Immunological Disorders: Regulation of Ca2+ Signaling in T Lymphocytes

  • Sonal Srikanth
  • Jin Seok Woo
  • Zuoming Sun
  • Yousang GwackEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 993)


Engagement of T cell receptors (TCRs) with cognate antigens triggers cascades of signaling pathways in helper T cells. TCR signaling is essential for the effector function of helper T cells including proliferation, differentiation, and cytokine production. It also modulates effector T cell fate by inducing cell death, anergy (nonresponsiveness), exhaustion, and generation of regulatory T cells. One of the main axes of TCR signaling is the Ca2+-calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway. Stimulation of TCRs triggers depletion of intracellular Ca2+ store and, in turn, activates store-operated Ca2+ entry (SOCE) to raise the intracellular Ca2+ concentration. SOCE in T cells is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels, which have been very well characterized in terms of their electrophysiological properties. Identification of STIM1 as a sensor to detect depletion of the endoplasmic reticulum (ER) Ca2+ store and Orai1 as the pore subunit of CRAC channels has dramatically advanced our understanding of the regulatory mechanism of Ca2+ signaling in T cells. In this review, we discuss our current understanding of Ca2+ signaling in T cells with specific focus on the mechanism of CRAC channel activation and regulation via protein interactions. In addition, we will discuss the role of CRAC channels in effector T cells, based on the analyses of genetically modified animal models.


T-cell receptor signaling CRAC channels Orai and STIM proteins Effector T cells Cytokine production Differentiation of T cells 



This work was supported by National Institute of Health grants AI-083432 and AI109059 (Y.G.).


  1. Aramburu J, Yaffe MB, Lopez-Rodriguez C, Cantley LC, Hogan PG, Rao A (1999) Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science 285:2129–2133PubMedCrossRefGoogle Scholar
  2. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, Yamasaki N, Miyakawa T, Francke U, Graef IA, Crabtree GR (2006) NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441:595–600PubMedCrossRefGoogle Scholar
  3. Badou A, Jha MK, Matza D, Flavell RA (2013) Emerging roles of L-type voltage-gated and other calcium channels in T lymphocytes. Front Immunol 4:243PubMedPubMedCentralCrossRefGoogle Scholar
  4. Baine I, Abe BT, Macian F (2009) Regulation of T-cell tolerance by calcium/NFAT signaling. Immunol Rev 231:225–240PubMedCrossRefGoogle Scholar
  5. Balagopalan L, Coussens NP, Sherman E, Samelson LE, Sommers CL (2010) The LAT story: a tale of cooperativity, coordination, and choreography. Cold Spring Harb Perspect Biol 2:a005512PubMedPubMedCentralCrossRefGoogle Scholar
  6. Barr VA, Bernot KM, Srikanth S, Gwack Y, Balagopalan L, Regan CK, Helman DJ, Sommers CL, Oh-Hora M, Rao A, Samelson LE (2008) Dynamic movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells: puncta and distal caps. Mol Biol Cell 19:2802–2817PubMedPubMedCentralCrossRefGoogle Scholar
  7. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529PubMedCrossRefGoogle Scholar
  8. Brandman O, Liou J, Park WS, Meyer T (2007) STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131:1327–1339PubMedPubMedCentralCrossRefGoogle Scholar
  9. Budd RC (2001) Activation-induced cell death. Curr Opin Immunol 13:356–362PubMedCrossRefGoogle Scholar
  10. Cahalan MD, Chandy KG (2009) The functional network of ion channels in T lymphocytes. Immunol Rev 231:59–87PubMedPubMedCentralCrossRefGoogle Scholar
  11. Carrasco S, Meyer T (2011) STIM proteins and the endoplasmic reticulum-plasma membrane junctions. Annu Rev Biochem 80:973–1000PubMedPubMedCentralCrossRefGoogle Scholar
  12. Christel C, Lee A (2012) Ca2+-dependent modulation of voltage-gated Ca2+ channels. Biochim Biophys Acta 1820:1243–1252PubMedCrossRefGoogle Scholar
  13. Constant SL, Bottomly K (1997) Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol 15:297–322PubMedCrossRefGoogle Scholar
  14. Coudronniere N, Villalba M, Englund N, Altman A (2000) NF-kappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta. Proc Natl Acad Sci USA 97:3394–3399PubMedPubMedCentralGoogle Scholar
  15. Desvignes L, Weidinger C, Shaw P, Vaeth M, Ribierre T, Liu M, Fergus T, Kozhaya L, McVoy L, Unutmaz D, Ernst JD, Feske S (2015) STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection. J Clin Invest 125:2347–2362PubMedPubMedCentralCrossRefGoogle Scholar
  16. Dolmetsch RE, Lewis RS (1994) Signaling between intracellular Ca2+ stores and depletion-activated Ca2+ channels generates [Ca2+]i oscillations in T lymphocytes. J Gen Physiol 103:365–388PubMedCrossRefGoogle Scholar
  17. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI (1997) Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386:855–858PubMedCrossRefGoogle Scholar
  18. Dolmetsch RE, Xu K, Lewis RS (1998) Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392:933–936PubMedCrossRefGoogle Scholar
  19. 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
  20. Garbino A, van Oort RJ, Dixit SS, Landstrom AP, Ackerman MJ, Wehrens XH (2009) Molecular evolution of the junctophilin gene family. Physiol Genomics 37:175–186PubMedPubMedCentralCrossRefGoogle Scholar
  21. Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H, Bolton D, Feske S, Hogan PG, Rao A (2006) A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441:646–650PubMedCrossRefGoogle Scholar
  22. Gwack Y, Feske S, Srikanth S, Hogan PG, Rao A (2007a) Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. Cell Calcium 42:145–156PubMedCrossRefGoogle Scholar
  23. Gwack Y, Srikanth S, Feske S, Cruz-Guilloty F, Oh-hora M, Neems DS, Hogan PG, Rao A (2007b) Biochemical and functional characterization of Orai proteins. J Biol Chem 282:16232–16243PubMedCrossRefGoogle Scholar
  24. 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 28:5209–5222PubMedPubMedCentralCrossRefGoogle Scholar
  25. Hartzell CA, Jankowska KI, Burkhardt JK, Lewis RS (2016) Calcium influx through CRAC channels controls actin organization and dynamics at the immune synapse. Elife 21:5Google Scholar
  26. Hildeman DA, Zhu Y, Mitchell TC, Bouillet P, Strasser A, Kappler J, Marrack P (2002) Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity 16:759–767PubMedCrossRefGoogle Scholar
  27. Hildeman D, Jorgensen T, Kappler J, Marrack P (2007) Apoptosis and the homeostatic control of immune responses. Curr Opin Immunol 19:516–521PubMedPubMedCentralCrossRefGoogle Scholar
  28. Hodge MR, Ranger AM, Charles de la Brousse F, Hoey T, Grusby MJ, Glimcher LH (1996) Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Immunity 4:397–405PubMedCrossRefGoogle Scholar
  29. Hogan PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17:2205–2232PubMedCrossRefGoogle Scholar
  30. Hogan PG, Lewis RS, Rao A (2010) Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol 28:491–533PubMedPubMedCentralCrossRefGoogle Scholar
  31. Hoth M, Penner R (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–356PubMedCrossRefGoogle Scholar
  32. Hoth M, Penner R (1993) Calcium release-activated calcium current in rat mast cells. J Physiol 465:359–386PubMedPubMedCentralCrossRefGoogle Scholar
  33. Ishiguro K, Green T, Rapley J, Wachtel H, Giallourakis C, Landry A, Cao Z, Lu N, Takafumi A, Goto H, Daly MJ, Xavier RJ (2006) Ca2+/calmodulin-dependent protein kinase II is a modulator of CARMA1-mediated NF-kappaB activation. Mol Cell Biol 26:5497–5508PubMedPubMedCentralCrossRefGoogle Scholar
  34. Ishiguro K, Ando T, Goto H, Xavier R (2007) Bcl10 is phosphorylated on Ser138 by Ca2+/calmodulin-dependent protein kinase II. Mol Immunol 44:2095–2100PubMedCrossRefGoogle Scholar
  35. Jha A, Ahuja M, Maleth J, Moreno CM, Yuan JP, Kim MS, Muallem S (2013) The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function. J Cell Biol 202:71–79PubMedPubMedCentralCrossRefGoogle Scholar
  36. Jha A, Singh AK, Weissgerber P, Freichel M, Flockerzi V, Flavell RA, Jha MK (2015) Essential roles for Cavbeta2 and Cav1 channels in thymocyte development and T cell homeostasis. Sci Signal 8:ra103PubMedCrossRefGoogle Scholar
  37. Jing J, He L, Sun A, Quintana A, Ding Y, Ma G, Tan P, Liang X, Zheng X, Chen L, Shi X, Zhang SL, Zhong L, Huang Y, Dong MQ, Walker CL, Hogan PG, Wang Y, Zhou Y (2015) Proteomic mapping of ER-PM junctions identifies STIMATE as a regulator of Ca(2)(+) influx. Nat Cell Biol 17:1339–1347PubMedPubMedCentralCrossRefGoogle Scholar
  38. Kar P, Nelson C, Parekh AB (2011) Selective activation of the transcription factor NFAT1 by calcium microdomains near Ca2+ release-activated Ca2+ (CRAC) channels. J Biol Chem 286:14795–14803PubMedPubMedCentralCrossRefGoogle Scholar
  39. Kaufmann U, Shaw PJ, Kozhaya L, Subramanian R, Gaida K, Unutmaz D, McBride HJ, Feske S (2016) Selective ORAI1 inhibition ameliorates autoimmune central nervous system inflammation by suppressing effector but not regulatory T cell function. J Immunol 196:573–585PubMedCrossRefGoogle Scholar
  40. Kim KD, Srikanth S, Yee MK, Mock DC, Lawson GW, Gwack Y (2011) ORAI1 deficiency impairs activated T cell death and enhances T cell survival. J Immunol 187:3620–3630PubMedPubMedCentralCrossRefGoogle Scholar
  41. Kim KD, Srikanth S, Tan YV, Yee MK, Jew M, Damoiseaux R, Jung ME, Shimizu S, An DS, Ribalet B, Waschek JA, Gwack Y (2014) Calcium signaling via Orai1 is essential for induction of the nuclear orphan receptor pathway to drive Th17 differentiation. J Immunol 192:110–122PubMedCrossRefGoogle Scholar
  42. Krammer PH, Arnold R, Lavrik IN (2007) Life and death in peripheral T cells. Nat Rev Immunol 7:532–542PubMedCrossRefGoogle Scholar
  43. Krapivinsky G, Krapivinsky L, Stotz SC, Manasian Y, Clapham DE (2011) POST, partner of stromal interaction molecule 1 (STIM1), targets STIM1 to multiple transporters. Proc Natl Acad Sci USA 108:19234–19239PubMedPubMedCentralCrossRefGoogle Scholar
  44. Kyriakis JM, Avruch J (2012) Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev 92:689–737PubMedCrossRefGoogle Scholar
  45. 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 USA 106:14687–14692PubMedPubMedCentralCrossRefGoogle Scholar
  46. Lewis RS (2011) Store-operated calcium channels: new perspectives on mechanism and function. Cold Spring Harb Perspect Biol 3(12):a003970PubMedPubMedCentralCrossRefGoogle Scholar
  47. Lewis RS, Cahalan MD (1989) Mitogen-induced oscillations of cytosolic Ca2+ and transmembrane Ca2+ current in human leukemic T cells. Cell Regul 1:99–112PubMedPubMedCentralGoogle Scholar
  48. Li P, Miao Y, Dani A, Vig M (2016) alpha-SNAP regulates dynamic, on-site assembly and calcium selectivity of Orai1 channels. Mol Biol Cell 27(16):2542–2553PubMedPubMedCentralCrossRefGoogle Scholar
  49. Lin X, O’Mahony A, Mu Y, Geleziunas R, Greene WC (2000) Protein kinase C-theta participates in NF-kappaB activation induced by CD3-CD28 costimulation through selective activation of IkappaB kinase beta. Mol Cell Biol 20:2933–2940PubMedPubMedCentralCrossRefGoogle Scholar
  50. Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T (2005) STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol 15:1235–1241PubMedPubMedCentralCrossRefGoogle Scholar
  51. 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 USA 104:9301–9306PubMedPubMedCentralCrossRefGoogle Scholar
  52. Lioudyno MI, Kozak JA, Penna A, Safrina O, Zhang SL, Sen D, Roos J, Stauderman KA, Cahalan MD (2008) Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. Proc Natl Acad Sci USA 105:2011–2016PubMedPubMedCentralCrossRefGoogle Scholar
  53. Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ (2011) The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 12:1063–1070PubMedPubMedCentralCrossRefGoogle Scholar
  54. Liu X, Berry CT, Ruthel G, Madara JJ, MacGillivray K, Gray CM, Madge LA, McCorkell KA, Beiting DP, Hershberg U, May MJ, Freedman BD (2016) T cell receptor-induced Nuclear Factor kappaB (NF-kappaB) signaling and transcriptional activation are regulated by STIM1- and Orai1-mediated calcium entry. J Biol Chem 291:8440–8452PubMedPubMedCentralCrossRefGoogle Scholar
  55. 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 174:815–825PubMedPubMedCentralCrossRefGoogle Scholar
  56. Ma J, McCarl CA, Khalil S, Luthy K, Feske S (2010) 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 40:3028–3042PubMedPubMedCentralCrossRefGoogle Scholar
  57. Macian F (2005) NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5:472–484PubMedCrossRefGoogle Scholar
  58. Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A (2002) Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109:719–731PubMedCrossRefGoogle Scholar
  59. Marrack P, Kappler J (2004) Control of T cell viability. Annu Rev Immunol 22:765–787PubMedCrossRefGoogle Scholar
  60. Marsden VS, Strasser A (2003) Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more. Annu Rev Immunol 21:71–105PubMedCrossRefGoogle Scholar
  61. Matsumoto M, Fujii Y, Baba A, Hikida M, Kurosaki T, Baba Y (2011) The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. Immunity 34:703–714PubMedCrossRefGoogle Scholar
  62. McCarl CA, Khalil S, Ma J, Oh-hora M, Yamashita M, Roether J, Kawasaki T, Jairaman A, Sasaki Y, Prakriya M, Feske S (2010) Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection. J Immunol 185:5845–5858PubMedPubMedCentralCrossRefGoogle Scholar
  63. McNally BA, Somasundaram A, Yamashita M, Prakriya M (2012) Gated regulation of CRAC channel ion selectivity by STIM1. Nature 482:241–245PubMedPubMedCentralGoogle Scholar
  64. Miao Y, Miner C, Zhang L, Hanson PI, Dani A, Vig M (2013) An essential and NSF independent role for alpha-SNAP in store-operated calcium entry. Elife 2:e00802PubMedPubMedCentralCrossRefGoogle Scholar
  65. Mognol GP, Carneiro FR, Robbs BK, Faget DV, Viola JP (2016) Cell cycle and apoptosis regulation by NFAT transcription factors: new roles for an old player. Cell Death Dis 7:e2199PubMedPubMedCentralCrossRefGoogle Scholar
  66. Mor A, Philips MR (2006) Compartmentalized Ras/MAPK signaling. Annu Rev Immunol 24:771–800PubMedCrossRefGoogle Scholar
  67. Morreale A, Venkatesan M, Mott HR, Owen D, Nietlispach D, Lowe PN, Laue ED (2000) Structure of Cdc42 bound to the GTPase binding domain of PAK. Nat Struct Biol 7:384–388PubMedCrossRefGoogle Scholar
  68. 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
  69. 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 284:8421–8426PubMedPubMedCentralCrossRefGoogle Scholar
  70. Muller MR, Rao A (2010) NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol 10:645–656PubMedCrossRefGoogle Scholar
  71. 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 USA 106:15495–15500PubMedPubMedCentralCrossRefGoogle Scholar
  72. 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 586:5383–5401PubMedPubMedCentralCrossRefGoogle Scholar
  73. Nishi M, Sakagami H, Komazaki S, Kondo H, Takeshima H (2003) Coexpression of junctophilin type 3 and type 4 in brain. Brain Res Mol Brain Res 118:102–110PubMedCrossRefGoogle Scholar
  74. Nohara LL, Stanwood SR, Omilusik KD, Jefferies WA (2015) Tweeters, woofers and horns: the complex orchestration of calcium currents in T lymphocytes. Front Immunol 6:234PubMedPubMedCentralCrossRefGoogle Scholar
  75. Oh-Hora M, Yamashita M, Hogan PG, 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 9:432–443PubMedPubMedCentralCrossRefGoogle Scholar
  76. Oh-Hora M, Komatsu N, Pishyareh M, Feske S, Hori S, Taniguchi M, Rao A, Takayanagi H (2013) Agonist-selected T cell development requires strong T cell receptor signaling and store-operated calcium entry. Immunity 38(5):881–895PubMedPubMedCentralCrossRefGoogle Scholar
  77. Omilusik K, Priatel JJ, Chen X, Wang YT, Xu H, Choi KB, Gopaul R, McIntyre-Smith A, Teh HS, Tan R, Bech-Hansen NT, Waterfield D, Fedida D, Hunt SV, Jefferies WA (2011) The Ca(v)1.4 calcium channel is a critical regulator of T cell receptor signaling and naive T cell homeostasis. Immunity 35:349–360PubMedCrossRefGoogle Scholar
  78. Oruganti SR, Edin S, Grundstrom C, Grundstrom T (2011) CaMKII targets Bcl10 in T-cell receptor induced activation of NF-kappaB. Mol Immunol 48:1448–1460PubMedCrossRefGoogle Scholar
  79. Palty R, Raveh A, Kaminsky I, Meller R, Reuveny E (2012) SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling. Cell 149:425–438PubMedCrossRefGoogle Scholar
  80. 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 136:876–890PubMedPubMedCentralCrossRefGoogle Scholar
  81. 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 360:1971–1980PubMedPubMedCentralCrossRefGoogle Scholar
  82. Putney JW Jr (1986) A model for receptor-regulated calcium entry. Cell Calcium 7:1–12PubMedCrossRefGoogle Scholar
  83. Putney JW Jr (2009) Capacitative calcium entry: from concept to molecules. Immunol Rev 231:10–22PubMedCrossRefGoogle Scholar
  84. Quintana A, Rajanikanth V, Farber-Katz S, Gudlur A, Zhang C, Jing J, Zhou Y, Rao A, Hogan PG (2015) TMEM110 regulates the maintenance and remodeling of mammalian ER-plasma membrane junctions competent for STIM-ORAI signaling. Proc Natl Acad Sci USA 112:E7083–E7092PubMedPubMedCentralGoogle Scholar
  85. Ritchie MF, Samakai E, Soboloff J (2012) STIM1 is required for attenuation of PMCA-mediated Ca2+ clearance during T-cell activation. EMBO J 31:1123–1133PubMedPubMedCentralCrossRefGoogle Scholar
  86. Robbs BK, Cruz AL, Werneck MB, Mognol GP, Viola JP (2008) Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol Cell Biol 28:7168–7181PubMedPubMedCentralCrossRefGoogle Scholar
  87. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Veliçelebi G, Stauderman KA (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169:435–445PubMedPubMedCentralCrossRefGoogle Scholar
  88. Samelson LE (2011) Immunoreceptor signaling. Cold Spring Harb Perspect Biol 3(12):a011510PubMedPubMedCentralCrossRefGoogle Scholar
  89. Schuhmann MK, Stegner D, Berna-Erro A, Bittner S, Braun A, Kleinschnitz C, Stoll G, Wiendl H, Meuth SG, Nieswandt B (2010) Stromal interaction molecules 1 and 2 are key regulators of autoreactive T cell activation in murine autoimmune central nervous system inflammation. J Immunol 184:1536–1542PubMedCrossRefGoogle Scholar
  90. Scrimgeour N, Litjens T, Ma L, Barritt GJ, Rychkov GY (2009) Properties of Orai1 mediated store-operated current depend on the expression levels of STIM1 and Orai1 proteins. J Physiol 587:2903–2918PubMedPubMedCentralCrossRefGoogle Scholar
  91. Serfling E, Klein-Hessling S, Palmetshofer A, Bopp T, Stassen M, Schmitt E (2006) NFAT transcription factors in control of peripheral T cell tolerance. Eur J Immunol 36:2837–2843PubMedCrossRefGoogle Scholar
  92. Serfling E, Avots A, Klein-Hessling S, Rudolf R, Vaeth M, Berberich-Siebelt F (2012) NFATc1/alphaA: the other face of NFAT Factors in lymphocytes. Cell Commun Signal 10:16PubMedPubMedCentralCrossRefGoogle Scholar
  93. Sharma S, Findlay GM, Bandukwala HS, Oberdoerffer S, Baust B, Li Z, Schmidt V, Hogan PG, Sacks DB, Rao A (2011) Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc Natl Acad Sci USA 108:11381–11386PubMedPubMedCentralCrossRefGoogle Scholar
  94. Shi X, Bi Y, Yang W, Guo X, Jiang Y, Wan C, Li L, Bai Y, Guo J, Wang Y, Chen X, Wu B, Sun H, Liu W, Wang J, Xu C (2013) Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids. Nature 493:111–115PubMedCrossRefGoogle Scholar
  95. Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619PubMedPubMedCentralCrossRefGoogle Scholar
  96. Soboloff J, Rothberg BS, Madesh M, Gill DL (2012) STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol 13:549–565PubMedPubMedCentralCrossRefGoogle Scholar
  97. Sprent J, Surh CD (2011) Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat Immunol 12:478–484PubMedPubMedCentralCrossRefGoogle Scholar
  98. Srikanth S, Gwack Y (2012) Orai1, STIM1, and their associating partners. J Physiol 590:4169–4177PubMedPubMedCentralCrossRefGoogle Scholar
  99. Srikanth S, Gwack Y (2013a) Molecular regulation of the pore component of CRAC channels, Orai1. Curr Top Membr 71:181–207PubMedCrossRefGoogle Scholar
  100. Srikanth S, Gwack Y (2013b) Orai1-NFAT signalling pathway triggered by T cell receptor stimulation. Mol Cells 35:182–194PubMedPubMedCentralCrossRefGoogle Scholar
  101. Srikanth S, Jung HJ, Kim KD, Souda P, Whitelegge J, Gwack Y (2010a) A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that stabilizes CRAC channels in T cells. Nat Cell Biol 12:436–446PubMedPubMedCentralCrossRefGoogle Scholar
  102. Srikanth S, Jung HJ, Ribalet B, Gwack Y (2010b) The intracellular loop of Orai1 plays a central role in fast inactivation of Ca2+ release-activated Ca2+ channels. J Biol Chem 285:5066–5075PubMedCrossRefGoogle Scholar
  103. Srikanth S, Jew M, Kim KD, Yee MK, Abramson J, Gwack Y (2012) Junctate is a Ca2+-sensing structural component of Orai1 and stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA 109:8682–8687PubMedPubMedCentralCrossRefGoogle Scholar
  104. Srikanth S, Ribalet B, Gwack Y (2013) Regulation of CRAC channels by protein interactions and post-translational modification. Channels (Austin) 7(5):354–363CrossRefGoogle Scholar
  105. Srikanth S, Kim KD, Gao Y, Woo JS, Ghosh S, Calmettes G, Paz A, Abramson J, Jiang M, Gwack Y (2016a) A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals. Sci Signal 9:ra31PubMedPubMedCentralCrossRefGoogle Scholar
  106. Srikanth S, Woo JS, Gwack Y (2016b) A large Rab GTPase family in a small GTPase world. Small GTPases 24:1–6Google Scholar
  107. Srinivasan M, Frauwirth KA (2007) Reciprocal NFAT1 and NFAT2 nuclear localization in CD8+ anergic T cells is regulated by suboptimal calcium signaling. J Immunol 179:3734–3741PubMedCrossRefGoogle Scholar
  108. Strasser A (2005) The role of BH3-only proteins in the immune system. Nat Rev Immunol 5:189–200PubMedCrossRefGoogle Scholar
  109. Strasser A, Pellegrini M (2004) T-lymphocyte death during shutdown of an immune response. Trends Immunol 25:610–615PubMedCrossRefGoogle Scholar
  110. Sun Z (2012) Intervention of PKC-theta as an immunosuppressive regimen. Front Immunol 3:225PubMedPubMedCentralGoogle Scholar
  111. Sun Z, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ, Gandhi L, Annes J, Petrzilka D, Kupfer A, Schwartzberg PL, Littman DR (2000) PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes. Nature 404:402–407PubMedCrossRefGoogle Scholar
  112. Takeshima H, Komazaki S, Nishi M, Iino M, Kangawa K (2000) Junctophilins: a novel family of junctional membrane complex proteins. Mol Cell 6:11–22PubMedGoogle Scholar
  113. Tybulewicz VL (2005) Vav-family proteins in T-cell signalling. Curr Opin Immunol 17:267–274PubMedCrossRefGoogle Scholar
  114. Varnai P, Toth B, Toth DJ, Hunyady L, Balla T (2007) 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 282:29678–29690PubMedCrossRefGoogle Scholar
  115. Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinnet JP (2006) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220–1223PubMedCrossRefGoogle Scholar
  116. Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, Weiss A (2010) ZAP-70: an essential kinase in T-cell signaling. Cold Spring Harb Perspect Biol 2:a002279PubMedPubMedCentralCrossRefGoogle Scholar
  117. Weisleder N, Takeshima H, Ma J (2008) Immuno-proteomic approach to excitation–contraction coupling in skeletal and cardiac muscle: molecular insights revealed by the mitsugumins. Cell Calcium 43:1–8PubMedCrossRefGoogle Scholar
  118. Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB, Schultz PG (2005) A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309:1570–1573PubMedCrossRefGoogle Scholar
  119. Wilson LA, McKeown L, Tumova S, Li J, Beech DJ (2015) Expression of a long variant of CRACR2A that belongs to the Rab GTPase protein family in endothelial cells. Biochem Biophys Res Commun 456:398–402PubMedPubMedCentralCrossRefGoogle Scholar
  120. Woo JS, Srikanth S, Nishi M, Ping P, Takeshima H, Gwack Y (2016) Junctophilin-4, a component of the endoplasmic reticulum-plasma membrane junctions, regulates Ca2+ dynamics in T cells. Proc Natl Acad Sci USA 113:2762–2767PubMedPubMedCentralCrossRefGoogle Scholar
  121. 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 174:803–813PubMedPubMedCentralCrossRefGoogle Scholar
  122. Wu H, Peisley A, Graef IA, Crabtree GR (2007) NFAT signaling and the invention of vertebrates. Trends Cell Biol 17:251–260PubMedCrossRefGoogle Scholar
  123. Yuan JP, Zeng W, Dorwart MR, Choi YJ, Worley PF, Muallem S (2009) SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat Cell Biol 11:337–343PubMedPubMedCentralCrossRefGoogle Scholar
  124. Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD (2005) STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437:902–905PubMedPubMedCentralCrossRefGoogle Scholar
  125. Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD (2006) Genome-wide RNAi screen of Ca(2+) influx identifies genes that regulate Ca(2+) release-activated Ca(2+) channel activity. Proc Natl Acad Sci USA 103:9357–9362PubMedPubMedCentralCrossRefGoogle Scholar
  126. Zhang SL, Yeromin AV, Hu J, Amcheslavsky A, Zheng H, Cahalan MD (2011) Mutations in Orai1 transmembrane segment 1 cause STIM1-independent activation of Orai1 channels at glycine 98 and channel closure at arginine 91. Proc Natl Acad Sci USA 108:17838–17843PubMedPubMedCentralCrossRefGoogle Scholar
  127. Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations. Annu Rev Immunol 28:445–489PubMedPubMedCentralCrossRefGoogle Scholar
  128. Zweifach A, Lewis RS (1995) Rapid inactivation of depletion-activated calcium current (ICRAC) due to local calcium feedback. J Gen Physiol 105:209–226PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Sonal Srikanth
    • 1
  • Jin Seok Woo
    • 1
  • Zuoming Sun
    • 2
  • Yousang Gwack
    • 1
    Email author
  1. 1.Department of PhysiologyDavid Geffen School of Medicine at UCLALos AngelesUSA
  2. 2.Department of Molecular Immunology, Beckman Research InstituteCity of HopeDuarteUSA

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