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Ion channels and transporters in lymphocyte function and immunity

Key Points

  • Lymphocyte function is regulated by a network of different ion channels and transporters in the plasma membrane. These ion transport proteins modulate the cytoplasmic concentrations of cations, such as Ca2+, Mg2+ and Zn2+, which function as second messengers and thereby regulate gene expression, lymphocyte differentiation and effector functions.

  • The repertoire of ion channels in lymphocytes includes Ca2+ release-activated Ca2+ (CRAC) channels, P2X receptors, transient receptor potential (TRP) channels, K+ channels, Cl channels, Mg2+ transporter protein 1 (MAGT1) and Zn2+ transporters of the ZIP and ZNT families.

  • CRAC channels composed of ORAI and stromal interaction molecule (STIM) proteins mediate store-operated Ca2+ entry (SOCE) in lymphocytes following antigen receptor engagement. ORAI1, ORAI2 and ORAI3 constitute the Ca2+-conducting pore of the CRAC channel, whereas STIM1 and STIM2 function as sensors of the Ca2+ concentration in the endoplasmic reticulum and activators of CRAC channels.

  • SOCE is the major pathway for increasing intracellular Ca2+ levels in lymphocytes. Inherited mutations of ORAI1 or STIM1 abolish Ca2+ influx in lymphocytes and result in a severe immunodeficiency syndrome termed CRAC channelopathy.

  • P2X receptors are Ca2+-permeable ion channels activated by extracellular ATP. Genetic deletion or inhibition of P2X receptors impairs T cell function.

  • The voltage-activated K+ channel KV1.3 and the Ca2+-activated K+ channel KCa3.1 regulate the membrane potential of lymphocytes and thereby provide the electrical driving force for the influx of divalent cations such as Ca2+. Inhibition of K+ channels has a profound effect on T cell activation.

  • Mg2+ channels and transporters (such as TRPM7 and MAGT1, respectively) regulate the influx of Mg2+ ions into T cells. Genetic deletion of TRPM7 and inherited mutations in MAGT1 impair T cell function and development.

  • Zn2+ transporters of the ZIP and ZNT families regulate Zn2+ uptake from the gut and Zn2+ levels in various tissues. In lymphocytes, several Zn2+ transporters have recently been reported to mediate Zn2+ signalling and T cell function, but the molecular regulation of these channels and their role in immunity remain to be defined.

  • Several Cl channels are expressed by lymphocytes, including volume-activated Cl channels, GABA (γ-aminobutyric acid) receptors and the cystic fibrosis transmembrane conductance regulator (CFTR). These roles of these proteins are currently not well understood in lymphocytes, but they have been implicated in the regulation of apoptosis, cytokine gene expression and T cell-mediated autoimmunity.

  • Inhibition of several ion channels in lymphocytes — such as CRAC channels, K+ channels and P2X receptors — modulates the severity of T cell-mediated autoimmunity and inflammation in animal models of disease, and inhibition of these channels is being explored as an approach to therapeutic immune modulation in patients.

Abstract

Lymphocyte function is regulated by a network of ion channels and transporters in the plasma membrane of B and T cells. These proteins modulate the cytoplasmic concentrations of diverse cations, such as calcium, magnesium and zinc ions, which function as second messengers to regulate crucial lymphocyte effector functions, including cytokine production, differentiation and cytotoxicity. The repertoire of ion-conducting proteins includes calcium release-activated calcium (CRAC) channels, P2X receptors, transient receptor potential (TRP) channels, potassium channels, chloride channels and magnesium and zinc transporters. This Review discusses the roles of ion conduction pathways in lymphocyte function and immunity.

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Figure 1: Ion channels regulating calcium signalling in lymphocytes.
Figure 2: The molecular choreography of CRAC channel activation.
Figure 3: P2X receptors are non-selective calcium channels mediating T cell activation.
Figure 4: Magnesium channels and transporters in lymphocytes.
Figure 5: Zinc signalling and zinc transporters in T cells.

References

  1. 1

    Lewis, R. S. Calcium signaling mechanisms in T lymphocytes. Annu. Rev. Immunol. 19, 497–521 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2

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

    CAS  PubMed  Article  Google Scholar 

  3. 3

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

    Article  CAS  PubMed  Google Scholar 

  4. 4

    Zweifach, A. & Lewis, R. S. Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc. Natl Acad. Sci. USA 90, 6295–6299 (1993).

  5. 5

    Prakriya, M. The molecular physiology of CRAC channels. Immunol. Rev. 231, 88–98 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Hogan, P. G., Lewis, R. S. & Rao, A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 28, 491–533 (2010). This article provides an excellent overview of the molecular regulation and function of CRAC channels in lymphocytes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Feske, S., Giltnane, J., Dolmetsch, R., Staudt, L. M. & Rao, A. Gene regulation mediated by calcium signals in T lymphocytes. Nature Immunol. 2, 316–324 (2001).

    Article  CAS  Google Scholar 

  8. 8

    Feske, S. et al. 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, 2119–2126 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Feske, S., Prakriya, M., Rao, A. & Lewis, R. S. A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients. J. Exp. Med. 202, 651–662 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

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

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

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

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

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

    Article  CAS  PubMed  Google Scholar 

  13. 13

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Zhang, S. L. et al. Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity. Proc. Natl Acad. Sci. USA 103, 9357–9362 (2006). References 12–14 describe the discovery of ORAI1 (also known as CRACM1 ) as the gene encoding the CRAC channel. In addition, reference 12 shows that a single point mutation in ORAI1 abolishes CRAC channel function in T cells and causes combined immunodeficiency.

    Article  CAS  PubMed  Google Scholar 

  15. 15

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

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

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Feske, S. Calcium signalling in lymphocyte activation and disease. Nature Rev. Immunol. 7, 690–702 (2007).

    Article  CAS  Google Scholar 

  18. 18

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Roos, J. et al. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J. Cell Biol. 169, 435–445 (2005). References 18 and 19 provide the first description of STIM1 as the ER Ca2+ sensor and activator of CRAC channels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Cahalan, M. D. STIMulating store-operated Ca2+ entry. Nature Cell Biol. 11, 669–677 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. 21

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Stathopulos, P. B., Li, G. Y., Plevin, M. J., Ames, J. B. & Ikura, M. Stored Ca2+ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: an initiation mechanism for capacitive Ca2+ entry. J. Biol. Chem. 281, 35855–35862 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. 24

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

    Article  PubMed  Google Scholar 

  25. 25

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

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

    Article  CAS  Google Scholar 

  28. 28

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Park, C. Y. et al. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136, 876–890 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Oh-Hora, M. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nature Immunol. 9, 432–443 (2008). This study shows that STIM1 and STIM2 mediate Ca2+ influx in T cells and that complete deletion of Stim1 and Stim2 in mouse T cells interferes with the development and function of T Reg cells.

    Article  CAS  Google Scholar 

  32. 32

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

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

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Shaw, P. J. & Feske, S. Physiological and pathophysiological functions of SOCE in the immune system. Front. Biosci. 4, 2253–2268 (2012).

    Article  Google Scholar 

  35. 35

    Byun, M. et al. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J. Exp. Med. 207, 2307–2312 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Picard, C. et al. STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N. Engl. J. Med. 360, 1971–1980 (2009). This study describes the first patients to be identified with immunodeficiency caused by a mutation of STIM1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Feske, S. CRAC channelopathies. Pflugers Arch. 460, 417–435 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Feske, S. Immunodeficiency due to defects in store-operated calcium entry. Ann. NY Acad. Sci. 1238, 74–90 (2011). This article provides a current review of the clinical and immunological phenotype associated with CRAC channelopathy.

    Article  CAS  PubMed  Google Scholar 

  40. 40

    Feske, S. 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 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Maul-Pavicic, A. et al. ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis. Proc. Natl Acad. Sci. USA 108, 3324–3329 (2011).

    Article  PubMed  Google Scholar 

  42. 42

    Gwack, Y. et al. Hair loss and defective T- and B-cell function in mice lacking ORAI1. Mol. Cell. Biol. 28, 5209–5222 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Beyersdorf, N. et al. STIM1-independent T cell development and effector function in vivo. J. Immunol. 182, 3390–3397 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. 44

    Feske, S., Picard, C. & Fischer, A. Immunodeficiency due to mutations in ORAI1 and STIM1. Clin. Immunol. 135, 169–182 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    McCarl, C. A. et al. Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection. J. Immunol. 185, 5845–5858 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Ma, J., McCarl, C. A., Khalil, S., Luthy, K. & Feske, S. T-cell-specific deletion of STIM1 and STIM2 protects mice from EAE by impairing the effector functions of TH1 and TH17 cells. Eur. J. Immunol. 40, 3028–3042 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Schuhmann, M. K. et al. Stromal interaction molecules 1 and 2 are key regulators of autoreactive T cell activation in murine autoimmune central nervous system inflammation. J. Immunol. 184, 1536–1542 (2010). References 46 and 47 show that STIM1 and STIM2 are required for the pro-inflammatory function of T H 1 and T H 17 cells and the induction of EAE.

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Stromnes, I. M., Cerretti, L. M., Liggitt, D., Harris, R. A. & Goverman, J. M. Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nature Med. 14, 337–342 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    El-behi, M., Rostami, A. & Ciric, B. Current views on the roles of TH1 and TH17 cells in experimental autoimmune encephalomyelitis. J. Neuroimmune Pharmacol. 5, 189–197 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Oh-hora, M. Calcium signaling in the development and function of T-lineage cells. Immunol. Rev. 231, 210–224 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nature Immunol. 9, 194–202 (2008).

    Article  CAS  Google Scholar 

  52. 52

    Junger, W. G. Immune cell regulation by autocrine purinergic signalling. Nature Rev. Immunol. 11, 201–212 (2011). This article provides an excellent overview of signalling by P2X receptors and other purinergic receptors in immune cells.

    Article  CAS  Google Scholar 

  53. 53

    Woehrle, T. et al. Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse. Blood 116, 3475–3484 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Yip, L. et al. Autocrine regulation of T-cell activation by ATP release and P2X7 receptors. FASEB J. 23, 1685–1693 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Baricordi, O. R. et al. An ATP-activated channel is involved in mitogenic stimulation of human T lymphocytes. Blood 87, 682–690 (1996).

    CAS  PubMed  Google Scholar 

  56. 56

    Padeh, S., Cohen, A. & Roifman, C. M. ATP-induced activation of human B lymphocytes via P2-purinoceptors. J. Immunol. 146, 1626–1632 (1991).

    CAS  Google Scholar 

  57. 57

    Adinolfi, E. et al. 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, 3260–3272 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Schenk, U. et al. Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels. Sci. Signal. 1, ra6 (2008).

    Article  CAS  Google Scholar 

  59. 59

    Schenk, U. et al. ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci. Signal. 4, ra12 (2011).

    Article  PubMed  Google Scholar 

  60. 60

    Ratner, D. & Mueller, C. Immune responses in cystic fibrosis; are they intrinsically defective? Am. J. Respir. Cell Mol. Biol. 8 Mar 2012 (doi: 10.1165/rcmb.2011-0399RT).

  61. 61

    Sharp, A. J. et al. P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis. J. Neuroinflammation 5, 33 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Mulryan, K. et al. Reduced vas deferens contraction and male infertility in mice lacking P2X1 receptors. Nature 403, 86–89 (2000).

    Article  CAS  Google Scholar 

  63. 63

    Solle, M. et al. Altered cytokine production in mice lacking P2X7 receptors. J. Biol. Chem. 276, 125–132 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    Yamamoto, K. et al. Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nature Med. 12, 133–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Tsien, R. W., Hess, P., McCleskey, E. W. & Rosenberg, R. L. Calcium channels: mechanisms of selectivity, permeation, and block. Annu. Rev. Biophys. Biophys. Chem. 16, 265–290 (1987).

    Article  CAS  PubMed  Google Scholar 

  66. 66

    Badou, A. et al. Critical role for the β regulatory subunits of Cav channels in T lymphocyte function. Proc. Natl Acad. Sci. USA 103, 15529–15534 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Kotturi, M. F. & Jefferies, W. A. Molecular characterization of L-type calcium channel splice variants expressed in human T lymphocytes. Mol. Immunol. 42, 1461–1474 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Stokes, L., Gordon, J. & Grafton, G. Non-voltage-gated L-type Ca2+ channels in human T cells: pharmacology and molecular characterization of the major α pore-forming and auxiliary β-subunits. J. Biol. Chem. 279, 19566–19573 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Jha, M. K. et al. Defective survival of naive CD8+ T lymphocytes in the absence of the β3 regulatory subunit of voltage-gated calcium channels. Nature Immunol. 10, 1275–1282 (2009).

    Article  CAS  Google Scholar 

  70. 70

    Omilusik, K. et al. The CaV1.4 calcium channel is a critical regulator of T cell receptor signaling and naive T cell homeostasis. Immunity 35, 349–360 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Cabral, M. D. et al. Knocking down Cav1 calcium channels implicated in TH2 cell activation prevents experimental asthma. Am. J. Respir. Crit. Care Med. 181, 1310–1317 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Park, C. Y., Shcheglovitov, A. & Dolmetsch, R. The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels. Science 330, 101–105 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Wang, Y. et al. The calcium store sensor, STIM1, reciprocally controls Orai and CaV1.2 channels. Science 330, 105–109 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Striessnig, J., Bolz, H. J. & Koschak, A. Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels. Pflugers Arch. 460, 361–374 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Lewis, R. S. & Cahalan, M. D. Potassium and calcium channels in lymphocytes. Annu. Rev. Immunol. 13, 623–653 (1995).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Cahalan, M. D. & Chandy, K. G. The functional network of ion channels in T lymphocytes. Immunol. Rev. 231, 59–87 (2009). This article is an excellent review from two of the pioneers studying ion channels in lymphocytes in which they describe the molecular properties and functions of ion channels in T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Cahalan, M. D., Chandy, K. G., DeCoursey, T. E. & Gupta, S. A voltage-gated potassium channel in human T lymphocytes. J. Physiol. 358, 197–237 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Bezanilla, F. How membrane proteins sense voltage. Nature Rev. Mol. Cell Biol. 9, 323–332 (2008).

    Article  CAS  Google Scholar 

  79. 79

    Xia, X. M. et al. Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature 395, 503–507 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Srivastava, S. et al. Phosphatidylinositol-3 phosphatase myotubularin-related protein 6 negatively regulates CD4 T cells. Mol. Cell. Biol. 26, 5595–5602 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Srivastava, S. et al. The phosphatidylinositol 3-phosphate phosphatase myotubularin-related protein 6 (MTMR6) is a negative regulator of the Ca2+-activated K+ channel KCa3.1. Mol. Cell. Biol. 25, 3630–3638 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Srivastava, S. et al. Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1. Proc. Natl Acad. Sci. USA 105, 14442–14446 (2008).

    Article  PubMed  Google Scholar 

  83. 83

    Cai, X. et al. Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β. Proc. Natl Acad. Sci. USA 108, 20072–20077 (2011).

    Article  PubMed  Google Scholar 

  84. 84

    Leonard, R. J., Garcia, M. L., Slaughter, R. S. & Reuben, J. P. Selective blockers of voltage-gated K+ channels depolarize human T lymphocytes: mechanism of the antiproliferative effect of charybdotoxin. Proc. Natl Acad. Sci. USA 89, 10094–10098 (1992).

    Article  CAS  PubMed  Google Scholar 

  85. 85

    Ghanshani, S. et al. Up-regulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. J. Biol. Chem. 275, 37137–37149 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Fanger, C., Neben, A. L. & Cahalan, M. D. Differential Ca2+ influx, KCa channel activity, and Ca2+ clearance distinguish TH1 and TH2 lymphocytes. J. Immunol. 164, 1153–1160 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Fanger, C. M. et al. Calcium-activated potassium channels sustain calcium signaling in T lymphocytes. Selective blockers and manipulated channel expression levels. J. Biol. Chem. 276, 12249–12256 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    Di, L. et al. Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis. Proc. Natl Acad. Sci. USA 107, 1541–1546 (2010). This study shows differential requirements for K Ca 3.1 and K V 1.3 for the activation of T H 1and T H 2 versus T H 17 cells and describes how targeting K Ca 3.1 can be used to treat animal models of colitis.

    Article  Google Scholar 

  89. 89

    Beeton, C. et al. Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Proc. Natl Acad. Sci. USA 98, 13942–13947 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Beeton, C. et al. Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc. Natl Acad. Sci. USA 103, 17414–17419 (2006). This study demonstrates that autoreactive CD4+ T cells from patients with rheumatoid arthritis and type 1 diabetes mellitus are T EM cells that express high levels of K V 1.3 channels and whose activation can be inhibited by K V 1.3 blockers in vitro and in animal models of these diseases.

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Castle, N. A. Pharmacological modulation of voltage-gated potassium channels as a therapeutic strategy. Expert Opin. Ther. Pat. 20, 1471–1503 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Chandy, G. K. et al. K+ channels as targets for specific immunomodulation. Trends Pharmacol. Sci. 25, 280–289 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Baell, J. B. et al. Khellinone derivatives as blockers of the voltage-gated potassium channel Kv1.3: synthesis and immunosuppressive activity. J. Med. Chem. 47, 2326–2336 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    Kalman, K. et al. ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide. J. Biol. Chem. 273, 32697–32707 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    Vennekamp, J. et al. Kv1.3-blocking 5-phenylalkoxypsoralens: a new class of immunomodulators. Mol. Pharmacol. 65, 1364–1374 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Wulff, H. et al. Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc. Natl Acad. Sci. USA 97, 8151–8156 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. 97

    Stocker, J. W. et al. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood 101, 2412–2418 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Koni, P. A. et al. Compensatory anion currents in Kv1.3 channel-deficient thymocytes. J. Biol. Chem. 278, 39443–39451 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Wulff, H. et al. The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS. J. Clin. Invest. 111, 1703–1713 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Fasth, A. E., Cao, D., van Vollenhoven, R., Trollmo, C. & Malmstrom, V. CD28nullCD4+ T cells — characterization of an effector memory T-cell population in patients with rheumatoid arthritis. Scand. J. Immunol. 60, 199–208 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. 101

    Friedrich, M. et al. Flow cytometric characterization of lesional T cells in psoriasis: intracellular cytokine and surface antigen expression indicates an activated, memory/effector type 1 immunophenotype. Arch. Dermatol. Res. 292, 519–521 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Gilhar, A., Bergman, R., Assay, B., Ullmann, Y. & Etzioni, A. The beneficial effect of blocking Kv1.3 in the psoriasiform SCID mouse model. J. Invest. Dermatol. 131, 118–124 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Jager, A. & Kuchroo, V. K. Effector and regulatory T-cell subsets in autoimmunity and tissue inflammation. Scand. J. Immunol. 72, 173–184 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Sallusto, F. & Lanzavecchia, A. Human TH17 cells in infection and autoimmunity. Microbes Infect. 11, 620–624 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Vennekens, R. & Nilius, B. Insights into TRPM4 function, regulation and physiological role. Handb. Exp. Pharmacol. 179, 269–285 (2007).

    Article  CAS  Google Scholar 

  106. 106

    Launay, P. et al. TRPM4 regulates calcium oscillations after T cell activation. Science 306, 1374–1377 (2004). This study shows that TRPM4 mediates Na+ influx in Jurkat T cells, thereby inducing membrane depolarization and decreasing the driving force for Ca2+ entry.

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Weber, K. S., Hildner, K., Murphy, K. M. & Allen, P. M. Trpm4 differentially regulates TH1 and TH2 function by altering calcium signaling and NFAT localization. J. Immunol. 185, 2836–2846 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Vennekens, R. et al. Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nature Immunol. 8, 312–320 (2007).

    Article  CAS  Google Scholar 

  109. 109

    Venkatachalam, K. & Montell, C. TRP channels. Annu. Rev. Biochem. 76, 387–417 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Wenning, A. S. et al. TRP expression pattern and the functional importance of TRPC3 in primary human T-cells. Biochim. Biophys. Acta 1813, 412–423 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Ramsey, I. S., Delling, M. & Clapham, D. E. An introduction to TRP channels. Annu. Rev. Physiol. 68, 619–647 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. 112

    Owsianik, G., Talavera, K., Voets, T. & Nilius, B. Permeation and selectivity of TRP channels. Annu. Rev. Physiol. 68, 685–717 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Nilius, B., Mahieu, F., Karashima, Y. & Voets, T. Regulation of TRP channels: a voltage–lipid connection. Biochem. Soc. Trans. 35, 105–108 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Wang, J. et al. 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, 4036–4045 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. 115

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Sumoza-Toledo, A. & Penner, R. TRPM2: a multifunctional ion channel for calcium signalling. J. Physiol. 589, 1515–1525 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Yamamoto, S., Takahashi, N. & Mori, Y. Chemical physiology of oxidative stress-activated TRPM2 and TRPC5 channels. Prog. Biophys. Mol. Biol. 103, 18–27 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Beck, A., Kolisek, M., Bagley, L. A., Fleig, A. & Penner, R. Nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose regulate TRPM2 channels in T lymphocytes. FASEB J. 20, 962–964 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Guse, A. H. et al. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 398, 70–73 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. 120

    Di, A. et al. The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation. Nature Immunol. 13, 29–34 (2012).

    Article  CAS  Google Scholar 

  121. 121

    Hara, Y. et al. LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol. Cell 9, 163–173 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Yamamoto, S. et al. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nature Med. 14, 738–747 (2008).

    Article  CAS  Google Scholar 

  123. 123

    Scarpa, A. & Brinley, F. J. In situ measurements of free cytosolic magnesium ions. Fed. Proc. 40, 2646–2652 (1981).

    CAS  PubMed  Google Scholar 

  124. 124

    Modiano, J. F., Kelepouris, E., Kern, J. A. & Nowell, P. C. Requirement for extracellular calcium or magnesium in mitogen-induced activation of human peripheral blood lymphocytes. J. Cell. Physiol. 135, 451–458 (1988).

    Article  CAS  PubMed  Google Scholar 

  125. 125

    Abboud, C. N., Scully, S. P., Lichtman, A. H., Brennan, J. K. & Segel, G. B. The requirements for ionized calcium and magnesium in lymphocyte proliferation. J. Cell. Physiol. 122, 64–72 (1985).

    Article  CAS  PubMed  Google Scholar 

  126. 126

    Li, F. Y. et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475, 471–476 (2011). This study shows that a mutation in the Mg2+ transporter MAGT1 impairs Mg2+ influx and indirectly impairs Ca2+ influx in T cells, resulting in CD4+ T cell lymphopenia and primary immunodeficiency (XMEN syndrome).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Jin, J. et al. Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis. Science 322, 756–760 (2008). This study describes how conditional deletion of Trpm7 in T cells causes a block in thymocyte development and the depletion of thymic medullary cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Bates-Withers, C., Sah, R. & Clapham, D. E. TRPM7, the Mg2+ inhibited channel and kinase. Adv. Exp. Med. Biol. 704, 173–183 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. 129

    Ryazanova, L. V. et al. TRPM7 is essential for Mg2+ homeostasis in mammals. Nature Commun. 1, 109 (2010).

    Article  CAS  Google Scholar 

  130. 130

    Schlingmann, K. P. et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nature Genet. 31, 166–170 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Walder, R. Y. et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nature Genet. 31, 171–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. 132

    Schmitz, C. et al. Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell 114, 191–200 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. 133

    Bae, C. Y. & Sun, H. S. TRPM7 in cerebral ischemia and potential target for drug development in stroke. Acta Pharmacol. Sin. 32, 725–733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Goytain, A. & Quamme, G. A. Identification and characterization of a novel mammalian Mg2+ transporter with channel-like properties. BMC Genomics 6, 48 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Zhou, H. & Clapham, D. E. Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development. Proc. Natl Acad. Sci. USA 106, 15750–15755 (2009).

    Article  PubMed  Google Scholar 

  136. 136

    Haase, H. & Rink, L. Functional significance of zinc-related signaling pathways in immune cells. Annu. Rev. Nutr. 29, 133–152 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. 137

    Hirano, T. et al. Roles of zinc and zinc signaling in immunity: zinc as an intracellular signaling molecule. Adv. Immunol. 97, 149–176 (2008). References 136 and 137 provide an excellent overview of the role of Zn2+ as an intracellular signalling molecule in immune cells.

    Article  CAS  PubMed  Google Scholar 

  138. 138

    Honscheid, A., Rink, L. & Haase, H. T-lymphocytes: a target for stimulatory and inhibitory effects of zinc ions. Endocr. Metab. Immune Disord. Drug Targets 9, 132–144 (2009).

    Article  PubMed  Google Scholar 

  139. 139

    Haase, H., Hebel, S., Engelhardt, G. & Rink, L. Flow cytometric measurement of labile zinc in peripheral blood mononuclear cells. Anal. Biochem. 352, 222–230 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    Rukgauer, M., Klein, J. & Kruse-Jarres, J. D. 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 (1997).

    Article  CAS  PubMed  Google Scholar 

  141. 141

    Kaltenberg, J. et al. Zinc signals promote IL-2-dependent proliferation of T cells. Eur. J. Immunol. 40, 1496–1503 (2010).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Aydemir, T. B., Liuzzi, J. P., McClellan, S. & Cousins, R. J. Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-γ expression in activated human T cells. J. Leukoc. Biol. 86, 337–348 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Yu, M. et al. Regulation of T cell receptor signaling by activation-induced zinc influx. J. Exp. Med. 208, 775–785 (2011). This study shows that TCR stimulation results in localized Zn2+ influx at the immune synapse between T cells and DCs, and that Zn2+ influx and T cell activation depend on ZIP6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Kury, S. et al. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nature Genet. 31, 239–240 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Wang, K., Zhou, B., Kuo, Y. M., Zemansky, J. & Gitschier, J. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am. J. Hum. Genet. 71, 66–73 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Ackland, M. L. & Michalczyk, A. Zinc deficiency and its inherited disorders — a review. Genes Nutr. 1, 41–49 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Fraker, P. J. & King, L. E. Reprogramming of the immune system during zinc deficiency. Annu. Rev. Nutr. 24, 277–298 (2004).

    Article  CAS  Google Scholar 

  148. 148

    Kirchner, H. & Ruhl, H. Stimulation of human peripheral lymphocytes by Zn2+in vitro. Exp. Cell Res. 61, 229–230 (1970).

    Article  CAS  PubMed  Google Scholar 

  149. 149

    Fraker, P. J., Jardieu, P. & Cook, J. Zinc deficiency and immune function. Arch. Dermatol. 123, 1699–1701 (1987).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Wellinghausen, N., Martin, M. & Rink, L. Zinc inhibits interleukin-1-dependent T cell stimulation. Eur. J. Immunol. 27, 2529–2535 (1997).

    Article  CAS  PubMed  Google Scholar 

  151. 151

    Tanaka, S., Akaishi, E., Hosaka, K., Okamura, S. & Kubohara, Y. Zinc ions suppress mitogen-activated interleukin-2 production in Jurkat cells. Biochem. Biophys. Res. Commun. 335, 162–167 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. 152

    Kim, P. W., Sun, Z. Y., Blacklow, S. C., Wagner, G. & Eck, M. J. A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8. Science 301, 1725–1728 (2003).

    Article  CAS  PubMed  Google Scholar 

  153. 153

    Huang, J. et al. An approach to assay calcineurin activity and the inhibitory effect of zinc ion. Anal. Biochem. 375, 385–387 (2008).

    Article  CAS  PubMed  Google Scholar 

  154. 154

    Takahashi, K. et al. Zinc inhibits calcineurin activity in vitro by competing with nickel. Biochem. Biophys. Res. Commun. 307, 64–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  155. 155

    Lichten, L. A. & Cousins, R. J. Mammalian zinc transporters: nutritional and physiologic regulation. Annu. Rev. Nutr. 29, 153–176 (2009).

    Article  PubMed  Google Scholar 

  156. 156

    Dufner-Beattie, J., Huang, Z. L., Geiser, J., Xu, W. & Andrews, G. K. Generation and characterization of mice lacking the zinc uptake transporter ZIP3. Mol. Cell. Biol. 25, 5607–5615 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Overbeck, S., Uciechowski, P., Ackland, M. L., Ford, D. & Rink, L. Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9. J. Leukoc. Biol. 83, 368–380 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. 158

    Nishida, K. et al. 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, 1351–1364 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Cahalan, M. D. & Lewis, R. S. Role of potassium and chloride channels in volume regulation by T lymphocytes. Soc. Gen. Physiol. Ser. 43, 281–301 (1988).

    CAS  PubMed  Google Scholar 

  160. 160

    Lewis, R. S., Ross, P. E. & Cahalan, M. D. Chloride channels activated by osmotic stress in T lymphocytes. J. Gen. Physiol. 101, 801–826 (1993).

    Article  CAS  PubMed  Google Scholar 

  161. 161

    Lepple-Wienhues, A. et al. The tyrosine kinase p56lck mediates activation of swelling-induced chloride channels in lymphocytes. J. Cell Biol. 141, 281–286 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Szabo, I. et al. Tyrosine kinase-dependent activation of a chloride channel in CD95-induced apoptosis in T lymphocytes. Proc. Natl Acad. Sci. USA 95, 6169–6174 (1998).

    Article  CAS  PubMed  Google Scholar 

  163. 163

    Tian, J. et al. γ-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. J. Immunol. 173, 5298–5304 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. 164

    Mendu, S. K. et al. 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 (2011).

    Article  CAS  PubMed  Google Scholar 

  165. 165

    Carter, C. R., Kozuska, J. L. & Dunn, S. M. Insights into the structure and pharmacology of GABAA receptors. Future Med. Chem. 2, 859–875 (2010).

    Article  CAS  PubMed  Google Scholar 

  166. 166

    Bhat, R. et al. Inhibitory role for GABA in autoimmune inflammation. Proc. Natl Acad. Sci. USA 107, 2580–2585 (2010).

    Article  PubMed  Google Scholar 

  167. 167

    Bjurstom, H. et al. GABA, a natural immunomodulator of T lymphocytes. J. Neuroimmunol. 205, 44–50 (2008).

    Article  CAS  PubMed  Google Scholar 

  168. 168

    Tian, J., Chau, C., Hales, T. G. & Kaufman, D. L. GABAA receptors mediate inhibition of T cell responses. J. Neuroimmunol. 96, 21–28 (1999).

    Article  CAS  PubMed  Google Scholar 

  169. 169

    Bergeret, M. et al. GABA modulates cytotoxicity of immunocompetent cells expressing GABAA receptor subunits. Biomed. Pharmacother. 52, 214–219 (1998).

    Article  CAS  PubMed  Google Scholar 

  170. 170

    Tian, J., Yong, J., Dang, H. & Kaufman, D. L. Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis. Autoimmunity 44, 465–470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Moss, R. B. et al. Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR). Clin. Exp. Immunol. 106, 374–388 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Chen, J. H., Schulman, H. & Gardner, P. A cAMP-regulated chloride channel in lymphocytes that is affected in cystic fibrosis. Science 243, 657–660 (1989).

    Article  CAS  PubMed  Google Scholar 

  173. 173

    Mueller, C. et al. 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, 922–929 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. 174

    Camerino, D. C., Tricarico, D. & Desaphy, J. F. Ion channel pharmacology. Neurotherapeutics 4, 184–198 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. 175

    Naylor, J., Milligan, C. J., Zeng, F., Jones, C. & Beech, D. J. Production of a specific extracellular inhibitor of TRPM3 channels. Br. J. Pharmacol. 155, 567–573 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Xu, S. Z. et al. Generation of functional ion-channel tools by E3 targeting. Nature Biotechnol. 23, 1289–1293 (2005).

    Article  CAS  Google Scholar 

  177. 177

    Chandy, K. G., DeCoursey, T. E., Cahalan, M. D., McLaughlin, C. & Gupta, S. Voltage-gated potassium channels are required for human T lymphocyte activation. J. Exp. Med. 160, 369–385 (1984).

    Article  CAS  PubMed  Google Scholar 

  178. 178

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

    Article  PubMed  Google Scholar 

  179. 179

    Zhou, Y., Ramachandran, S., Oh-Hora, M., Rao, A. & Hogan, P. G. Pore architecture of the ORAI1 store-operated calcium channel. Proc. Natl Acad. Sci. USA 107, 4896–4901 (2010).

    Article  PubMed  Google Scholar 

  180. 180

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

    Article  CAS  Google Scholar 

  181. 181

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Yamashita, M., Navarro-Borelly, L., McNally, B. A. & Prakriya, M. Orai1 mutations alter ion permeation and Ca2+-dependent inactivation of CRAC channels: evidence for coupling of permeation and gating. J. Gen. Physiol. 130, 525–540 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Yeromin, A. V. et al. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443, 226–229 (2006). References 180, 181 and 183 demonstrate that ORAI1 (also known as CRACM1) is the pore-forming subunit of the CRAC channel by identifying a glutamate residue in the first transmembrane domain of ORAI1 as the selectivity filter of the CRAC channel.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Kawasaki, T., Lange, I. & Feske, S. A minimal regulatory domain in the C terminus of STIM1 binds to and activates ORAI1 CRAC channels. Biochem. Biophys. Res. Commun. 385, 49–54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

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

    Article  PubMed  Google Scholar 

  186. 186

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

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

    Article  CAS  PubMed  Google Scholar 

  188. 188

    Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nature Rev. Immunol. 10, 210–215 (2010).

    Article  CAS  Google Scholar 

  189. 189

    Liuzzi, J. P. & Cousins, R. J. Mammalian zinc transporters. Annu. Rev. Nutr. 24, 151–172 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. 190

    Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).

  191. 191

    De Stefani, D. et al. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Romani, A. M. & Scarpa, A. Regulation of cellular magnesium. Front. Biosci. 5, D720–D734 (2000).

    Article  CAS  PubMed  Google Scholar 

  193. 193

    Desai, B. et al. Cleavage of TRPM7 releases the kinase domain from the ion channel and regulates its participation in Fas-induced apoptosis. Dev. Cell (in the press).

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Acknowledgements

We thank H. Wulff, B. N. Desai and H. McBride for their critical reading of the manuscript and their insightful comments. This work was supported in part by US National Institutes of Health grants AI066128 (to S.F.), NS057499 (to M.P.) and GM084195 (to E.Y.S.).

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Stefan Feske is a co-founder and scientific adviser to CalciMedica, Inc.

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Glossary

Ion channels

Pore-forming transmembrane proteins that enable the flow of ions down an electrochemical gradient.

Ion transporters

Pore-forming transmembrane proteins that carry ions against a concentration gradient using energy, typically in the form of ATP.

Ca2+ release-activated Ca2+ channels

(CRAC channels). Highly Ca2+-selective ion channels located in the plasma membrane that are encoded by ORAI proteins.

Inositol-1,4,5-trisphosphate receptor

(InsP3 receptor). A Ca2+-permeable channel located in the membrane of the endoplasmic reticulum (ER) that mediates the release of Ca2+ from ER stores following binding by the second messenger InsP3.

Ryanodine receptor

(RYR). A Ca2+-permeable channel located in the membrane of the sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) that mediates the release of Ca2+ from the SR or ER stores following binding by the second messenger cyclic ADP-ribose or Ca2+ itself.

Sarcoplasmic/endoplasmic reticulum Ca2+ ATPases

(SERCAs). Ca2+ pumps located in the membrane of the endoplasmic reticulum (ER) that move Ca2+ from the cytoplasm into the ER through the hydrolysis of ATP.

Plasma membrane Ca2+ ATPases

(PMCAs). A family of ion transport ATPases located in the plasma membrane that export Ca2+ from the cytoplasm.

Store-operated Ca2+ entry

(SOCE). A Ca2+-influx process triggered by the depletion of endoplasmic reticulum Ca2+ stores and activation of plasma membrane ORAI Ca2+ channels by STIM proteins.

Ion selectivity

The specificity of an ion channel for a particular species of ion, for example Ca2+, Mg2+, Na+ or K+. Non-selective channels do not discriminate between different types of ion.

Conductance

A measure of the ability of an ion channel to carry electrical charge. The conductance is determined by dividing the electrical current by the potential difference (voltage) and is measured in siemens.

Combined immunodeficiency

(CID). CID is caused by inherited defects in T cell function (but not T cell development). By contrast, severe CID (SCID) is caused by inherited defects in T cell (and in some cases B cell) development. SCID and CID result in severe (often lethal) infections in early infancy.

Nuclear factor of activated T cells

(NFAT). A family of Ca2+-dependent transcription factors that are activated via dephosphorylation by the phosphatase calcineurin. They mediate the expression of many cytokine genes in lymphocytes.

CRAC channelopathy

CRAC channel dysfunction caused by autosomal recessive mutations in ORAI1 and STIM1 that results in a pathognomonic clinical combination of immunodeficiency, autoimmunity, congenital muscular hypotonia and ectodermal dysplasia with impaired dental enamel calcification and sweat gland dysfunction.

Membrane potential

The difference between the electrical potential inside and outside a cell. It is typically −60 to −80 mV in resting cells.

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Feske, S., Skolnik, E. & Prakriya, M. Ion channels and transporters in lymphocyte function and immunity. Nat Rev Immunol 12, 532–547 (2012). https://doi.org/10.1038/nri3233

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