1932

Abstract

Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-032414-112212
2015-03-21
2024-04-22
Loading full text...

Full text loading...

/deliver/fulltext/immunol/33/1/annurev-immunol-032414-112212.html?itemId=/content/journals/10.1146/annurev-immunol-032414-112212&mimeType=html&fmt=ahah

Literature Cited

  1. Cahalan MD, Chandy KG. 1.  2009. The functional network of ion channels in T lymphocytes. Immunol. Rev. 231:59–87 [Google Scholar]
  2. Clapham DE. 2.  2007. Calcium signaling. Cell 131:1047–58 [Google Scholar]
  3. Feske S. 3.  2007. Calcium signalling in lymphocyte activation and disease. Nat. Rev. Immunol. 7:690–702 [Google Scholar]
  4. Feske S. 4.  2009. ORAI1 and STIM1 deficiency in human and mice: roles of store-operated Ca2+ entry in the immune system and beyond. Immunol. Rev. 231:189–209 [Google Scholar]
  5. Oh-hora M. 5.  2009. Calcium signaling in the development and function of T-lineage cells. Immunol. Rev. 231:210–24 [Google Scholar]
  6. Vig M, Kinet JP. 6.  2009. Calcium signaling in immune cells. Nat. Immunol. 10:21–27 [Google Scholar]
  7. Launay P, Cheng H, Srivatsan S, Penner R, Fleig A, Kinet JP. 7.  2004. TRPM4 regulates calcium oscillations after T cell activation. Science 306:1374–77 [Google Scholar]
  8. Launay P, Fleig A, Perraud AL, Scharenberg AM, Penner R, Kinet JP. 8.  2002. TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell 109:397–407 [Google Scholar]
  9. DeCoursey TE, Chandy KG, Gupta S, Cahalan MD. 9.  1985. Voltage-dependent ion channels in T-lymphocytes. J. Neuroimmunol. 10:71–95 [Google Scholar]
  10. Matteson DR, Deutsch C. 10.  1984. K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion. Nature 307:468–71 [Google Scholar]
  11. Grissmer S, Dethlefs B, Wasmuth JJ, Goldin AL, Gutman GA. 11.  et al. 1990. Expression and chromosomal localization of a lymphocyte K+ channel gene. PNAS 87:9411–15 [Google Scholar]
  12. Joiner WJ, Wang LY, Tang MD, Kaczmarek LK. 12.  1997. hSK4, a member of a novel subfamily of calcium-activated potassium channels. PNAS 94:11013–18 [Google Scholar]
  13. Fanger CM, Ghanshani S, Logsdon NJ, Rauer H, Kalman K. 13.  et al. 1999. Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCa1. J. Biol. Chem. 274:5746–54 [Google Scholar]
  14. Nicolaou SA, Neumeier L, Peng Y, Devor DC, Conforti L. 14.  2007. The Ca2+-activated K+ channel KCa3.1 compartmentalizes in the immunological synapse of human T lymphocytes. Am. J. Physiol. Cell Physiol. 292:C1431–39 [Google Scholar]
  15. Cai X, Srivastava S, Sun Y, Li Z, Wu H. 15.  et al. 2011. Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β. PNAS 108:20072–77 [Google Scholar]
  16. Srivastava S, Di L, Zhdanova O, Li Z, Vardhana S. 16.  et al. 2009. The class II phosphatidylinositol 3 kinase C2β is required for the activation of the K+ channel KCa3.1 and CD4 T-cells. Mol. Biol. Cell 20:3783–91 [Google Scholar]
  17. Gerlach AC, Syme CA, Giltinan L, Adelman JP, Devor DC. 17.  2001. ATP-dependent activation of the intermediate conductance, Ca2+-activated K+ channel, hIK1, is conferred by a C-terminal domain. J. Biol. Chem. 276:10963–70 [Google Scholar]
  18. Srivastava S, Li Z, Ko K, Choudhury P, Albaqumi M. 18.  et al. 2006. Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. Mol. Cell 24:665–75 [Google Scholar]
  19. Srivastava S, Choudhury P, Li Z, Liu G, Nadkarni V. 19.  et al. 2006. Phosphatidylinositol 3-phosphate indirectly activates KCa3.1 via 14 amino acids in the carboxy terminus of KCa3.1. Mol. Biol. Cell 17:146–54 [Google Scholar]
  20. Srivastava S, Ko K, Choudhury P, Li Z, Johnson AK. 20.  et al. 2006. Phosphatidylinositol-3 phosphatase myotubularin-related protein 6 negatively regulates CD4 T cells. Mol. Cell. Biol. 26:5595–602 [Google Scholar]
  21. Srivastava S, Zhdanova O, Di L, Li Z, Albaqumi M. 21.  et al. 2008. Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1. PNAS 105:14442–46 [Google Scholar]
  22. Hoth M, Penner R. 22.  1992. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–56 [Google Scholar]
  23. Lewis RS, Cahalan MD. 23.  1989. Mitogen-induced oscillations of cytosolic Ca2+ and transmembrane Ca2+ current in human leukemic T cells. Cell. Regul. 1:99–112 [Google Scholar]
  24. Zweifach A, Lewis RS. 24.  1993. Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. PNAS 90:6295–99 [Google Scholar]
  25. Ernst IM, Fliegert R, Guse AH. 25.  2013. Adenine dinucleotide second messengers and T-lymphocyte calcium signaling. Front. Immunol. 4:259 [Google Scholar]
  26. Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH. 26.  et al. 2006. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–85 [Google Scholar]
  27. Liou J, Kim M, Heo WD, Jones JT, Myers JW. 27.  et al. 2005. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 15:1235–41 [Google Scholar]
  28. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M. 28.  et al. 2005. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J. Cell Biol. 169:435–45 [Google Scholar]
  29. Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D. 29.  et al. 2006. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220–23 [Google Scholar]
  30. Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O. 30.  et al. 2006. Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity. PNAS 103:9357–62 [Google Scholar]
  31. Feske S. 31.  2010. CRAC channelopathies. Pflugers Arch. 460:417–35 [Google Scholar]
  32. Gwack Y, Srikanth S, Feske S, Cruz-Guilloty F, Oh-hora M. 32.  et al. 2007. Biochemical and functional characterization of Orai proteins. J. Biol. Chem. 282:16232–43 [Google Scholar]
  33. McCarl CA, Picard C, Khalil S, Kawasaki T, Rother J. 33.  et al. 2009. ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia. J. Allergy Clin. Immunol. 124:1311–18.e7 [Google Scholar]
  34. Williams RT, Manji SS, Parker NJ, Hancock MS, Van Stekelenburg L. 34.  et al. 2001. Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem. J. 357:673–85 [Google Scholar]
  35. Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG. 35.  2006. Orai1 is an essential pore subunit of the CRAC channel. Nature 443:230–33 [Google Scholar]
  36. Vig M, Beck A, Billingsley JM, Lis A, Parvez S. 36.  et al. 2006. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr. Biol. 16:2073–79 [Google Scholar]
  37. Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD. 37.  2006. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443:226–29 [Google Scholar]
  38. McNally BA, Yamashita M, Engh A, Prakriya M. 38.  2009. Structural determinants of ion permeation in CRAC channels. PNAS 106:22516–21 [Google Scholar]
  39. Zhou Y, Ramachandran S, Oh-hora M, Rao A, Hogan PG. 39.  2010. Pore architecture of the ORAI1 store-operated calcium channel. PNAS 107:4896–901 [Google Scholar]
  40. Lis A, Peinelt C, Beck A, Parvez S, Monteilh-Zoller M. 40.  et al. 2007. CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr. Biol. 17:794–800 [Google Scholar]
  41. Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M. 41.  2008. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 135:110–22 [Google Scholar]
  42. Hogan PG, Lewis RS, Rao A. 42.  2010. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 28:491–533 [Google Scholar]
  43. Lewis RS. 43.  2011. Store-operated calcium channels: new perspectives on mechanism and function. Cold Spring Harb. Perspect. Biol. 3:a003970 [Google Scholar]
  44. Shaw PJ, Qu B, Hoth M, Feske S. 44.  2013. Molecular regulation of CRAC channels and their role in lymphocyte function. Cell. Mol. Life Sci. 70:2637–56 [Google Scholar]
  45. Shaw PJ, Feske S. 45.  2012. Regulation of lymphocyte function by ORAI and STIM proteins in infection and autoimmunity. J. Physiol. 590:4157–67 [Google Scholar]
  46. Di L, Srivastava S, Zhdanova O, Sun Y, Li Z, Skolnik EY. 46.  2010. Nucleoside diphosphate kinase B knock-out mice have impaired activation of the K+ channel KCa3.1, resulting in defective T cell activation. J. Biol. Chem. 285:38765–71 [Google Scholar]
  47. Hess SD, Oortgiesen M, Cahalan MD. 47.  1993. Calcium oscillations in human T and natural killer cells depend upon membrane potential and calcium influx. J. Immunol. 150:2620–33 [Google Scholar]
  48. Leonard RJ, Garcia ML, Slaughter RS, Reuben JP. 48.  1992. Selective blockers of voltage-gated K+ channels depolarize human T lymphocytes: mechanism of the antiproliferative effect of charybdotoxin. PNAS 89:10094–98 [Google Scholar]
  49. Wu LJ, Sweet TB, Clapham DE. 49.  2010. International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol. Rev. 62:381–404 [Google Scholar]
  50. Billeter AT, Hellmann JL, Bhatnagar A, Polk HC Jr. 50.  2014. Transient receptor potential ion channels: powerful regulators of cell function. Ann. Surg. 259:229–35 [Google Scholar]
  51. Moran MM, McAlexander MA, Biro T, Szallasi A. 51.  2011. Transient receptor potential channels as therapeutic targets. Nat. Rev. Drug Discov. 10:601–20 [Google Scholar]
  52. Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P. 52.  et al. 2001. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411:595–99 [Google Scholar]
  53. Sano Y, Inamura K, Miyake A, Mochizuki S, Yokoi H. 53.  et al. 2001. Immunocyte Ca2+ influx system mediated by LTRPC2. Science 293:1327–30 [Google Scholar]
  54. Beck A, Kolisek M, Bagley LA, Fleig A, Penner R. 54.  2006. Nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose regulate TRPM2 channels in T lymphocytes. FASEB J. 20:962–64 [Google Scholar]
  55. Perraud AL, Schmitz C, Scharenberg AM. 55.  2003. TRPM2 Ca2+ permeable cation channels: from gene to biological function. Cell Calcium 33:519–31 [Google Scholar]
  56. Saito M, Hanson PI, Schlesinger P. 56.  2007. Luminal chloride-dependent activation of endosome calcium channels: patch clamp study of enlarged endosomes. J. Biol. Chem. 282:27327–33 [Google Scholar]
  57. Nagasawa M, Nakagawa Y, Tanaka S, Kojima I. 57.  2007. Chemotactic peptide fMetLeuPhe induces translocation of the TRPV2 channel in macrophages. J. Cell. Physiol. 210:692–702 [Google Scholar]
  58. Link TM, Park U, Vonakis BM, Raben DM, Soloski MJ, Caterina MJ. 58.  2010. TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat. Immunol. 11:232–39 [Google Scholar]
  59. Idzko M, Ferrari D, Eltzschig HK. 59.  2014. Nucleotide signalling during inflammation. Nature 509:310–17 [Google Scholar]
  60. Feuvre RA, Brough D, Iwakura Y, Takeda K, Rothwell NJ. 60.  Le 2002. Priming of macrophages with lipopolysaccharide potentiates P2X7-mediated cell death via a caspase-1-dependent mechanism, independently of cytokine production. J. Biol. Chem. 277:3210–18 [Google Scholar]
  61. Mehta N, Kaur M, Singh M, Chand S, Vyas B. 61.  et al. 2014. Purinergic receptor P2X(7): a novel target for anti-inflammatory therapy. Bioorg. Med. Chem. 22:54–88 [Google Scholar]
  62. Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A. 62.  et al. 2006. The P2X7 receptor: a key player in IL-1 processing and release. J. Immunol. 176:3877–83 [Google Scholar]
  63. Junger WG. 63.  2011. Immune cell regulation by autocrine purinergic signalling. Nat. Rev. Immunol. 11:201–12 [Google Scholar]
  64. Trautmann A. 64.  2009. Extracellular ATP in the immune system: more than just a “danger signal.”. Sci. Signal. 2:pe6 [Google Scholar]
  65. Adamson SE, Leitinger N. 65.  2014. The role of pannexin1 in the induction and resolution of inflammation. FEBS Lett. 588:1416–22 [Google Scholar]
  66. Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM. 66.  et al. 2010. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467:863–67 [Google Scholar]
  67. Catterall WA. 67.  2011. Voltage-gated calcium channels. Cold Spring Harb. Perspect. Biol. 3:a003947 [Google Scholar]
  68. Omilusik K, Priatel JJ, Chen X, Wang YT, Xu H. 68.  et al. 2011. The CaV1.4 calcium channel is a critical regulator of T cell receptor signaling and naive T cell homeostasis. Immunity 5:3349–60 [Google Scholar]
  69. Badou A, Jha MK, Matza D, Mehal WZ, Freichel M. 69.  et al. 2006. Critical role for the beta regulatory subunits of Cav channels in T lymphocyte function. PNAS 103:15529–34 [Google Scholar]
  70. Jha MK, Badou A, Meissner M, McRory JE, Freichel M. 70.  et al. 2009. Defective survival of naive CD8+ T lymphocytes in the absence of the β3 regulatory subunit of voltage-gated calcium channels. Nat. Immunol. 10:1275–82 [Google Scholar]
  71. Cabral MD, Paulet PE, Robert V, Gomes B, Renoud ML. 71.  et al. 2010. Knocking down Cav1 calcium channels implicated in Th2 cell activation prevents experimental asthma. Am. J. Respir. Crit. Care Med. 181:1310–17 [Google Scholar]
  72. Di L, Srivastava S, Zhdanova O, Ding Y, Li Z. 72.  et al. 2010. Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis. PNAS 107:1541–46 [Google Scholar]
  73. Brandao K, Deason-Towne F, Perraud AL, Schmitz C. 73.  2013. The role of Mg2+ in immune cells. Immunol. Res. 55:261–69 [Google Scholar]
  74. Scarpa A, Brinley FJ. 74.  1981. In situ measurements of free cytosolic magnesium ions. Fed. Proc. 40:2646–52 [Google Scholar]
  75. Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF. 75.  et al. 2011. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475:471–76 [Google Scholar]
  76. Goytain A, Quamme GA. 76.  2005. Identification and characterization of a novel mammalian Mg2+ transporter with channel-like properties. BMC Genomics 6:48 [Google Scholar]
  77. Zhou H, Clapham DE. 77.  2009. Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development. PNAS 106:15750–55 [Google Scholar]
  78. Bates-Withers C, Sah R, Clapham DE. 78.  2011. TRPM7, the Mg2+ inhibited channel and kinase. Adv. Exp. Med. Biol. 704:173–83 [Google Scholar]
  79. Bae CY, Sun HS. 79.  2011. TRPM7 in cerebral ischemia and potential target for drug development in stroke. Acta Pharmacol. Sin. 32:725–33 [Google Scholar]
  80. Aydemir TB, Liuzzi JP, McClellan S, Cousins RJ. 80.  2009. Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-γ expression in activated human T cells. J. Leukoc. Biol. 86:337–48 [Google Scholar]
  81. Kaltenberg J, Plum LM, Ober-Blobaum JL, Honscheid A, Rink L, Haase H. 81.  2010. Zinc signals promote IL-2-dependent proliferation of T cells. Eur. J. Immunol. 40:1496–503 [Google Scholar]
  82. Yu M, Lee WW, Tomar D, Pryshchep S, Czesnikiewicz-Guzik M. 82.  et al. 2011. Regulation of T cell receptor signaling by activation-induced zinc influx. J. Exp. Med. 208:775–85 [Google Scholar]
  83. Haase H, Hebel S, Engelhardt G, Rink L. 83.  2006. Flow cytometric measurement of labile zinc in peripheral blood mononuclear cells. Anal. Biochem. 352:222–30 [Google Scholar]
  84. Rukgauer M, Klein J, Kruse-Jarres JD. 84.  1997. Reference values for the trace elements copper, manganese, selenium, and zinc in the serum/plasma of children, adolescents, and adults. J. Trace Elem. Med. Biol. 11:92–98 [Google Scholar]
  85. Huang L, Tepaamorndech S. 85.  2013. The SLC30 family of zinc transporters—a review of current understanding of their biological and pathophysiological roles. Mol. Aspects Med. 34:548–60 [Google Scholar]
  86. Jeong J, Eide DJ. 86.  2013. The SLC39 family of zinc transporters. Mol. Aspects Med. 34:612–19 [Google Scholar]
  87. Lichten LA, Cousins RJ. 87.  2009. Mammalian zinc transporters: nutritional and physiologic regulation. Annu. Rev. Nutr. 29:153–76 [Google Scholar]
  88. Dufner-Beattie J, Huang ZL, Geiser J, Xu W, Andrews GK. 88.  2005. Generation and characterization of mice lacking the zinc uptake transporter ZIP3. Mol. Cell. Biol. 25:5607–15 [Google Scholar]
  89. Overbeck S, Uciechowski P, Ackland ML, Ford D, Rink L. 89.  2008. Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9. J. Leukoc. Biol. 83:368–80 [Google Scholar]
  90. Nishida K, Hasegawa A, Nakae S, Oboki K, Saito H. 90.  et al. 2009. Zinc transporter Znt5/Slc30a5 is required for the mast cell-mediated delayed-type allergic reaction but not the immediate-type reaction. J. Exp. Med. 206:1351–64 [Google Scholar]
  91. Cahalan MD, Chandy KG, DeCoursey TE, Gupta S. 91.  1985. A voltage-gated potassium channel in human T lymphocytes. J. Physiol. 358:197–237 [Google Scholar]
  92. Verheugen JA, Oortgiesen M, Vijverberg HP. 92.  1994. Veratridine blocks voltage-gated potassium current in human T lymphocytes and in mouse neuroblastoma cells. J. Membr. Biol. 137:205–14 [Google Scholar]
  93. Fraser SP, Diss JK, Lloyd LJ, Pani F, Chioni AM. 93.  et al. 2004. T-lymphocyte invasiveness: control by voltage-gated Na+ channel activity. FEBS Lett. 569:191–94 [Google Scholar]
  94. Lai ZF, Chen YZ, Nishimura Y, Nishi K. 94.  2000. An amiloride-sensitive and voltage-dependent Na+ channel in an HLA-DR-restricted human T cell clone. J. Immunol. 165:83–90 [Google Scholar]
  95. Lo WL, Donermeyer DL, Allen PM. 95.  2012. A voltage-gated sodium channel is essential for the positive selection of CD4+ T cells. Nat. Immunol. 13:880–87 [Google Scholar]
  96. Carrithers MD, Dib-Hajj S, Carrithers LM, Tokmoulina G, Pypaert M. 96.  et al. 2007. Expression of the voltage-gated sodium channel NaV1.5 in the macrophage late endosome regulates endosomal acidification. J. Immunol. 178:7822–32 [Google Scholar]
  97. Carrithers LM, Hulseberg P, Sandor M, Carrithers MD. 97.  2011. The human macrophage sodium channel NaV1.5 regulates mycobacteria processing through organelle polarization and localized calcium oscillations. FEMS Immunol. Med. Microbiol. 63:319–27 [Google Scholar]
  98. Black JA, Newcombe J, Waxman SG. 98.  2013. Nav1.5 sodium channels in macrophages in multiple sclerosis lesions. Mult. Scler. 19:532–42 [Google Scholar]
  99. Craner MJ, Damarjian TG, Liu S, Hains BC, Lo AC. 99.  et al. 2005. Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia 49:220–29 [Google Scholar]
  100. Zsiros E, Kis-Toth K, Hajdu P, Gaspar R, Bielanska J. 100.  et al. 2009. Developmental switch of the expression of ion channels in human dendritic cells. J. Immunol. 183:4483–92 [Google Scholar]
  101. Voss FK, Ullrich F, Munch J, Lazarow K, Lutter D. 101.  et al. 2014. Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science 344:634–38 [Google Scholar]
  102. Qiu Z, Dubin AE, Mathur J, Tu B, Reddy K. 102.  et al. 2014. SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell 157:447–58 [Google Scholar]
  103. Tian J, Lu Y, Zhang H, Chau CH, Dang HN, Kaufman DL. 103.  2004. Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. J. Immunol. 173:5298–304 [Google Scholar]
  104. Mendu SK, Akesson L, Jin Z, Edlund A, Cilio C. 104.  et al. 2011. Increased GABAA channel subunits expression in CD8+ but not in CD4+ T cells in BB rats developing diabetes compared to their congenic littermates. Mol. Immunol. 48:399–407 [Google Scholar]
  105. Moss RB, Bocian RC, Hsu YP, Dong YJ, Kemna M. 105.  et al. 1996. Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR). Clin. Exp. Immunol. 106:374–88 [Google Scholar]
  106. Chen JH, Schulman H, Gardner P. 106.  1989. A cAMP-regulated chloride channel in lymphocytes that is affected in cystic fibrosis. Science 243:657–60 [Google Scholar]
  107. Decoursey TE. 107.  2012. Voltage-gated proton channels. Compr. Physiol. 2:1355–85 [Google Scholar]
  108. Demaurex N, El Chemaly A. 108.  2010. Physiological roles of voltage-gated proton channels in leukocytes. J. Physiol. 588:4659–65 [Google Scholar]
  109. DeCoursey TE. 109.  2013. Voltage-gated proton channels: molecular biology, physiology, and pathophysiology of the HV family. Physiol. Rev. 93:599–652 [Google Scholar]
  110. El Chemaly A, Okochi Y, Sasaki M, Arnaudeau S, Okamura Y, Demaurex N. 110.  2010. VSOP/Hv1 proton channels sustain calcium entry, neutrophil migration, and superoxide production by limiting cell depolarization and acidification. J. Exp. Med. 207:129–39 [Google Scholar]
  111. Morgan D, Capasso M, Musset B, Cherny VV, Rios E. 111.  et al. 2009. Voltage-gated proton channels maintain pH in human neutrophils during phagocytosis. PNAS 106:18022–27 [Google Scholar]
  112. Capasso M, Bhamrah MK, Henley T, Boyd RS, Langlais C. 112.  et al. 2010. HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species. Nat. Immunol. 11:265–72 [Google Scholar]
  113. Roos A, Boron WF. 113.  1981. Intracellular pH. Physiol. Rev. 61:296–434 [Google Scholar]
  114. Meuth SG, Bittner S, Meuth P, Simon OJ, Budde T, Wiendl H. 114.  2008. TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions. J. Biol. Chem. 283:14559–70 [Google Scholar]
  115. Bittner S, Bobak N, Herrmann AM, Gobel K, Meuth P. 115.  et al. 2010. Upregulation of K2P5.1 potassium channels in multiple sclerosis. Ann. Neurol. 68:58–69 [Google Scholar]
  116. Bobak N, Bittner S, Andronic J, Hartmann S, Muhlpfordt F. 116.  et al. 2011. Volume regulation of murine T lymphocytes relies on voltage-dependent and two-pore domain potassium channels. Biochim. Biophys. Acta 1808:2036–44 [Google Scholar]
  117. Bittner S, Meuth SG, Gobel K, Melzer N, Herrmann AM. 117.  et al. 2009. TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system. Brain 132:2501–16 [Google Scholar]
  118. Aifantis I, Gounari F, Scorrano L, Borowski C, Von Boehmer H. 118.  2001. Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-κB and NFAT. Nat. Immunol. 2:403–9 [Google Scholar]
  119. Bhakta NR, Oh DY, Lewis RS. 119.  2005. Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nat. Immunol. 6:143–51 [Google Scholar]
  120. Daniels MA, Teixeiro E, Gill J, Hausmann B, Roubaty D. 120.  et al. 2006. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444:724–29 [Google Scholar]
  121. Nakayama T, Ueda Y, Yamada H, Shores EW, Singer A, June CH. 121.  1992. In vivo calcium elevations in thymocytes with T cell receptors that are specific for self ligands. Science 257:96–99 [Google Scholar]
  122. Feske S, Muller JM, Graf D, Kroczek RA, Drager R. 122.  et al. 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. 26:2119–26 [Google Scholar]
  123. Fuchs S, Rensing-Ehl A, Speckmann C, Bengsch B, Schmitt-Graeff A. 123.  et al. 2012. Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency. J. Immunol. 188:1523–33 [Google Scholar]
  124. Le Deist F, Hivroz C, Partiseti M, Thomas C, Buc HA. 124.  et al. 1995. A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood 85:1053–62 [Google Scholar]
  125. Picard C, McCarl CA, Papolos A, Khalil S, Luthy K. 125.  et al. 2009. STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N. Engl. J. Med. 360:1971–80 [Google Scholar]
  126. Gwack Y, Srikanth S, Oh-hora M, Hogan PG, Lamperti ED. 126.  et al. 2008. Hair loss and defective T- and B-cell function in mice lacking ORAI1. Mol. Cell. Biol. 28:5209–22 [Google Scholar]
  127. McCarl CA, Khalil S, Ma J, Oh-hora M, Yamashita M. 127.  et al. 2010. Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection. J. Immunol. 185:5845–58 [Google Scholar]
  128. Beyersdorf N, Braun A, Vogtle T, Varga-Szabo D, Galdos R. 128.  et al. 2009. STIM1-independent T cell development and effector function in vivo. J. Immunol. 182:3390–97 [Google Scholar]
  129. Vig M, DeHaven WI, Bird GS, Billingsley JM, Wang H. 129.  et al. 2008. Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels. Nat. Immunol. 9:89–96 [Google Scholar]
  130. Baba Y, Nishida K, Fujii Y, Hirano T, Hikida M, Kurosaki T. 130.  2008. Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses. Nat. Immunol. 9:81–88 [Google Scholar]
  131. Oh-hora M, Yamashita M, Hogan PG, Sharma S, Lamperti E. 131.  et al. 2008. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nat. Immunol. 9:432–43 [Google Scholar]
  132. Oh-hora M, Komatsu N, Pishyareh M, Feske S, Hori S. 132.  et al. 2013. Agonist-selected T cell development requires strong T cell receptor signaling and store-operated calcium entry. Immunity 38:881–95 [Google Scholar]
  133. Grgic I, Wulff H, Eichler I, Flothmann C, Kohler R, Hoyer J. 133.  2009. Blockade of T-lymphocyte KCa3.1 and Kv1.3 channels as novel immunosuppression strategy to prevent kidney allograft rejection. Transplant. Proc. 41:2601–6 [Google Scholar]
  134. Gocke AR, Lebson LA, Grishkan IV, Hu L, Nguyen HM. 134.  et al. 2012. Kv1.3 deletion biases T cells toward an immunoregulatory phenotype and renders mice resistant to autoimmune encephalomyelitis. J. Immunol. 188:5877–86 [Google Scholar]
  135. Ouyang K, Leandro Gomez-Amaro R, Stachura DL, Tang H, Peng X. 134a.  et al. 2014. Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia. Nat. Commun. 5:4814 [Google Scholar]
  136. Stritesky GL, Jameson SC, Hogquist KA. 135.  2012. Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30:95–114 [Google Scholar]
  137. Brigl M, Bry L, Kent SC, Gumperz JE, Brenner MB. 136.  2003. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat. Immunol. 4:1230–37 [Google Scholar]
  138. Kronenberg M, Kinjo Y. 137.  2009. Innate-like recognition of microbes by invariant natural killer T cells. Curr. Opin. Immunol. 21:391–96 [Google Scholar]
  139. Godfrey DI, Berzins SP. 138.  2007. Control points in NKT-cell development. Nat. Rev. Immunol. 7:505–18 [Google Scholar]
  140. Lin J, Krishnaraj R, Kemp RG. 139.  1985. Exogenous ATP enhances calcium influx in intact thymocytes. J. Immunol. 135:3403–10 [Google Scholar]
  141. Chused TM, Apasov S, Sitkovsky M. 140.  1996. Murine T lymphocytes modulate activity of an ATP-activated P2Z-type purinoceptor during differentiation. J. Immunol. 157:1371–80 [Google Scholar]
  142. Ross PE, Ehring GR, Cahalan MD. 141.  1997. Dynamics of ATP-induced calcium signaling in single mouse thymocytes. J. Cell Biol. 138:987–98 [Google Scholar]
  143. Pizzo P, Zanovello P, Bronte V. Virgilio F. 142. , Di 1991. Extracellular ATP causes lysis of mouse thymocytes and activates a plasma membrane ion channel. Biochem. J. 274:Pt. 1139–44 [Google Scholar]
  144. Freedman BD, Liu QH, Gaulton G, Kotlikoff MI, Hescheler J, Fleischmann BK. 143.  1999. ATP-evoked Ca2+ transients and currents in murine thymocytes: possible role for P2X receptors in death by neglect. Eur. J. Immunol. 29:1635–46 [Google Scholar]
  145. Mulryan K, Gitterman DP, Lewis CJ, Vial C, Leckie BJ. 144.  et al. 2000. Reduced vas deferens contraction and male infertility in mice lacking P2X1 receptors. Nature 403:86–89 [Google Scholar]
  146. Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N. 145.  et al. 2001. Altered cytokine production in mice lacking P2X(7) receptors. J. Biol. Chem. 276:125–32 [Google Scholar]
  147. Yamamoto K, Sokabe T, Matsumoto T, Yoshimura K, Shibata M. 146.  et al. 2006. Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nat. Med. 12:133–37 [Google Scholar]
  148. Cockayne DA, Dunn PM, Zhong Y, Rong W, Hamilton SG. 147.  et al. 2005. P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP. J. Physiol. 567:621–39 [Google Scholar]
  149. Li FY, Chaigne-Delalande B, Su H, Uzel G, Matthews H, Lenardo MJ. 148.  2014. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood 123:2148–52 [Google Scholar]
  150. Jin J, Desai BN, Navarro B, Donovan A, Andrews NC, Clapham DE. 149.  2008. Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis. Science 322:756–60 [Google Scholar]
  151. Ackland ML, Michalczyk A. 150.  2006. Zinc deficiency and its inherited disorders—a review. Genes Nutr. 1:41–49 [Google Scholar]
  152. Fraker PJ, King LE. 151.  2004. Reprogramming of the immune system during zinc deficiency. Annu. Rev. Nutr. 24:277–98 [Google Scholar]
  153. Kury S, Dreno B, Bezieau S, Giraudet S, Kharfi M. 152.  et al. 2002. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat. Genet. 31:239–40 [Google Scholar]
  154. Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. 153.  2002. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am. J. Hum. Genet. 71:66–73 [Google Scholar]
  155. Geiser J, Venken KJ, De Lisle RC, Andrews GK. 154.  2012. A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity. PLOS Genet. 8:e1002766 [Google Scholar]
  156. Kumar L, Chou J, Yee CS, Borzutzky A, Vollmann EH. 154a.  et al. 2014. Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. J. Exp. Med. 211:929–42 [Google Scholar]
  157. Szabò I, Lepple-Wienhues A, Kaba KN, Zoratti M, Gulbins E, Lang F. 154b.  1998. Tyrosine kinase-dependent activation of a chloride channel in CD95-induced apoptosis in T lymphocytes. PNAS 95:6169–74 [Google Scholar]
  158. Feske S, Giltnane J, Dolmetsch R, Staudt LM, Rao A. 155.  2001. Gene regulation mediated by calcium signals in T lymphocytes. Nat. Immunol. 2:316–24 [Google Scholar]
  159. Matsumoto M, Fujii Y, Baba A, Hikida M, Kurosaki T, Baba Y. 156.  2011. The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. Immunity 34:703–14 [Google Scholar]
  160. Limnander A, Depeille P, Freedman TS, Liou J, Leitges M. 157.  et al. 2011. STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nat. Immunol. 12:425–33 [Google Scholar]
  161. Miller AT, Sandberg M, Huang YH, Young M, Sutton S. 158.  et al. 2007. Production of Ins(1,3,4,5)P4 mediated by the kinase Itpkb inhibits store-operated calcium channels and regulates B cell selection and activation. Nat. Immunol. 8:514–21 [Google Scholar]
  162. Miyai T, Hojyo S, Ikawa T, Kawamura M, Irie T. 159.  et al. 2014. Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development. PNAS 111:11780–85 [Google Scholar]
  163. Sawada A, Takihara Y, Kim JY, Matsuda-Hashii Y, Tokimasa S. 160.  et al. 2003. A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J. Clin. Investig. 112:1707–13 [Google Scholar]
  164. Byun M, Abhyankar A, Lelarge V, Plancoulaine S, Palanduz A. 161.  et al. 2010. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J. Exp. Med. 207:2307–12 [Google Scholar]
  165. Feske S. 162.  2011. Immunodeficiency due to defects in store-operated calcium entry. Ann. NY Acad. Sci. 123874–90
  166. Feske S, Prakriya M, Rao A, Lewis RS. 163.  2005. A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients. J. Exp. Med. 202:651–62 [Google Scholar]
  167. Ma J, McCarl CA, Khalil S, Luthy K, Feske S. 164.  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. 40:3028–42 [Google Scholar]
  168. Kim KD, Srikanth S, Yee MK, Mock DC, Lawson GW, Gwack Y. 165.  2011. ORAI1 deficiency impairs activated T cell death and enhances T cell survival. J. Immunol. 187:3620–30 [Google Scholar]
  169. Macian F. 166.  2005. NFAT proteins: key regulators of T-cell development and function. Nat. Rev. Immunol. 5:472–84 [Google Scholar]
  170. Feske S, Draeger R, Peter HH, Eichmann K, Rao A. 167.  2000. The duration of nuclear residence of NFAT determines the pattern of cytokine expression in human SCID T cells. J. Immunol. 165:297–305 [Google Scholar]
  171. Kim KD, Srikanth S, Tan YV, Yee MK, Jew M. 168.  et al. 2014. Calcium signaling via Orai1 is essential for induction of the nuclear orphan receptor pathway to drive Th17 differentiation. J. Immunol. 192:110–22 [Google Scholar]
  172. Schuhmann MK, Stegner D, Berna-Erro A, Bittner S, Braun A. 169.  et al. 2010. Stromal interaction molecules 1 and 2 are key regulators of autoreactive T cell activation in murine autoimmune central nervous system inflammation. J. Immunol. 184:1536–42 [Google Scholar]
  173. Weidinger C, Shaw PJ, Feske S. 170.  2013. STIM1 and STIM2-mediated Ca2+ influx regulates antitumour immunity by CD8+ T cells. EMBO Mol. Med. 5:1311–21 [Google Scholar]
  174. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D. 171.  et al. 2009. Late developmental plasticity in the T helper 17 lineage. Immunity 30:92–107 [Google Scholar]
  175. Zhou L, Chong MM, Littman DR. 172.  2009. Plasticity of CD4+ T cell lineage differentiation. Immunity 30:646–55 [Google Scholar]
  176. Dearman RJ, Kimber I. 173.  2000. Role of CD4+ T helper 2-type cells in cutaneous inflammatory responses induced by fluorescein isothiocyanate. Immunology 101:442–51 [Google Scholar]
  177. Yu Y, Wang D, Liu C, Kaosaard K, Semple K. 174.  et al. 2011. Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice. Blood 118:5011–20 [Google Scholar]
  178. Maynard CL, Weaver CT. 175.  2009. Intestinal effector T cells in health and disease. Immunity 31:389–400 [Google Scholar]
  179. Jin S, Chin J, Kitson C, Woods J, Majmudar R. 176.  et al. 2013. Natural regulatory T cells are resistant to calcium release-activated calcium (CRAC/ORAI) channel inhibition. Int. Immunol. 25:497–506 [Google Scholar]
  180. Curotto de Lafaille MA, Lafaille JJ. 177.  2009. Natural and adaptive Foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity 30:626–35 [Google Scholar]
  181. Greenberg ML, Yu Y, Leverrier S, Zhang SL, Parker I, Cahalan MD. 178.  2013. Orai1 function is essential for T cell homing to lymph nodes. J. Immunol. 190:3197–206 [Google Scholar]
  182. Waite JC, Vardhana S, Shaw PJ, Jang JE, McCarl CA. 179.  et al. 2013. Interference with Ca2+ release activated Ca2+ (CRAC) channel function delays T-cell arrest in vivo. Eur. J. Immunol. 43:3343–54 [Google Scholar]
  183. Negulescu PA, Krasieva TB, Khan A, Kerschbaum HH, Cahalan MD. 180.  1996. Polarity of T cell shape, motility, and sensitivity to antigen. Immunity 4:421–30 [Google Scholar]
  184. MacLennan IC, Gotch FM, Golstein P. 181.  1980. Limited specific T-cell mediated cytolysis in the absence of extracellular Ca2+. Immunology 39:109–17 [Google Scholar]
  185. Takayama H, Sitkovsky MV. 182.  1987. Antigen receptor-regulated exocytosis in cytotoxic T lymphocytes. J. Exp. Med. 166:725–43 [Google Scholar]
  186. Shaw PJ, Weidinger C, Vaeth M, Luethy K, Kaech S, Feske S. 183.  2014. CD4+ and CD8+ T cell-dependent antiviral immunity requires STIM1 and STIM2. J. Clin. Investig. 124:4549–63 [Google Scholar]
  187. Maul-Pavicic A, Chiang SC, Rensing-Ehl A, Jessen B, Fauriat C. 184.  et al. 2011. ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis. PNAS 108:3324–29 [Google Scholar]
  188. Sahin G, Palanduz A, Aydogan G, Cassar O, Ertem AU. 185.  et al. 2010. Classic Kaposi sarcoma in 3 unrelated Turkish children born to consanguineous kindreds. Pediatrics 125:e704–8 [Google Scholar]
  189. Robert V, Triffaux E, Paulet PE, Guery JC, Pelletier L, Savignac M. 186.  2014. Protein kinase C-dependent activation of CaV1.2 channels selectively controls human TH2-lymphocyte functions. J. Allergy Clin. Immunol. 133:1175–83 [Google Scholar]
  190. Splawski I, Timothy K, Sharpe L, Decher N, Kumar P. 187.  et al. 2004. CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31 [Google Scholar]
  191. Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B. 188.  et al. 1998. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat. Genet. 19:260–63 [Google Scholar]
  192. Striessnig J, Bolz HJ, Koschak A. 189.  2010. Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels. Pflugers Arch. 460:361–74 [Google Scholar]
  193. Baricordi OR, Ferrari D, Melchiorri L, Chiozzi P, Hanau S. 190.  et al. 1996. An ATP-activated channel is involved in mitogenic stimulation of human T lymphocytes. Blood 87:682–90 [Google Scholar]
  194. Padeh S, Cohen A, Roifman CM. 191.  1991. ATP-induced activation of human B lymphocytes via P2-purinoceptors. J. Immunol. 146:1626–32 [Google Scholar]
  195. Adinolfi E, Callegari MG, Ferrari D, Bolognesi C, Minelli M. 192.  et al. 2005. Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol. Biol. Cell 16:3260–72 [Google Scholar]
  196. Woehrle T, Yip L, Elkhal A, Sumi Y, Chen Y. 193.  et al. 2010. Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse. Blood 116:3475–84 [Google Scholar]
  197. Schenk U, Westendorf AM, Radaelli E, Casati A, Ferro M. 194.  et al. 2008. Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels. Sci. Signal. 1:ra6 [Google Scholar]
  198. Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E. 195.  et al. 2011. ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci. Signal. 4:ra12 [Google Scholar]
  199. Vergani A, Tezza S, D'Addio F, Fotino C, Liu K. 196.  et al. 2013. Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. Circulation 127:463–75 [Google Scholar]
  200. Vergani A, Fotino C, D'Addio F, Tezza S, Podetta M. 197.  et al. 2013. Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. Diabetes 62:1665–75 [Google Scholar]
  201. Sharp AJ, Polak PE, Simonini V, Lin SX, Richardson JC. 198.  et al. 2008. P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis. J. Neuroinflamm. 5:33 [Google Scholar]
  202. Chen L, Brosnan CF. 199.  2006. Exacerbation of experimental autoimmune encephalomyelitis in P2X7R−/− mice: evidence for loss of apoptotic activity in lymphocytes. J. Immunol. 176:3115–26 [Google Scholar]
  203. Taylor SR, Gonzalez-Begne M, Sojka DK, Richardson JC, Sheardown SA. 200.  et al. 2009. Lymphocytes from P2X7-deficient mice exhibit enhanced P2X7 responses. J. Leukoc. Biol. 85:978–86 [Google Scholar]
  204. Saul S, Stanisz H, Backes CS, Schwarz EC, Hoth M. 201.  2013. How ORAI and TRP channels interfere with each other: Interaction models and examples from the immune system and the skin. Eur. J. Pharmacol. 739:49–59 [Google Scholar]
  205. Wenning AS, Neblung K, Strauss B, Wolfs MJ, Sappok A. 202.  et al. 2011. TRP expression pattern and the functional importance of TRPC3 in primary human T-cells. Biochim. Biophys. Acta 1813:412–23 [Google Scholar]
  206. Wang J, Lu ZH, Gabius HJ, Rohowsky-Kochan C, Ledeen RW, Wu G. 203.  2009. Cross-linking of GM1 ganglioside by galectin-1 mediates regulatory T cell activity involving TRPC5 channel activation: possible role in suppressing experimental autoimmune encephalomyelitis. J. Immunol. 182:4036–45 [Google Scholar]
  207. Suzuki Y, Kovacs CS, Takanaga H, Peng JB, Landowski CP, Hediger MA. 204.  2008. Calcium channel TRPV6 is involved in murine maternal-fetal calcium transport. J. Bone Miner. Res. 23:1249–56 [Google Scholar]
  208. Guse AH, da Silva CP, Berg I, Skapenko AL, Weber K. 205.  et al. 1999. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 398:70–73 [Google Scholar]
  209. Melzer N, Hicking G, Gobel K, Wiendl H. 206.  2012. TRPM2 cation channels modulate T cell effector functions and contribute to autoimmune CNS inflammation. PLOS ONE 7:e47617 [Google Scholar]
  210. Weber KS, Hildner K, Murphy KM, Allen PM. 207.  2010. Trpm4 differentially regulates Th1 and Th2 function by altering calcium signaling and NFAT localization. J. Immunol. 185:2836–46 [Google Scholar]
  211. Verheugen JA, Vijverberg HP, Oortgiesen M, Cahalan MD. 208.  1995. Voltage-gated and Ca2+-activated K+ channels in intact human T lymphocytes. Noninvasive measurements of membrane currents, membrane potential, and intracellular calcium. J. Gen. Physiol. 105:765–94 [Google Scholar]
  212. Ghanshani S, Wulff H, Miller MJ, Rohm H, Neben A. 209.  et al. 2000. Up-regulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. J. Biol. Chem. 275:37137–49 [Google Scholar]
  213. Fanger CM, Neben AL, Cahalan MD. 210.  2000. Differential Ca2+ influx, KCa channel activity, and Ca2+ clearance distinguish Th1 and Th2 lymphocytes. J. Immunol. 164:1153–60 [Google Scholar]
  214. Fanger CM, Rauer H, Neben AL, Miller MJ, Wulff H. 211.  et al. 2001. Calcium-activated potassium channels sustain calcium signaling in T lymphocytes. Selective blockers and manipulated channel expression levels. J. Biol. Chem. 276:12249–56 [Google Scholar]
  215. Ishida Y, Chused TM. 212.  1993. Lack of voltage sensitive potassium channels and generation of membrane potential by sodium potassium ATPase in murine T lymphocytes. J. Immunol. 151:610–20 [Google Scholar]
  216. Koo GC, Blake JT, Talento A, Nguyen M, Lin S. 213.  et al. 1997. Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo. J. Immunol. 158:5120–28 [Google Scholar]
  217. Pereira LE, Villinger F, Wulff H, Sankaranarayanan A, Raman G, Ansari AA. 214.  2007. Pharmacokinetics, toxicity, and functional studies of the selective Kv1.3 channel blocker 5-(4-phenoxybutoxy)psoralen in rhesus macaques. Exp. Biol. Med. 232:1338–54 [Google Scholar]
  218. Liu QH, Fleischmann BK, Hondowicz B, Maier CC, Turka LA. 215.  et al. 2002. Modulation of Kv channel expression and function by TCR and costimulatory signals during peripheral CD4+ lymphocyte differentiation. J. Exp. Med. 196:897–909 [Google Scholar]
  219. Grissmer S, Ghanshani S, Dethlefs B, McPherson JD, Wasmuth JJ. 216.  et al. 1992. The Shaw-related potassium channel gene, Kv3.1, on human chromosome 11, encodes the type l K+ channel in T cells. J. Biol. Chem. 267:20971–79 [Google Scholar]
  220. Beeton C, Chandy KG. 217.  2005. Potassium channels, memory T cells, and multiple sclerosis. Neuroscientist 11:550–62 [Google Scholar]
  221. Sallusto F, Geginat J, Lanzavecchia A. 218.  2004. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22:745–63 [Google Scholar]
  222. Wulff H, Calabresi PA, Allie R, Yun S, Pennington M. 219.  et al. 2003. The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS. J. Clin. Investig. 111:1703–13 [Google Scholar]
  223. Beeton C, Wulff H, Standifer NE, Azam P, Mullen KM. 220.  et al. 2006. Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. PNAS 103:17414–19 [Google Scholar]
  224. Azam P, Sankaranarayanan A, Homerick D, Griffey S, Wulff H. 221.  2007. Targeting effector memory T cells with the small molecule Kv1.3 blocker PAP-1 suppresses allergic contact dermatitis. J. Investig. Dermatol. 127:1419–29 [Google Scholar]
  225. Matheu MP, Beeton C, Garcia A, Chi V, Rangaraju S. 222.  et al. 2008. Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block. Immunity 29:602–14 [Google Scholar]
  226. Hu L, Gocke AR, Knapp E, Rosenzweig JM, Grishkan IV. 223.  et al. 2012. Functional blockade of the voltage-gated potassium channel Kv1.3 mediates reversion of T effector to central memory lymphocytes through SMAD3/p21cip1 signaling. J. Biol. Chem. 287:1261–68 [Google Scholar]
  227. Chaigne-Delalande B, Li FY, O'Connor GM, Lukacs MJ, Jiang P. 224.  et al. 2013. Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science 341:186–91 [Google Scholar]
  228. Rezaei N, Hedayat M, Aghamohammadi A, Nichols KE. 225.  2011. Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies. J. Allergy Clin. Immunol. 127:1329–41.e2 [Google Scholar]
  229. Desai B, Krapivinsky G, Navarro B, Krapivinsky L, Carter BC. 226.  et al. 2012. Cleavage of TRPM7 releases the kinase domain from the ion channel and regulates its participation in Fas-induced apoptosis. Dev. Cell 22:61149–62 [Google Scholar]
  230. Haase H, Rink L. 227.  2009. Functional significance of zinc-related signaling pathways in immune cells. Annu. Rev. Nutr. 29:133–52 [Google Scholar]
  231. Hirano T, Murakami M, Fukada T, Nishida K, Yamasaki S, Suzuki T. 228.  2008. Roles of zinc and zinc signaling in immunity: zinc as an intracellular signaling molecule. Adv. Immunol. 97:149–76 [Google Scholar]
  232. Honscheid A, Rink L, Haase H. 229.  2009. T-lymphocytes: a target for stimulatory and inhibitory effects of zinc ions. Endocr. Metab. Immune Disord. Drug Targets 9:132–44 [Google Scholar]
  233. Kirchner H, Ruhl H. 230.  1970. Stimulation of human peripheral lymphocytes by Zn2+ in vitro. Exp. Cell Res. 61:229–30 [Google Scholar]
  234. Fraker PJ, Jardieu P, Cook J. 231.  1987. Zinc deficiency and immune function. Arch. Dermatol. 123:1699–701 [Google Scholar]
  235. Wellinghausen N, Martin M, Rink L. 232.  1997. Zinc inhibits interleukin-1-dependent T cell stimulation. Eur. J. Immunol. 27:2529–35 [Google Scholar]
  236. Tanaka S, Akaishi E, Hosaka K, Okamura S, Kubohara Y. 233.  2005. Zinc ions suppress mitogen-activated interleukin-2 production in Jurkat cells. Biochem. Biophys. Res. Commun. 335:162–67 [Google Scholar]
  237. Bjurstom H, Wang J, Ericsson I, Bengtsson M, Liu Y. 234.  et al. 2008. GABA, a natural immunomodulator of T lymphocytes. J. Neuroimmunol. 205:44–50 [Google Scholar]
  238. Tian J, Chau C, Hales TG, Kaufman DL. 235.  1999. GABAA receptors mediate inhibition of T cell responses. J. Neuroimmunol. 96:21–28 [Google Scholar]
  239. Tian J, Yong J, Dang H, Kaufman DL. 236.  2011. Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis. Autoimmunity 44:465–70 [Google Scholar]
  240. Grinstein S, Clarke CA, Dupre A, Rothstein A. 237.  1982. Volume-induced increase of anion permeability in human lymphocytes. J. Gen. Physiol. 80:801–23 [Google Scholar]
  241. Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R. 238.  2007. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol. Rev. 87:1215–84 [Google Scholar]
  242. Spitzer NC. 239.  2010. How GABA generates depolarization. J. Physiol. 588:757–58 [Google Scholar]
  243. Mueller C, Braag SA, Keeler A, Hodges C, Drumm M, Flotte TR. 240.  2011. Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses. Am. J. Respir. Cell Mol. Biol. 44:922–29 [Google Scholar]
  244. Mori Y, Wakamori M, Miyakawa T, Hermosura M, Hara Y. 241.  et al. 2002. Transient receptor potential 1 regulates capacitative Ca2+ entry and Ca2+ release from endoplasmic reticulum in B lymphocytes. J. Exp. Med. 195:673–81 [Google Scholar]
  245. Lievremont JP, Numaga T, Vazquez G, Lemonnier L, Hara Y. 242.  et al. 2005. The role of canonical transient receptor potential 7 in B-cell receptor-activated channels. J. Biol. Chem. 280:35346–51 [Google Scholar]
  246. Liu QH, Liu X, Wen Z, Hondowicz B, King L. 243.  et al. 2005. Distinct calcium channels regulate responses of primary B lymphocytes to B cell receptor engagement and mechanical stimuli. J. Immunol. 174:68–79 [Google Scholar]
  247. Bubien JK, Zhou LJ, Bell PD, Frizzell RA, Tedder TF. 244.  1993. Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J. Cell Biol. 121:1121–32 [Google Scholar]
  248. Anolik J, Looney RJ, Bottaro A, Sanz I, Young F. 245.  2003. Down-regulation of CD20 on B cells upon CD40 activation. Eur. J. Immunol. 33:2398–409 [Google Scholar]
  249. Wulff H, Knaus HG, Pennington M, Chandy KG. 246.  2004. K+ channel expression during B cell differentiation: implications for immunomodulation and autoimmunity. J. Immunol. 173:776–86 [Google Scholar]
  250. Moritoki Y, Lian ZX, Wulff H, Yang GX, Chuang YH. 247.  et al. 2007. AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers. Hepatology 45:314–22 [Google Scholar]
  251. Schmitz C, Perraud AL, Johnson CO, Inabe K, Smith MK. 248.  et al. 2003. Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell 114:191–200 [Google Scholar]
  252. Hojyo S, Miyai T, Fujishiro H, Kawamura M, Yasuda T. 249.  et al. 2014. Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength. PNAS 111:11786–91 [Google Scholar]
  253. Chen BC, Chou CF, Lin WW. 250.  1998. Pyrimidinoceptor-mediated potentiation of inducible nitric-oxide synthase induction in J774 macrophages. Role of intracellular calcium. J. Biol. Chem. 273:29754–63 [Google Scholar]
  254. Watanabe N, Suzuki J, Kobayashi Y. 251.  1996. Role of calcium in tumor necrosis factor-α production by activated macrophages. J. Biochem. 120:1190–95 [Google Scholar]
  255. Malik ZA, Denning GM, Kusner DJ. 252.  2000. Inhibition of Ca2+ signaling by Mycobacterium tuberculosis is associated with reduced phagosome-lysosome fusion and increased survival within human macrophages. J. Exp. Med. 191:287–302 [Google Scholar]
  256. Vergne I, Chua J, Deretic V. 253.  2003. Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/calmodulin-PI3K hVPS34 cascade. J. Exp. Med. 198:653–59 [Google Scholar]
  257. Zimmerli S, Majeed M, Gustavsson M, Stendahl O, Sanan DA, Ernst JD. 254.  1996. Phagosome-lysosome fusion is a calcium-independent event in macrophages. J. Cell Biol. 132:49–61 [Google Scholar]
  258. Braun A, Gessner JE, Varga-Szabo D, Syed SN, Konrad S. 255.  et al. 2009. STIM1 is essential for Fcγ receptor activation and autoimmune inflammation. Blood 113:1097–104 [Google Scholar]
  259. Connolly SF, Kusner DJ. 256.  2007. The regulation of dendritic cell function by calcium-signaling and its inhibition by microbial pathogens. Immunol. Res. 39:115–27 [Google Scholar]
  260. Hsu S, O'Connell PJ, Klyachko VA, Badminton MN, Thomson AW. 257.  et al. 2001. Fundamental Ca2+ signaling mechanisms in mouse dendritic cells: CRAC is the major Ca2+ entry pathway. J. Immunol. 166:6126–33 [Google Scholar]
  261. Matzner N, Zemtsova IM, Nguyen TX, Duszenko M, Shumilina E, Lang F. 258.  2008. Ion channels modulating mouse dendritic cell functions. J. Immunol. 181:6803–9 [Google Scholar]
  262. Felix R, Crottes D, Delalande A, Fauconnier J, Lebranchu Y. 259.  et al. 2013. The Orai-1 and STIM-1 complex controls human dendritic cell maturation. PLOS ONE 8:e61595 [Google Scholar]
  263. Schaff UY, Dixit N, Procyk E, Yamayoshi I, Tse T, Simon SI. 260.  2010. Orai1 regulates intracellular calcium, arrest, and shape polarization during neutrophil recruitment in shear flow. Blood 115:657–66 [Google Scholar]
  264. Zhang H, Clemens RA, Liu F, Hu Y, Baba Y. 261.  et al. 2014. STIM1 calcium sensor is required for activation of the phagocyte oxidase during inflammation and host defense. Blood 123:2238–49 [Google Scholar]
  265. Brechard S, Plancon S, Melchior C, Tschirhart EJ. 262.  2009. STIM1 but not STIM2 is an essential regulator of Ca2+ influx-mediated NADPH oxidase activity in neutrophil-like HL-60 cells. Biochem. Pharmacol. 78:504–13 [Google Scholar]
  266. Steinckwich N, Schenten V, Melchior C, Brechard S, Tschirhart EJ. 263.  2011. An essential role of STIM1, Orai1, and S100A8-A9 proteins for Ca2+ signaling and FcγR-mediated phagosomal oxidative activity. J. Immunol. 186:2182–91 [Google Scholar]
  267. Nunes P, Cornut D, Bochet V, Hasler U, Oh-hora M. 264.  et al. 2012. STIM1 juxtaposes ER to phagosomes, generating Ca2+ hotspots that boost phagocytosis. Curr. Biol. 22:1990–97 [Google Scholar]
  268. Gallin EK. 265.  1981. Voltage clamp studies in macrophages from mouse spleen cultures. Science 214:458–60 [Google Scholar]
  269. Vicente R, Escalada A, Coma M, Fuster G, Sanchez-Tillo E. 266.  et al. 2003. Differential voltage-dependent K+ channel responses during proliferation and activation in macrophages. J. Biol. Chem. 278:46307–20 [Google Scholar]
  270. Gallin EK. 267.  1984. Calcium- and voltage-activated potassium channels in human macrophages. Biophys. J. 46:821–25 [Google Scholar]
  271. Hanley PJ, Musset B, Renigunta V, Limberg SH, Dalpke AH. 268.  et al. 2004. Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages. PNAS 101:9479–84 [Google Scholar]
  272. Chung I, Zelivyanskaya M, Gendelman HE. 269.  2002. Mononuclear phagocyte biophysiology influences brain transendothelial and tissue migration: implication for HIV-1-associated dementia. J. Neuroimmunol. 122:40–54 [Google Scholar]
  273. Nelson DJ, Jow B, Jow F. 270.  1992. Lipopolysaccharide induction of outward potassium current expression in human monocyte-derived macrophages: lack of correlation with secretion. J. Membr. Biol. 125:207–18 [Google Scholar]
  274. Seydel U, Scheel O, Muller M, Brandenburg K, Blunck R. 271.  2001. A K+ channel is involved in LPS signaling. J. Endotoxin Res. 7:243–47 [Google Scholar]
  275. DeCoursey TE, Kim SY, Silver MR, Quandt FN. 272.  1996. Ion channel expression in PMA-differentiated human THP-1 macrophages. J. Membr. Biol. 152:141–57 [Google Scholar]
  276. Mackenzie AB, Chirakkal H, North RA. 273.  2003. Kv1.3 potassium channels in human alveolar macrophages. Am. J. Physiol. Lung. Cell Mol. Physiol. 285:L862–68 [Google Scholar]
  277. Liu QH, Williams DA, McManus C, Baribaud F, Doms RW. 274.  et al. 2000. HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation. PNAS 97:4832–37 [Google Scholar]
  278. Gao YD, Hanley PJ, Rinne S, Zuzarte M, Daut J. 275.  2010. Calcium-activated K+ channel (KCa3.1) activity during Ca2+ store depletion and store-operated Ca2+ entry in human macrophages. Cell Calcium 48:19–27 [Google Scholar]
  279. Strobaek D, Brown DT, Jenkins DP, Chen YJ, Coleman N. 276.  et al. 2013. NS6180, a new KCa3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease. Br. J. Pharmacol. 168:432–44 [Google Scholar]
  280. Toyama K, Wulff H, Chandy KG, Azam P, Raman G. 277.  et al. 2008. The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans. J. Clin. Investig. 118:3025–37 [Google Scholar]
  281. Chen YJ, Lam J, Gregory CR, Schrepfer S, Wulff H. 278.  2013. The Ca2+-activated K+ channel KCa3.1 as a potential new target for the prevention of allograft vasculopathy. PLOS ONE 8:e81006 [Google Scholar]
  282. Fordyce CB, Jagasia R, Zhu X, Schlichter LC. 279.  2005. Microglia Kv1.3 channels contribute to their ability to kill neurons. J. Neurosci. 25:7139–49 [Google Scholar]
  283. Maezawa I, Calafiore M, Wulff H, Jin LW. 280.  2011. Does microglial dysfunction play a role in autism and Rett syndrome?. Neuron Glia Biol. 7:85–97 [Google Scholar]
  284. Peng Y, Lu K, Li Z, Zhao Y, Wang Y. 281.  et al. 2014. Blockade of Kv1.3 channels ameliorates radiation-induced brain injury. Neuro Oncol. 16:528–39 [Google Scholar]
  285. Mauler F, Hinz V, Horvath E, Schuhmacher J, Hofmann HA. 282.  et al. 2004. Selective intermediate-/small-conductance calcium-activated potassium channel (KCNN4) blockers are potent and effective therapeutics in experimental brain oedema and traumatic brain injury caused by acute subdural haematoma. Eur. J. Neurosci. 20:1761–68 [Google Scholar]
  286. Chen YJ, Raman G, Bodendiek S, O'Donnell ME, Wulff H. 283.  2011. The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke. J. Cereb. Blood Flow Metab. 31:2363–74 [Google Scholar]
  287. Mullen KM, Rozycka M, Rus H, Hu L, Cudrici C. 284.  et al. 2006. Potassium channels Kv1.3 and Kv1.5 are expressed on blood-derived dendritic cells in the central nervous system. Ann. Neurol. 60:118–27 [Google Scholar]
  288. Kanneganti TD. 285.  2010. Central roles of NLRs and inflammasomes in viral infection. Nat. Rev. Immunol. 10:688–98 [Google Scholar]
  289. Lamkanfi M, Dixit VM. 286.  2012. Inflammasomes and their roles in health and disease. Annu. Rev. Cell Dev. Biol. 28:137–61 [Google Scholar]
  290. Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K. 287.  et al. 2006. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–32 [Google Scholar]
  291. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. 288.  2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–41 [Google Scholar]
  292. Schroder K, Zhou R, Tschopp J. 289.  2010. The NLRP3 inflammasome: a sensor for metabolic danger?. Science 327:296–300 [Google Scholar]
  293. Tschopp J, Schroder K. 290.  2010. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production?. Nat. Rev. Immunol. 10:210–15 [Google Scholar]
  294. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. 291.  2009. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458:509–13 [Google Scholar]
  295. Bauernfeind F, Ablasser A, Bartok E, Kim S, Schmid-Burgk J. 292.  et al. 2011. Inflammasomes: current understanding and open questions. Cell. Mol. Life Sci. 68:765–83 [Google Scholar]
  296. Franchi L, Kamada N, Nakamura Y, Burberry A, Kuffa P. 293.  et al. 2012. NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat. Immunol. 13:449–56 [Google Scholar]
  297. Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, Nunez G. 294.  2013. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38:1142–53 [Google Scholar]
  298. Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. 295.  2007. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14:1583–89 [Google Scholar]
  299. Kahlenberg JM, Dubyak GR. 296.  2004. Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am. J. Physiol. Cell Physiol. 286:C1100–8 [Google Scholar]
  300. Andrei C, Margiocco P, Poggi A, Lotti LV, Torrisi MR, Rubartelli A. 297.  2004. Phospholipases C and A2 control lysosome-mediated IL-1β secretion: implications for inflammatory processes. PNAS 101:9745–50 [Google Scholar]
  301. He Y, Franchi L, Nunez G. 298.  2013. TLR agonists stimulate Nlrp3-dependent IL-1β production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J. Immunol. 190:334–39 [Google Scholar]
  302. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y. 299.  et al. 2009. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat. Med. 15:1170–78 [Google Scholar]
  303. Wilhelm K, Ganesan J, Muller T, Durr C, Grimm M. 300.  et al. 2010. Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat. Med. 16:1434–38 [Google Scholar]
  304. Azad AK, Sadee W, Schlesinger LS. 301.  2012. Innate immune gene polymorphisms in tuberculosis. Infect. Immun. 80:3343–59 [Google Scholar]
  305. Coutinho-Silva R, Ojcius DM. 302.  2012. Role of extracellular nucleotides in the immune response against intracellular bacteria and protozoan parasites. Microbes Infect. 14:1271–77 [Google Scholar]
  306. Kusner DJ, Adams J. 303.  2000. ATP-induced killing of virulent Mycobacterium tuberculosis within human macrophages requires phospholipase D. J. Immunol. 164:379–88 [Google Scholar]
  307. Lammas DA, Stober C, Harvey CJ, Kendrick N, Panchalingam S, Kumararatne DS. 304.  1997. ATP-induced killing of mycobacteria by human macrophages is mediated by purinergic P2Z(P2X7) receptors. Immunity 7:433–44 [Google Scholar]
  308. Santos AA Jr, Rodrigues-Junior V, Zanin RF, Borges TJ, Bonorino C. 305.  et al. 2013. Implication of purinergic P2X7 receptor in M. tuberculosis infection and host interaction mechanisms: a mouse model study. Immunobiology 218:1104–12 [Google Scholar]
  309. Saunders BM, Fernando SL, Sluyter R, Britton WJ, Wiley JS. 306.  2003. A loss-of-function polymorphism in the human P2X7 receptor abolishes ATP-mediated killing of mycobacteria. J. Immunol. 171:5442–46 [Google Scholar]
  310. Areeshi MY, Mandal RK, Panda AK, Bisht SC, Haque S. 307.  2013. CD14–159 C>T gene polymorphism with increased risk of tuberculosis: evidence from a meta-analysis. PLOS ONE 8:e64747 [Google Scholar]
  311. Fernando SL, Saunders BM, Sluyter R, Skarratt KK, Goldberg H. 308.  et al. 2007. A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis. Am. J. Respir. Crit. Care Med. 175:360–66 [Google Scholar]
  312. Perraud AL, Takanishi CL, Shen B, Kang S, Smith MK. 309.  et al. 2005. Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. J. Biol. Chem. 280:6138–48 [Google Scholar]
  313. Knowles H, Li Y, Perraud AL. 310.  2013. The TRPM2 ion channel, an oxidative stress and metabolic sensor regulating innate immunity and inflammation. Immunol. Res. 55:241–48 [Google Scholar]
  314. Knowles H, Heizer JW, Li Y, Chapman K, Ogden CA. 311.  et al. 2011. Transient receptor potential melastatin 2 (TRPM2) ion channel is required for innate immunity against Listeria monocytogenes. PNAS 108:11578–83 [Google Scholar]
  315. Yamamoto S, Shimizu S, Kiyonaka S, Takahashi N, Wajima T. 312.  et al. 2008. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat. Med. 14:738–47 [Google Scholar]
  316. Zhang Z, Zhang W, Jung DY, Ko HJ, Lee Y. 313.  et al. 2012. TRPM2 Ca2+ channel regulates energy balance and glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 302:E807–16 [Google Scholar]
  317. Zhong Z, Zhai Y, Liang S, Mori Y, Han R. 314.  et al. 2013. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat. Commun. 4:1611 [Google Scholar]
  318. Di A, Gao XP, Qian F, Kawamura T, Han J. 315.  et al. 2011. The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation. Nat. Immunol. 13:29–34 [Google Scholar]
  319. Serafini N, Dahdah A, Barbet G, Demion M, Attout T. 316.  et al. 2012. The TRPM4 channel controls monocyte and macrophage, but not neutrophil, function for survival in sepsis. J. Immunol. 189:3689–99 [Google Scholar]
  320. Barbet G, Demion M, Moura I, Serafini N, Léger T. 317.  et al. 2008. The calcium-activated nonselective cation channel TRPM4 is essential for the migration but not the maturation of dendritic cells. Nat. Immunol. 9:1148–56 [Google Scholar]
  321. Holmes B, Quie PG, Windhorst DB, Good RA. 318.  1966. Fatal granulomatous disease of childhood. An inborn abnormality of phagocytic function. Lancet 1:1225–28 [Google Scholar]
  322. DeCoursey TE. 319.  2010. Voltage-gated proton channels find their dream job managing the respiratory burst in phagocytes. Physiology 25:27–40 [Google Scholar]
  323. Femling JK, Cherny VV, Morgan D, Rada B, Davis AP. 320.  et al. 2006. The antibacterial activity of human neutrophils and eosinophils requires proton channels but not BK channels. J. Gen. Physiol. 127:659–72 [Google Scholar]
  324. Okamura Y, Sasaki M. 321.  2007. [Phagocytosis and membrane potential]. Seikagaku 79:454–58 (in Japanese) [Google Scholar]
  325. Ramsey IS, Ruchti E, Kaczmarek JS, Clapham DE. 322.  2009. Hv1 proton channels are required for high-level NADPH oxidase-dependent superoxide production during the phagocyte respiratory burst. PNAS 106:7642–47 [Google Scholar]
  326. Shiloh MU, MacMicking JD, Nicholson S, Brause JE, Potter S. 323.  et al. 1999. Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. Immunity 10:29–38 [Google Scholar]
  327. Wu LJ, Wu G, Akhavan Sharif MR, Baker A, Jia Y. 324.  et al. 2012. The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke. Nat. Neurosci. 15:565–73 [Google Scholar]
  328. Nowak JE, Harmon K, Caldwell CC, Wong HR. 325.  2012. Prophylactic zinc supplementation reduces bacterial load and improves survival in a murine model of sepsis. Pediatr. Crit. Care Med. 13:e323–29 [Google Scholar]
  329. Brazao V, Caetano LC, Del Vecchio Filipin M, Paula Alonso Toldo M, Caetano LN, do Prado JC Jr. 326.  2008. Zinc supplementation increases resistance to experimental infection by Trypanosoma cruzi. Vet. Parasitol. 154:32–37 [Google Scholar]
  330. Hasan R, Rink L, Haase H. 327.  2013. Zinc signals in neutrophil granulocytes are required for the formation of neutrophil extracellular traps. Innate Immun. 19:253–64 [Google Scholar]
  331. Haase H, Ober-Blobaum JL, Engelhardt G, Hebel S, Heit A. 328.  et al. 2008. Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes. J. Immunol. 181:6491–502 [Google Scholar]
  332. Ryu MS, Langkamp-Henken B, Chang SM, Shankar MN, Cousins RJ. 329.  2011. Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis. PNAS 108:20970–75 [Google Scholar]
  333. Rink L, Haase H. 330.  2007. Zinc homeostasis and immunity. Trends Immunol. 28:1–4 [Google Scholar]
  334. Liu MJ, Bao S, Galvez-Peralta M, Pyle CJ, Rudawsky AC. 331.  et al. 2013. ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB. Cell Rep. 3:386–400 [Google Scholar]
  335. Sayadi A, Nguyen AT, Bard FA, Bard-Chapeau EA. 332.  2013. Zip14 expression induced by lipopolysaccharides in macrophages attenuates inflammatory response. Inflamm. Res. 62:133–43 [Google Scholar]
  336. Kitamura H, Morikawa H, Kamon H, Iguchi M, Hojyo S. 333.  et al. 2006. Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat. Immunol. 7:971–77 [Google Scholar]
  337. Galli SJ, Tsai M. 334.  2012. IgE and mast cells in allergic disease. Nat. Med. 18:693–704 [Google Scholar]
  338. Ashmole I, Duffy SM, Leyland ML, Morrison VS, Begg M, Bradding P. 335.  2012. CRACM/Orai ion channel expression and function in human lung mast cells. J. Allergy Clin. Immunol. 129:1628–35 e2 [Google Scholar]
  339. Di Capite J, Nelson C, Bates G, Parekh AB. 336.  2009. Targeting Ca2+ release-activated Ca2+ channel channels and leukotriene receptors provides a novel combination strategy for treating nasal polyposis. J. Allergy Clin. Immunol. 124:1014–21.e3 [Google Scholar]
  340. Wareham K, Vial C, Wykes RC, Bradding P, Seward EP. 337.  2009. Functional evidence for the expression of P2X1, P2X4 and P2X7 receptors in human lung mast cells. Br. J. Pharmacol. 157:1215–24 [Google Scholar]
  341. Bulanova E, Bulfone-Paus S. 338.  2010. P2 receptor-mediated signaling in mast cell biology. Purinergic Signal. 6:3–17 [Google Scholar]
  342. Kurashima Y, Amiya T, Nochi T, Fujisawa K, Haraguchi T. 339.  et al. 2012. Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors. Nat. Commun. 3:1034 [Google Scholar]
  343. Sudo N, Tanaka K, Koga Y, Okumura Y, Kubo C, Nomoto K. 340.  1996. Extracellular ATP activates mast cells via a mechanism that is different from the activation induced by the cross-linking of Fc receptors. J. Immunol. 156:3970–79 [Google Scholar]
  344. Freichel M, Almering J, Tsvilovskyy V. 341.  2012. The role of TRP proteins in mast cells. Front. Immunol. 3:150 [Google Scholar]
  345. Duffy SM, Lawley WJ, Conley EC, Bradding P. 342.  2001. Resting and activation-dependent ion channels in human mast cells. J. Immunol. 167:4261–70 [Google Scholar]
  346. Duffy SM, Leyland ML, Conley EC, Bradding P. 343.  2001. Voltage-dependent and calcium-activated ion channels in the human mast cell line HMC-1. J. Leukoc. Biol. 70:233–40 [Google Scholar]
  347. Shumilina E, Lam RS, Wolbing F, Matzner N, Zemtsova IM. 344.  et al. 2008. Blunted IgE-mediated activation of mast cells in mice lacking the Ca2+-activated K+ channel KCa3.1. J. Immunol. 180:8040–47 [Google Scholar]
  348. Girodet PO, Ozier A, Carvalho G, Ilina O, Ousova O. 345.  et al. 2013. Ca2+-activated K+ channel-3.1 blocker TRAM-34 attenuates airway remodeling and eosinophilia in a murine asthma model. Am. J. Respir. Cell Mol. Biol. 48:212–19 [Google Scholar]
  349. Van Der Velden J, Sum G, Barker D, Koumoundouros E, Barcham G. 346.  et al. 2013. KCa3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma. PLOS ONE 8:e66886 [Google Scholar]
  350. Srivastava S, Cai X, Li Z, Sun Y, Skolnik EY. 347.  2012. Phosphatidylinositol-3-kinase C2β and TRIM27 function to positively and negatively regulate IgE receptor activation of mast cells. Mol. Cell. Biol. 32:3132–39 [Google Scholar]
  351. Sobiesiak M, Shumilina E, Lam RS, Wolbing F, Matzner N. 348.  et al. 2009. Impaired mast cell activation in gene-targeted mice lacking the serum- and glucocorticoid-inducible kinase SGK1. J. Immunol. 183:4395–402 [Google Scholar]
  352. Wolbing F, Sobiesiak M, Shumilina E, Kaesler S, Lam RS. 349.  et al. 2009. Impaired anaphylaxis and mast cell degranulation in mice lacking serum- and glucocorticoid-inducible kinase 1. J. Investig. Dermatol. 129:S8 [Google Scholar]
  353. Vennekens R, Olausson J, Meissner M, Bloch W, Mathar I. 350.  et al. 2007. Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nat. Immunol. 8:312–20 [Google Scholar]
  354. Yamasaki S, Sakata-Sogawa K, Hasegawa A, Suzuki T, Kabu K. 351.  et al. 2007. Zinc is a novel intracellular second messenger. J. Cell Biol. 177:637–45 [Google Scholar]
  355. Kabu K, Yamasaki S, Kamimura D, Ito Y, Hasegawa A. 352.  et al. 2006. Zinc is required for Fc epsilon RI-mediated mast cell activation. J. Immunol. 177:1296–305 [Google Scholar]
  356. Di Sabatino A, Rovedatti L, Kaur R, Spencer JP, Brown JT. 353.  et al. 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. 183:3454–62 [Google Scholar]
  357. Derler I, Schindl R, Fritsch R, Heftberger P, Riedl MC. 354.  et al. 2013. The action of selective CRAC channel blockers is affected by the Orai pore geometry. Cell Calcium 53:139–51 [Google Scholar]
  358. Chen G, Panicker S, Lau KY, Apparsundaram S, Patel VA. 355.  et al. 2013. Characterization of a novel CRAC inhibitor that potently blocks human T cell activation and effector functions. Mol. Immunol. 54:355–67 [Google Scholar]
  359. Grundy S, Kaur M, Plumb J, Reynolds S, Hall S. 356.  et al. 2014. CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients. Clin. Sci. 126:223–32 [Google Scholar]
  360. Yoshino T, Ishikawa J, Ohga K, Morokata T, Takezawa R. 357.  et al. 2007. 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. 560:225–33 [Google Scholar]
  361. Cox JH, Hussell S, Sondergaard H, Roepstorff K, Bui JV. 358.  et al. 2013. Antibody-mediated targeting of the orai1 calcium channel inhibits T cell function. PLOS ONE 8:e82944 [Google Scholar]
  362. Lin FF, Elliott R, Colombero A, Gaida K, Kelley L. 359.  et al. 2013. Generation and characterization of fully human monoclonal antibodies against human Orai1 for autoimmune disease. J. Pharmacol. Exp. Ther. 345:225–38 [Google Scholar]
  363. Gaida K, Salimi-Moosavi H, Subramanian R, Almon V, Knize A. 360.  et al. 2014. Inhibition of CRAC with a human anti-ORAI1 monoclonal antibody inhibits T-cell-derived cytokine production but fails to inhibit a T-cell-dependent antibody response in the cynomolgus monkey. J. Immunotoxicol. 31–10
  364. Cheng KT, Alevizos I, Liu X, Swaim WD, Yin H. 361.  et al. 2012. STIM1 and STIM2 protein deficiency in T lymphocytes underlies development of the exocrine gland autoimmune disease, Sjogren's syndrome. PNAS 109:14544–49 [Google Scholar]
  365. Chandy KG, DeCoursey TE, Cahalan MD, McLaughlin C, Gupta S. 362.  1984. Voltage-gated potassium channels are required for human T lymphocyte activation. J. Exp. Med. 160:369–85 [Google Scholar]
  366. Wulff H, Beeton C, Chandy KG. 363.  2003. Potassium channels as therapeutic targets for autoimmune disorders. Curr. Opin. Drug Discov. Devel. 6:640–47 [Google Scholar]
  367. Beeton C, Pennington MW, Wulff H, Singh S, Nugent D. 364.  et al. 2005. Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Mol. Pharmacol. 67:1369–81 [Google Scholar]
  368. Rus H, Pardo CA, Hu L, Darrah E, Cudrici C. 365.  et al. 2005. The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. PNAS 102:11094–99 [Google Scholar]
  369. Beeton C, Barbaria J, Giraud P, Devaux J, Benoliel AM. 366.  et al. 2001. Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation. J. Immunol. 166:936–44 [Google Scholar]
  370. Beeton C, Wulff H, Barbaria J, Clot-Faybesse O, Pennington M. 367.  et al. 2001. Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. PNAS 98:13942–47 [Google Scholar]
  371. Tarcha EJ, Chi V, Munoz-Elias EJ, Bailey D, Londono LM. 368.  et al. 2012. Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease. J. Pharmacol. Exp. Ther. 342:642–53 [Google Scholar]
  372. Hyodo T, Oda T, Kikuchi Y, Higashi K, Kushiyama T. 369.  et al. 2010. Voltage-gated potassium channel Kv1.3 blocker as a potential treatment for rat anti-glomerular basement membrane glomerulonephritis. Am. J. Physiol. Renal Physiol. 299:F1258–69 [Google Scholar]
  373. Gilhar A, Bergman R, Assay B, Ullmann Y, Etzioni A. 370.  2011. The beneficial effect of blocking Kv1.3 in the psoriasiform SCID mouse model. J. Investig. Dermatol. 131:118–24 [Google Scholar]
  374. Gilhar A, Keren A, Shemer A, Ullmann Y, Paus R. 371.  2013. Blocking potassium channels (Kv1.3): a new treatment option for alopecia areata?. J. Investig. Dermatol. 133:2088–91 [Google Scholar]
  375. Kundu-Raychaudhuri S, Chen YJ, Wulff H, Raychaudhuri SP. 371a.  2014. Kv1.3 in psoriatic disease: PAP-1, a small molecule inhibitor of Kv1.3 is effective in the SCID mouse psoriasis–Xenograft model. J. Autoimmun. 55:63–72 [Google Scholar]
  376. Koshy S, Huq R, Tanner MR, Atik MA, Porter PC. 372.  et al. 2014. Blocking KV1.3 channels inhibits Th2 lymphocyte function and treats a rat model of asthma. J. Biol. Chem. 289:12623–32 [Google Scholar]
  377. Edwards W, Fung-Leung WP, Huang C, Chi E, Wu N. 373.  et al. 2014. Targeting the ion channel Kv1.3 with scorpion venom peptides engineered for potency, selectivity, and half-life. J. Biol. Chem. 289:22704–14 [Google Scholar]
  378. Cruse G, Duffy SM, Brightling CE, Bradding P. 374.  2006. Functional KCa3.1 K+ channels are required for human lung mast cell migration. Thorax 61:880–85 [Google Scholar]
  379. Ataga KI, Stocker J. 375.  2009. Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia. Expert Opin. Investig. Drugs 18:231–39 [Google Scholar]
  380. Bartlett R, Stokes L, Sluyter R. 376.  2014. The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease. Pharmacol. Rev. 66:638–75 [Google Scholar]
  381. Arulkumaran N, Unwin RJ, Tam FW. 377.  2011. A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin. Investig. Drugs 20:897–915 [Google Scholar]
  382. Taylor SR, Turner CM, Elliott JI, McDaid J, Hewitt R. 378.  et al. 2009. P2X7 deficiency attenuates renal injury in experimental glomerulonephritis. J. Am. Soc. Nephrol. 20:1275–81 [Google Scholar]
  383. Keystone EC, Wang MM, Layton M, Hollis S, McInnes IB. 379.  2012. Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann. Rheum. Dis. 71:1630–35 [Google Scholar]
  384. Stock TC, Bloom BJ, Wei N, Ishaq S, Park W. 380.  et al. 2012. Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J. Rheumatol. 39:720–27 [Google Scholar]
  385. Hou X, Pedi L, Diver MM, Long SB. 381.  2012. Crystal structure of the calcium release-activated calcium channel Orai. Science 338:1308–13 [Google Scholar]
/content/journals/10.1146/annurev-immunol-032414-112212
Loading
/content/journals/10.1146/annurev-immunol-032414-112212
Loading

Data & Media loading...

  • Article Type: Review Article