrossRefGoogle Scholar
  26. 26.
    DeHaven WI, Smyth JT, Boyles RR, Putney JW (2007) Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels. J Biol Chem 282:17548–17556PubMedCrossRefGoogle Scholar
  27. 27.
    Derler I, Fahrner M, Carugo O, Muik M, Bergsmann J, Schindl R, Frischauf I, Eshaghi S, Romanin C (2009) Increased hydrophobicity at the N-terminus/membrane interface impairs gating of the SCID-related ORAI1 mutant. J Biol Chem 284:15903–15915PubMedCrossRefGoogle Scholar
  28. 28.
    Derler I, Fahrner M, Muik M, Lackner B, Schindl R, Groschner K, Romanin C (2009) A Ca2+ release-activated Ca2+ (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca2+-dependent inactivation of ORAI1 channels. J Biol Chem 284:24933–24938PubMedCrossRefGoogle Scholar
  29. 29.
    Di Sabatino A, Rovedatti L, Kaur R, Spencer JP, Brown JT, Morisset VD, Biancheri P, Leakey NA, Wilde JI, Scott L, Corazza GR, Lee K, Sengupta N, Knowles CH, Gunthorpe MJ, McLean PG, MacDonald TT, Kruidenier L (2009) 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 183:3454–3462PubMedCrossRefGoogle Scholar
  30. 30.
    Dietrich A, Kalwa H, Storch U, Mederos y Schnitzler M, Salanova B, Pinkenburg O, Dubrovska G, Essin K, Gollasch M, Birnbaumer L, Gudermann T (2007) Pressure-induced and store-operated cation influx in vascular smooth muscle cells is independent of TRPC1. Pflugers Arch 455:465–477PubMedCrossRefGoogle Scholar
  31. 31.
    Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, Bodemer C, Kenwrick S, Dupuis-Girod S, Blanche S, Wood P, Rabia SH, Headon DJ, Overbeek PA, Le Deist F, Holland SM, Belani K, Kumararatne DS, Fischer A, Shapiro R, Conley ME, Reimund E, Kalhoff H, Abinun M, Munnich A, Israel A, Courtois G, Casanova JL (2001) X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 27:277–285PubMedCrossRefGoogle Scholar
  32. 32.
    Dziadek MA, Johnstone LS (2007) Biochemical properties and cellular localisation of STIM proteins. Cell Calcium 42:123–132PubMedCrossRefGoogle Scholar
  33. 33.
    Ely JA, Ambroz C, Baukal AJ, Christensen SB, Balla T, Catt KJ (1991) Relationship between agonist- and thapsigargin-sensitive calcium pools in adrenal glomerulosa cells. Thapsigargin-induced Ca2+ mobilization and entry. J Biol Chem 266:18635–18641PubMedGoogle Scholar
  34. 34.
    Fahrner M, Muik M, Derler I, Schindl R, Fritsch R, Frischauf I, Romanin C (2009) Mechanistic view on domains mediating STIM1-Orai coupling. Immunol Rev 231:99–112PubMedCrossRefGoogle Scholar
  35. 35.
    Fasolato C, Nilius B (1998) Store depletion triggers the calcium release-activated calcium current ICRAC in macrovascular endothelial cells: a comparison with Jurkat and embryonic kidney cell lines. Pflugers Arch 436:69–74PubMedCrossRefGoogle Scholar
  36. 36.
    Feske S (2007) Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7:690–702PubMedCrossRefGoogle Scholar
  37. 37.
    Feske S (2009) ORAI1 and STIM1 deficiency in human and mice: roles of store-operated Ca2+ entry in the immune system and beyond. Immunol Rev 231:189–209PubMedCrossRefGoogle Scholar
  38. 38.
    Feske S, Draeger R, Peter HH, Eichmann K, Rao A (2000) The duration of nuclear residence of NFAT determines the pattern of cytokine expression in human SCID T cells. J Immunol 165:297–305PubMedGoogle Scholar
  39. 39.
    Feske S, Giltnane J, Dolmetsch R, Staudt LM, Rao A (2001) Gene regulation mediated by calcium signals in T lymphocytes. Nat Immunol 2:316–324PubMedCrossRefGoogle Scholar
  40. 40.
    Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–185PubMedCrossRefGoogle Scholar
  41. 41.
    Feske S, Muller JM, Graf D, Kroczek RA, Drager R, Niemeyer C, Baeuerle PA, Peter HH, Schlesier M (1996) Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings. Eur J Immunol 26:2119–2126PubMedCrossRefGoogle Scholar
  42. 42.
    Feske S, Prakriya M, Rao A, Lewis RS (2005) A severe defect in CRAC Ca2+ channel activation and altered K + channel gating in T cells from immunodeficient patients. J Exp Med 202:651–662PubMedCrossRefGoogle Scholar
  43. 43.
    Fomina AF, Nowycky MC (1999) A current activated on depletion of intracellular Ca2+ stores can regulate exocytosis in adrenal chromaffin cells. J Neurosci 19:3711–3722PubMedGoogle Scholar
  44. 44.
    Freichel M, Suh SH, Pfeifer A, Schweig U, Trost C, Weissgerber P, Biel M, Philipp S, Freise D, Droogmans G, Hofmann F, Flockerzi V, Nilius B (2001) Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4-/- mice. Nat Cell Biol 3:121–127PubMedCrossRefGoogle Scholar
  45. 45.
    Gibson A, McFadzean I, Wallace P, Wayman CP (1998) Capacitative Ca2+ entry and the regulation of smooth muscle tone. Trends Pharmacol Sci 19:266–269PubMedCrossRefGoogle Scholar
  46. 46.
    Grosse J, Braun A, Varga-Szabo D, Beyersdorf N, Schneider B, Zeitlmann L, Hanke P, Schropp P, Muhlstedt S, Zorn C, Huber M, Schmittwolf C, Jagla W, Yu P, Kerkau T, Schulze H, Nehls M, Nieswandt B (2007) An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice. J Clin Invest 117:3540–3550PubMedCrossRefGoogle Scholar
  47. 47.
    Guibert C, Ducret T, Savineau JP (2008) Voltage-independent calcium influx in smooth muscle. Prog Biophys Mol Biol 98:10–23PubMedCrossRefGoogle Scholar
  48. 48.
    Guo RW, Wang H, Gao P, Li MQ, Zeng CY, Yu Y, Chen JF, Song MB, Shi YK, Huang L (2009) An essential role for stromal interaction molecule 1 in neointima formation following arterial injury. Cardiovasc Res 81:660–668PubMedCrossRefGoogle Scholar
  49. 49.
    Gwack Y, Srikanth S, Feske S, Cruz-Guilloty F, Oh-hora M, Neems DS, Hogan PG, Rao A (2007) Biochemical and functional characterization of Orai proteins. J Biol Chem 282:16232–16243PubMedCrossRefGoogle Scholar
  50. 50.
    Gwack Y, Srikanth S, Oh-Hora M, Hogan PG, Lamperti ED, Yamashita M, Gelinas C, Neems DS, Sasaki Y, Feske S, Prakriya M, Rajewsky K, Rao A (2008) Hair loss and defective T- and B-cell function in mice lacking ORAI1. Mol Cell Biol 28:5209–5222PubMedCrossRefGoogle Scholar
  51. 51.
    Hassock SR, Zhu MX, Trost C, Flockerzi V, Authi KS (2002) Expression and role of TRPC proteins in human platelets: evidence that TRPC6 forms the store-independent calcium entry channel. Blood 100:2801–2811PubMedCrossRefGoogle Scholar
  52. 52.
    Hechler B, Lenain N, Marchese P, Vial C, Heim V, Freund M, Cazenave JP, Cattaneo M, Ruggeri ZM, Evans R, Gachet C (2003) A role of the fast ATP-gated P2X1 cation channel in thrombosis of small arteries in vivo. J Exp Med 198:661–667PubMedCrossRefGoogle Scholar
  53. 53.
    Hoth M, Penner R (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–356PubMedCrossRefGoogle Scholar
  54. 54.
    Hu JC, Yamakoshi Y (2003) Enamelin and autosomal-dominant amelogenesis imperfecta. Crit Rev Oral Biol Med 14:387–398PubMedCrossRefGoogle Scholar
  55. 55.
    Huang YH, Hoebe K, Sauer K (2008) New therapeutic targets in immune disorders: ItpkB, Orai1 and UNC93B. Expert Opin Ther Targets 12:391–413PubMedCrossRefGoogle Scholar
  56. 56.
    Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF (2006) STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat Cell Biol 8:1003–1010PubMedCrossRefGoogle Scholar
  57. 57.
    Hubbard (2000) Calcium transport across the dental enamel epithelium. Crit Rev Oral Biol Med 11:437–466PubMedCrossRefGoogle Scholar
  58. 58.
    Itin PH, Fistarol SK (2004) Ectodermal dysplasias. Am J Med Genet C Semin Med Genet 131C:45–51PubMedCrossRefGoogle Scholar
  59. 59.
    Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W (2001) Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2:223–228PubMedCrossRefGoogle Scholar
  60. 60.
    Ji W, Xu P, Li Z, Lu J, Liu L, Zhan Y, Chen Y, Hille B, Xu T, Chen L (2008) Functional stoichiometry of the unitary calcium-release-activated calcium channel. Proc Natl Acad Sci U S A 105:13668–13673PubMedCrossRefGoogle Scholar
  61. 61.
    Jones BF, Boyles RR, Hwang SY, Bird GS, Putney JW (2008) Calcium influx mechanisms underlying calcium oscillations in rat hepatocytes. Hepatology 48:1273–1281PubMedCrossRefGoogle Scholar
  62. 62.
    Kahr H, Schindl R, Fritsch R, Heinze B, Hofbauer M, Hack ME, Mortelmaier MA, Groschner K, Peng JB, Takanaga H, Hediger MA, Romanin C (2004) CaT1 knock-down strategies fail to affect CRAC channels in mucosal-type mast cells. J Physiol 557:121–132PubMedCrossRefGoogle Scholar
  63. 63.
    Kawasaki T, Lange I, Feske S (2009) A minimal regulatory domain in the C terminus of STIM1 binds to and activates ORAI1 CRAC channels. Biochem Biophys Res Commun 385:49–54PubMedCrossRefGoogle Scholar
  64. 64.
    Kennedy WR, Sakuta M, Quick DC (1984) Rodent eccrine sweat glands: a case of multiple efferent innervation. Neuroscience 11:741–749PubMedCrossRefGoogle Scholar
  65. 65.
    Kim JW, Lee SK, Lee ZH, Park JC, Lee KE, Lee MH, Park JT, Seo BM, Hu JC, Simmer JP (2008) FAM83H mutations in families with autosomal-dominant hypocalcified amelogenesis imperfecta. Am J Hum Genet 82:489–494PubMedCrossRefGoogle Scholar
  66. 66.
    Ko WH, Chan HC, Wong PY (1996) Anion secretion induced by capacitative Ca2+ entry through apical and basolateral membranes of cultured equine sweat gland epithelium. J Physiol 497(Pt 1):19–29PubMedGoogle Scholar
  67. 67.
    Kurebayashi N, Ogawa Y (2001) Depletion of Ca2+in the sarcoplasmic reticulum stimulates Ca2+entry into mouse skeletal muscle fibres. J Physiol 533:185–199PubMedCrossRefGoogle Scholar
  68. 68.
    Le Deist F, Hivroz C, Partiseti M, Thomas C, Buc HA, Oleastro M, Belohradsky B, Choquet D, Fischer A (1995) A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood 85:1053–1062PubMedGoogle Scholar
  69. 69.
    Lee KP, Yuan JP, Zeng W, So I, Worley PF, Muallem S (2009) Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels. Proc Natl Acad Sci U S A 106:14687–14692PubMedCrossRefGoogle Scholar
  70. 70.
    Lewis RS (2007) The molecular choreography of a store-operated calcium channel. Nature 446:284–287PubMedCrossRefGoogle Scholar
  71. 71.
    Li J, Sukumar P, Milligan CJ, Kumar B, Ma ZY, Munsch CM, Jiang LH, Porter KE, Beech DJ (2008) Interactions, functions, and independence of plasma membrane STIM1 and TRPC1 in vascular smooth muscle cells. Circ Res 103:e97–e104PubMedCrossRefGoogle Scholar
  72. 72.
    Liou J, Fivaz M, Inoue T, Meyer T (2007) Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc Natl Acad Sci U S A 104:9301–9306PubMedCrossRefGoogle Scholar
  73. 73.
    Liou J, Kim M, Heo WD, Jones JT, Myers JW, Ferrell JE, Meyer T (2005) STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol 15:1235–1241PubMedCrossRefGoogle Scholar
  74. 74.
    Lis A, Peinelt C, Beck A, Parvez S, Monteilh-Zoller M, Fleig A, Penner R (2007) CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr Biol 17:794–800PubMedCrossRefGoogle Scholar
  75. 75.
    Lu W, Wang J, Peng G, Shimoda LA, Sylvester JT (2009) Knockdown of stromal interaction molecule 1 attenuates store-operated Ca2+ entry and Ca2+ responses to acute hypoxia in pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 297:L17–L25PubMedCrossRefGoogle Scholar
  76. 76.
    Luckhoff A, Clapham DE (1994) Calcium channels activated by depletion of internal calcium stores in A431 cells. Biophys J 67:177–182PubMedCrossRefGoogle Scholar
  77. 77.
    Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS (2008) Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454:538–542PubMedCrossRefGoogle Scholar
  78. 78.
    Luik RM, Wu MM, Buchanan J, Lewis RS (2006) The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J Cell Biol 174:815–825PubMedCrossRefGoogle Scholar
  79. 79.
    Lur G, Haynes LP, Prior IA, Gerasimenko OV, Feske S, Petersen OH, Burgoyne RD, Tepikin AV (2009) Ribosome-free terminals of rough ER allow formation of STIM1 puncta and segregation of STIM1 from IP(3) receptors. Curr Biol 19:1648–1653PubMedCrossRefGoogle Scholar
  80. 80.
    Lyfenko AD, Dirksen RT (2008) Differential dependence of store-operated and excitation-coupled Ca2+ entry in skeletal muscle on STIM1 and Orai1. J Physiol 586:4815–4824PubMedCrossRefGoogle Scholar
  81. 81.
    Manji SS, Parker NJ, Williams RS, Van Stekelenburg L, Pearson RB, Dziadek MA, Smith PJ (2000) STIM1: a novel phosphoprotein located at the cell surface. Biochim Biophys Acta 1481:147–155PubMedGoogle Scholar
  82. 82.
    McCarl CA, Picard C, Khalil S, Kawasaki T, Röther J, Papolos A, Kutok J, Hivroz C, LeDeist F, Plogmann K, Ehl S, Notheis G, Albert MH, Belohradsky BH, Kirschner J, Rao A, Fischer A, Feske S (2009) ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy and ectodermal dysplasia. J Allergy Clin Immunol 124:1311–18e7PubMedCrossRefGoogle Scholar
  83. 83.
    McFadzean I, Gibson A (2002) The developing relationship between receptor-operated and store-operated calcium channels in smooth muscle. Br J Pharmacol 135:1–13PubMedCrossRefGoogle Scholar
  84. 84.
    McNally B, Yamashita M, Engh A, Prakriya M (2009) Structural determinants of ion permeation in CRAC channels. Proc Natl Acad Sci U S A 106:22516–22521Google Scholar
  85. 85.
    Mignen O, Thompson JL, Shuttleworth TJ (2008) Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J Physiol 586:419–425PubMedCrossRefGoogle Scholar
  86. 86.
    Mogami H, Nakano K, Tepikin AV, Petersen OH (1997) Ca2+ flow via tunnels in polarized cells: recharging of apical Ca2+ stores by focal Ca2+ entry through basal membrane patch. Cell 88:49–55PubMedCrossRefGoogle Scholar
  87. 87.
    Muik M, Fahrner M, Derler I, Schindl R, Bergsmann J, Frischauf I, Groschner K, Romanin C (2009) A cytosolic homomerization and a modulatory domain within STIM1 C terminus determine coupling to ORAI1 channels. J Biol Chem 284:8421–8426PubMedCrossRefGoogle Scholar
  88. 88.
    Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C (2008) Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J Biol Chem 283:8014–8022PubMedCrossRefGoogle Scholar
  89. 89.
    Mullins FM, Park CY, Dolmetsch RE, Lewis RS (2009) STIM1 and calmodulin interact with Orai1 to induce Ca2+-dependent inactivation of CRAC channels. Proc Natl Acad Sci U S A 106:15495–15500PubMedCrossRefGoogle Scholar
  90. 90.
    Navarro-Borelly L, Somasundaram A, Yamashita M, Ren D, Miller RJ, Prakriya M (2008) STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. J Physiol 586:5383–5401PubMedCrossRefGoogle Scholar
  91. 91.
    Ng LC, McCormack MD, Airey JA, Singer CA, Keller PS, Shen XM, Hume JR (2009) TRPC1 and STIM1 mediate capacitative Ca2+ entry in mouse pulmonary arterial smooth muscle cells. J Physiol 587:2429–2442PubMedCrossRefGoogle Scholar
  92. 92.
    Nunez L, Valero RA, Senovilla L, Sanz-Blasco S, Garcia-Sancho J, Villalobos C (2006) Cell proliferation depends on mitochondrial Ca2+ uptake: inhibition by salicylate. J Physiol 571:57–73PubMedCrossRefGoogle Scholar
  93. 93.
    Ohana L, Newell EW, Stanley EF, Schlichter LC (2009) The Ca2+ release-activated Ca2+ current (I(crac)) mediates store-operated Ca2+ entry in rat microglia. Channels (Austin) 3:129–139Google Scholar
  94. 94.
    Oh-hora M (2009) Calcium signaling in the development and function of T-lineage cells. Immunol Rev 231:210–224PubMedCrossRefGoogle Scholar
  95. 95.
    Oh-Hora M, Yamashita M, Hogan P, Sharma S, Lamperti E, Chung W, Prakriya M, Feske S, Rao A (2008) Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nat Immunol 9:432–443PubMedCrossRefGoogle Scholar
  96. 96.
    Oike M, Gericke M, Droogmans G, Nilius B (1994) Calcium entry activated by store depletion in human umbilical vein endothelial cells. Cell Calcium 16:367–376PubMedCrossRefGoogle Scholar
  97. 97.
    Oritani K, Kincade PW (1996) Identification of stromal cell products that interact with pre-B cells. J Cell Biol 134:771–782PubMedCrossRefGoogle Scholar
  98. 98.
    Oury C, Kuijpers MJ, Toth-Zsamboki E, Bonnefoy A, Danloy S, Vreys I, Feijge MA, De Vos R, Vermylen J, Heemskerk JW, Hoylaerts MF (2003) Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype. Blood 101:3969–3976PubMedCrossRefGoogle Scholar
  99. 99.
    Pan Z, Yang D, Nagaraj RY, Nosek TA, Nishi M, Takeshima H, Cheng H, Ma J (2002) Dysfunction of store-operated calcium channel in muscle cells lacking mg29. Nat Cell Biol 4:379–383PubMedCrossRefGoogle Scholar
  100. 100.
    Pani B, Ong HL, Brazer SC, Liu X, Rauser K, Singh BB, Ambudkar IS (2009) Activation of TRPC1 by STIM1 in ER-PM microdomains involves release of the channel from its scaffold caveolin-1. Proc Natl Acad Sci U S A 106:20087–20092PubMedGoogle Scholar
  101. 101.
    Parekh AB, Penner R (1997) Store depletion and calcium influx. Physiol Rev 77:901–930PubMedGoogle Scholar
  102. 102.
    Parekh AB, Putney JW (2005) Store-operated calcium channels. Physiol Rev 85:757–810PubMedCrossRefGoogle Scholar
  103. 103.
    Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS (2009) STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136:876–890PubMedCrossRefGoogle Scholar
  104. 104.
    Parker (1996) Molecular cloning of a novel human gene (D11S4896E) at chromosomal region 11p15.5. Genomics 37:253–256PubMedCrossRefGoogle Scholar
  105. 105.
    Partiseti M, Le Deist F, Hivroz C, Fischer A, Korn H, Choquet D (1994) The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency. J Biol Chem 269:32327–32335PubMedGoogle Scholar
  106. 106.
    Pasyk E, Inazu M, Daniel EE (1995) CPA enhances Ca2+ entry in cultured bovine pulmonary arterial endothelial cells in an IP3-independent manner. Am J Physiol 268:H138–H146PubMedGoogle Scholar
  107. 107.
    Peinelt C, Vig M, Koomoa DL, Beck A, Nadler MJ, Koblan-Huberson M, Lis A, Fleig A, Penner R, Kinet JP (2006) Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 8:771–773PubMedCrossRefGoogle Scholar
  108. 108.
    Penna A, Demuro A, Yeromin A, Zhang S, Safrina O, Parker I, Cahalan M (2008) The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456:116–120PubMedCrossRefGoogle Scholar
  109. 109.
    Petersen OH (2003) Localization and regulation of Ca2+ entry and exit pathways in exocrine gland cells. Cell Calcium 33:337–344PubMedCrossRefGoogle Scholar
  110. 110.
    Picard C, McCarl CA, Papolos A, Khalil S, Luthy K, Hivroz C, LeDeist F, Rieux-Laucat F, Rechavi G, Rao A, Fischer A, Feske S (2009) STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med 360:1971–1980PubMedCrossRefGoogle Scholar
  111. 111.
    Pinheiro M, Freire-Maia N (1994) Ectodermal dysplasias: a clinical classification and a causal review. Am J Med Genet 53:153–162PubMedCrossRefGoogle Scholar
  112. 112.
    Potier M, Gonzalez J, Motiani R, Abdullaev I, Bisaillon J, Singer H, Trebak M (2009) Evidence for STIM1- and Orai1-dependent store-operated calcium influx through Icrac in vascular smooth muscle cells: role in proliferation and migration. FASEB J 23:2425–2437PubMedCrossRefGoogle Scholar
  113. 113.
    Prakriya M (2009) The molecular physiology of CRAC channels. Immunol Rev 231:88–98PubMedCrossRefGoogle Scholar
  114. 114.
    Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG (2006) Orai1 is an essential pore subunit of the CRAC channel. Nature 443:230–233PubMedCrossRefGoogle Scholar
  115. 115.
    Prompt (1978) Functions of calcium in sweat secretion. Nature 272:171–172PubMedCrossRefGoogle Scholar
  116. 116.
    Puel A, Picard C, Ku CL, Smahi A, Casanova JL (2004) Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol 16:34–41PubMedCrossRefGoogle Scholar
  117. 117.
    Putney JW (1986) A model for receptor-regulated calcium entry. Cell Calcium 7:1–12PubMedCrossRefGoogle Scholar
  118. 118.
    Putney JW (2009) Capacitative calcium entry: from concept to molecules. Immunol Rev 231:10–22PubMedCrossRefGoogle Scholar
  119. 119.
    Rao A, Hogan PG (2009) Calcium signaling in cells of the immune and hematopoietic systems. Immunol Rev 231:5–9PubMedCrossRefGoogle Scholar
  120. 120.
    Rohacs T, Bago A, Deak F, Hunyady L, Spat A (1994) Capacitative Ca2+ influx in adrenal glomerulosa cells: possible role in angiotensin II response. Am J Physiol 267:C1246–C1252PubMedGoogle Scholar
  121. 121.
    Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169:435–445PubMedCrossRefGoogle Scholar
  122. 122.
    Rychkov G, Brereton HM, Harland ML, Barritt GJ (2001) Plasma membrane Ca2+ release-activated Ca2+ channels with a high selectivity for Ca2+ identified by patch-clamp recording in rat liver cells. Hepatology 33:938–947PubMedCrossRefGoogle Scholar
  123. 123.
    Sabbioni S, Barbanti-Brodano G, Croce CM, Negrini M (1997) GOK: a gene at 11p15 involved in rhabdomyosarcoma and rhabdoid tumor development. Cancer Res 57:4493–4497PubMedGoogle Scholar
  124. 124.
    Sato K, Sato F (1988) Relationship between quin-2 determined cytosolic [Ca2+] and sweat secretion. Am J Phys 254:C310–C317Google Scholar
  125. 125.
    Schlesier M, Niemeyer C, Duffner U, Henschen M, Tanzi-Fetta R, Wolff-Vorbeck G, Drager R, Brandis M, Peter HH (1993) Primary severe immunodeficiency due to impaired signal transduction in T cells. Immunodeficiency 4:133–136PubMedGoogle Scholar
  126. 126.
    Scrimgeour (2009) Properties of orai1 mediated store-operated current depend on the expression levels of STIM1 and orai1 proteins. J Physiology 587:2903–2918CrossRefGoogle Scholar
  127. 127.
    Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL (2006) Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem 281:20661–20665PubMedCrossRefGoogle Scholar
  128. 128.
    Spassova MA, Soboloff J, He LP, Xu W, Dziadek MA, Gill DL (2006) STIM1 has a plasma membrane role in the activation of store-operated Ca2+ channels. Proc Natl Acad Sci U S A 103:4040–4045PubMedCrossRefGoogle Scholar
  129. 129.
    Stathopulos PB, Zheng L, Ikura M (2009) Stromal interaction molecule (STIM) 1 and STIM2 calcium sensing regions exhibit distinct unfolding and oligomerization kinetics. J Biol Chem 284:728–732PubMedCrossRefGoogle Scholar
  130. 130.
    Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M (2008) Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 135:110–122PubMedCrossRefGoogle Scholar
  131. 131.
    Stewart M (2005) “The Hours”, Greek Mythology: From the Iliad to the Fall of the Last Tyrant.
  132. 132.
    Stiber J, Hawkins A, Zhang ZS, Wang SW, Burch J, Graham V, Ward CC, Seth M, Finch E, Malouf N, Williams RS, Eu JP, Rosenberg P (2008) STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle. Nat Cell Biol 10:688–697PubMedCrossRefGoogle Scholar
  133. 133.
    Sweeney M, McDaniel SS, Platoshyn O, Zhang S, Yu Y, Lapp BR, Zhao Y, Thistlethwaite PA, Yuan JX (2002) Role of capacitative Ca2+ entry in bronchial contraction and remodeling. J Appl Physiol 92:1594–1602PubMedGoogle Scholar
  134. 134.
    Tiruppathi C, Freichel M, Vogel SM, Paria BC, Mehta D, Flockerzi V, Malik AB (2002) Impairment of store-operated Ca2+ entry in TRPC4-/- mice interferes with increase in lung microvascular permeability. Circ Res 91:70–76PubMedCrossRefGoogle Scholar
  135. 135.
    Trepakova ES, Gericke M, Hirakawa Y, Weisbrod RM, Cohen RA, Bolotina VM (2001) Properties of a native cation channel activated by Ca2+ store depletion in vascular smooth muscle cells. J Biol Chem 276:7782–7790PubMedCrossRefGoogle Scholar
  136. 136.
    Vaca L, Kunze DL (1994) Depletion of intracellular Ca2+ stores activates a Ca2+-selective channel in vascular endothelium. Am J Physiol 267:C920–C925PubMedGoogle Scholar
  137. 137.
    Vanden Abeele F, Shuba Y, Roudbaraki M, Lemonnier L, Vanoverberghe K, Mariot P, Skryma R, Prevarskaya N (2003) Store-operated Ca2+ channels in prostate cancer epithelial cells: function, regulation, and role in carcinogenesis. Cell Calcium 33:357–373PubMedCrossRefGoogle Scholar
  138. 138.
    Varga-Szabo D, Braun A, Kleinschnitz C, Bender M, Pleines I, Pham M, Renne T, Stoll G, Nieswandt B (2008) The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J Exp Med 205:1583–1591PubMedCrossRefGoogle Scholar
  139. 139.
    Varga-Szabo D, Braun A, Nieswandt B (2009) Calcium signaling in platelets. J Thromb Haemost 7:1057–1066PubMedCrossRefGoogle Scholar
  140. 140.
    Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387–417PubMedCrossRefGoogle Scholar
  141. 141.
    Vig M, Beck A, Billingsley JM, Lis A, Parvez S, Peinelt C, Koomoa DL, Soboloff J, Gill DL, Fleig A, Kinet JP, Penner R (2006) CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol 16:2073–2079PubMedCrossRefGoogle Scholar
  142. 142.
    Vig M, DeHaven WI, Bird GS, Billingsley JM, Wang H, Rao PE, Hutchings AB, Jouvin MH, Putney JW, Kinet JP (2008) Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels. Nat Immunol 9:89–96PubMedCrossRefGoogle Scholar
  143. 143.
    Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP (2006) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220–1223PubMedCrossRefGoogle Scholar
  144. 144.
    Villalobos C, Garcia-Sancho J (1995) Capacitative Ca2+ entry contributes to the Ca2+ influx induced by thyrotropin-releasing hormone (TRH) in GH3 pituitary cells. Pflugers Arch 430:923–935PubMedCrossRefGoogle Scholar
  145. 145.
    Voets T, Prenen J, Fleig A, Vennekens R, Watanabe H, Hoenderop JG, Bindels RJ, Droogmans G, Penner R, Nilius B (2001) CaT1 and the calcium release-activated calcium channel manifest distinct pore properties. J Biol Chem 276:47767–47770PubMedGoogle Scholar
  146. 146.
    Wechsler HL, Fisher ER (1968) Eccrine glands of the rat. Response to induced sweating, hypertension, uremia, and alterations of sodium state. Arch Dermatol 97:189–201PubMedCrossRefGoogle Scholar
  147. 147.
    Williams RT, Manji SS, Parker NJ, Hancock MS, Van Stekelenburg L, Eid JP, Senior PV, Kazenwadel JS, Shandala T, Saint R, Smith PJ, Dziadek MA (2001) Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem J 357:673–685PubMedCrossRefGoogle Scholar
  148. 148.
    Williams RT, Senior PV, Van Stekelenburg L, Layton JE, Smith PJ, Dziadek MA (2002) 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 1596:131–137PubMedGoogle Scholar
  149. 149.
    Worley PF, Zeng W, Huang GN, Yuan JP, Kim JY, Lee MG, Muallem S (2007) TRPC channels as STIM1-regulated store-operated channels. Cell Calcium 42:205–211PubMedCrossRefGoogle Scholar
  150. 150.
    Wright JT, Hart PS, Aldred MJ, Seow K, Crawford PJ, Hong SP, Gibson CW, Hart TC (2003) Relationship of phenotype and genotype in X-linked amelogenesis imperfecta. Connect Tissue Res 44(Suppl 1):72–78PubMedGoogle Scholar
  151. 151.
    Wu MM, Buchanan J, Luik RM, Lewis RS (2006) Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol 174:803–813PubMedCrossRefGoogle Scholar
  152. 152.
    Xu SZ, Beech DJ (2001) TrpC1 is a membrane-spanning subunit of store-operated Ca2+ channels in native vascular smooth muscle cells. Circ Res 88:84–87PubMedCrossRefGoogle Scholar
  153. 153.
    Yamashita M, Navarro-Borelly L, McNally BA, Prakriya M (2007) Orai1 mutations alter ion permeation and Ca2+-dependent fast inactivation of CRAC channels: evidence for coupling of permeation and gating. J Gen Physiol 130:525–540PubMedCrossRefGoogle Scholar
  154. 154.
    Yang S, Zhang J, Huang X (2009) Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell 15:124–134PubMedCrossRefGoogle Scholar
  155. 155.
    Yeromin AV, Zhang S, Jiang W, Yu Y, Safrina O, Cahalan MD (2006) Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443:226–229PubMedCrossRefGoogle Scholar
  156. 156.
    Yuan JP, Kim MS, Zeng W, Shin DM, Huang G, Worley PF, Muallem S (2009) TRPC channels as STIM1-regulated SOCs. Channels (Austin) 3:221–225Google Scholar
  157. 157.
    Yuan J, Zeng W, Dorwart MR, Choi Y, Worley P, Muallem S (2009) SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat Cell Biol 11:337–343PubMedCrossRefGoogle Scholar
  158. 158.
    Yue L, Peng J, Hediger M, Clapham D (2001) CaT1 manifests the pore properties of the calcium-release-activated calcium channel. Nature 410:705–709PubMedCrossRefGoogle Scholar
  159. 159.
    Zeng W, Yuan J, Kim M, Choi Y, Huang G, Worley P, Muallem S (2008) STIM1 Gates TRPC channels, but not Orai1, by electrostatic interaction. Mol Cell 32:439–448PubMedCrossRefGoogle Scholar
  160. 160.
    Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD (2006) Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity. Proc Natl Acad Sci U S A 103:9357–9362PubMedCrossRefGoogle Scholar
  161. 161.
    Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, Shapira SK, Farndon PA, Wara DW, Emmal SA, Ferguson BM (2000) A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKKγ (NEMO). Am J Hum Genet 67:1555–1562PubMedCrossRefGoogle Scholar
  162. 162.
    Zweifach A, Lewis RS (1993) Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc Natl Acad Sci U S A 90:6295–6299PubMedCrossRefGoogle Scholar

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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of PathologyNew York University, Langone Medical Center, SRB314New YorkUSA
  2. 2.Department of PathologyNew York University, Langone Medical CenterNew YorkUSA

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