Kv1.3 potassium channels as a therapeutic target in multiple sclerosis

Expert Opinion on Therapeutic Targets

Volumn 13, Issue 8, 2009, Pages 909-924

  Rangaraju, Srikant ^d   Chi, Victor ^a   Pennington, Michael W ^b   Chandy, K George ^a,c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b Bachem Holding AG   (Switzerland)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d NONE

Author keywords

Autoimmune disease; Effector memory T cell; Kv1.3 channel; Multiple sclerosis; Potassium channel

Indexed keywords

1 BENZYL 1,4 DIHYDRO 4 PENTYLIMINOQUINOLINE; 4 BENZHYDRYLOXYMETHYL 1 [3 (4 METHOXYPHENYL)PROPYL]PIPERIDINE; AGITOXIN 2; ALPHA DENDROTOXIN; ANANDAMIDE; ANUROCTOXIN; CHARYBDOTOXIN; CLOFAZIMINE; CORREOLIDE; HONGOTOXIN; KALIOTOXIN; KHELLINONE CHALCONE 16; KHELLINONE DIMMER 2; MARGATOXIN; MAUROTOXIN; N [2 (4 BROMOCINNAMYLAMINO)ETHYL] 5 ISOQUINOLINESULFONAMIDE; NIFEDIPINE; NOXIUSTOXIN; PAP 1; POTASSIUM CHANNEL BLOCKING AGENT; POTASSIUM CHANNEL KV1.3; PSORA 4; SHK 170; SHK 186; SULFAMIDBENZAMIDOINDANE; TETRAPHENYL PORPHYRIN 3; TRAM 34; TSTX KA; UNCLASSIFIED DRUG; UNINDEXED DRUG; WIN 173173;

ALLERGIC ENCEPHALOMYELITIS; AUTOIMMUNITY; CELL MOTILITY; CELL PROLIFERATION; CONTACT DERMATITIS; CYTOKINE PRODUCTION; DIABETES MELLITUS; DRUG TARGETING; ENTEROPATHY; HUMAN; IC 50; IMMUNE DEFICIENCY; IMMUNE RESPONSE; IMMUNE SYSTEM; INSULIN DEPENDENT DIABETES MELLITUS; KERATOPATHY; MEMORY T LYMPHOCYTE; MULTIPLE SCLEROSIS; NONHUMAN; OPPORTUNISTIC INFECTION; PRIMATE; RETINOPATHY; REVIEW; RHEUMATOID ARTHRITIS; RODENT; SKIN DISCOLORATION; SPLEEN INFARCTION; T LYMPHOCYTE;

ANIMALS; CELL PROLIFERATION; CYTOKINES; DRUG DELIVERY SYSTEMS; HUMANS; KV1.3 POTASSIUM CHANNEL; MULTIPLE SCLEROSIS; POTASSIUM CHANNEL BLOCKERS; T-LYMPHOCYTES;

EID: 69149099268     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728220903018957     Document Type: Review

References (158)

1. Mikol D, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol 2008;7(10):903-914
2. Goodin DS, Cohen BA, O'Connor P, et al. Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the therapeutics and technology assessment subcommittee of the american academy of neurology. Neurology 2008;71(10):766-773
3. Goodin DS. Disease-modifying therapy in multiple sclerosis: update and clinical implications. Neurology 2008;71(24 Suppl 3):S8-13
4. Brandes DW, Callender T, Lathi E, O'Leary S. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin 2009;25(1):77-92
5. Menge T, Weber MS, Hemmer B. Disease-modifying agents for multiple sclerosis: recent advances and future prospects. Drugs 2008;68(17):2445-2468
6. Linker RA, Kieseier BC, Gold R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci 2008;29(11):558-565
7. Kivisakk P, Mahad DJ, Callahan MK, et al. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol 2004;55(5):627-638 (Pubitemid 38544322)
8. Rus H, Pardo CA, Hu L, et al. The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. Proc Natl Acad Sci USA 2005;102(31):11094-11099 (Pubitemid 41105998)
9. Sorensen TL, Tani M, Jensen J, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 1999;103(6):807-815 (Pubitemid 29152626)
10. Calabresi PA, Tranquill LR, McFarland HF, Cowan EP. Cytokine gene expression in cells derived from CSF of multiple sclerosis patients. J Neuroimmunol 1998;89(1-2):198-205 (Pubitemid 28389593)
11. Plumb J, Armstrong MA, Duddy M, et al. CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions. Mult Scler 2003;9(2):142-147 (Pubitemid 36426988)
12. Serafini B, Rosicarelli B, Magliozzi R, et al. Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells. J Neuropathol Exp Neurol 2006;65(2):124-141 (Pubitemid 43755377)
13. Cudrici C, Ito T, Zafranskaia E, et al. Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis. Exp Mol Pathol 2007;83(2):198-206 (Pubitemid 47320666)
14. Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol 2006;6(6):476-483
15. Racke MK. The role of B cells in multiple sclerosis: rationale for B-cell-targeted therapies. Curr Opin Neurol 2008;21(Suppl 1):S9-18
16. Corcione A, Casazza S, Ferretti E, et al. Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc Natl Acad Sci USA 2004;101(30):11064-11069 (Pubitemid 38989584)
17. Cepok S, Rosche B, Grummel V, et al. Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain 2005;128(Pt 7):1667-1676 (Pubitemid 41373685)
18. Bar-Or A, Oliveira EM, Anderson DE, et al. Immunological memory: contribution of memory B cells expressing costimulatory molecules in the resting state. J Immunol 2001;167(10):5669-5677 (Pubitemid 33062757)
19. Cahalan MD, Chandy KG, Decoursey TE, Gupta S. A voltage-gated potassium channel in human T lymphocytes. J Physiol 1985;358:197-237 (Pubitemid 15150542)
20. DeCoursey TE, Chandy KG, Gupta S, Cahalan MD. Voltage-gated K + channels in human T lymphocytes: a role in mitogenesis? Nature 1984;307(5950):465-468
21. Matteson DR, Deutsch C. K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion. Nature 1984;307(5950):468-471 (Pubitemid 14132064)
22. Fukushima Y, Hagiwara S, Henkart M. Potassium current in clonal cytotoxic T lymphocytes from the mouse. J Physiol 1984;351:645-656 (Pubitemid 14060826)
23. Chandy KG, Wulff H, Beeton C, et al. K + channels as targets for specific immunomodulation. Trends Pharmacol Sci 2004;25(5):280-289
24. Beeton C, Wulff H, Standifer NE, et al. Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc Natl Acad Sci USA 2006;103(46):17414-17419 (Pubitemid 44788983)
25. Levite M, Cahalon L, Peretz A, et al. Extracellular K + and opening of voltage-gated potassium channels activate T cell integrin function: physical and functional association between Kv1.3 channels and β1 integrins. J Exp Med 2000;191(7):1167-1176 (Pubitemid 30207679)
26. Hanada T, Lin L, Chandy KG, et al. Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes. J Biol Chem 1997;272(43):26899-26904 (Pubitemid 27452639)
27. Pereira LE, Villinger F, Wulff H, et al. Pharmacokinetics, toxicity, and functional studies of the selective Kv1.3 channel blocker 5-(4-phenoxybutoxy) psoralen in rhesus macaques. Exp Biol Med (Maywood) 2007;232:1338-1354 (Pubitemid 350014424)
28. Beeton C, Pennington MW, Wulff H, et al. Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Mol Pharmacol 2005;67(4):1369-1381 (Pubitemid 40410438)
29. Lewis RS, Cahalan MD. Subset-specific expression of potassium channels in developing murine T lymphocytes. Science 1988;239(4841 Pt 1):771-775
30. Schmitz A, Sankaranarayanan A, Azam P, et al. Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases. Mol Pharmacol 2005;68(5):1254-1270 (Pubitemid 41539982)
31. Grissmer S, Nguyen AN, Cahalan MD. Calcium-activated potassium channels in resting and activated human T lymphocytes. Expression levels, calcium dependence, ion selectivity, and pharmacology. J Gen Physiol 1993;102(4):601-630 (Pubitemid 23328148)
32. Ishii TM, Silvia C, Hirschberg B, et al. A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci USA 1997;94(21):11651-11656 (Pubitemid 127650718)
33. Joiner WJ, Wang LY, Tang MD, Kaczmarek LK. hSK4, a member of a novel subfamily of calcium-activated potassium channels. Proc Natl Acad Sci USA 1997;94(20):11013-11018
34. Logsdon NJ, Kang J, Togo JA, et al. A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes. J Biol Chem 1997;272(52):32723-32726 (Pubitemid 28023600)
35. Fanger CM, Ghanshani S, Logsdon NJ, et al. Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCa1. J Biol Chem 1999;274(9):5746-5754 (Pubitemid 29109229)
36. Ghanshani S, Wulff H, Miller MJ, et al. Up-regulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. J Biol Chem 2000;275(47):37137-37149 (Pubitemid 32002132)
37. Grissmer S, Cahalan MD, Chandy KG. Abundant expression of type l K + channels. A marker for lymphoproliferative diseases? J Immunol 1988;141(4):1137-1142
38. Decoursey TE, Chandy KG, Gupta S, Cahalan MD. Two types of potassium channels in murine T lymphocytes. J Gen Physiol 1987;89(3):379-404 (Pubitemid 17039219)
39. Chandy KG, DeCoursey TE, Fischbach M, et al. Altered K + channel expression in abnormal T lymphocytes from mice with the lpr gene mutation. Science 1986;233(4769):1197-1200 (Pubitemid 16032175)
40. Grissmer S, Lewis RS, Cahalan MD. Ca2 + -activated K + channels in human leukemic T cells. J Gen Physiol 1992;99(1):63-84
41. Freedman BD, Fleischmann BK, Punt JA, et al. Identification of Kv1.1 expression by murine CD4-CD8- thymocytes. A role for voltage-dependent K + channels in murine thymocyte development. J Biol Chem 1995;270(38):22406-22411
42. Liu QH, Fleischmann BK, Hondowicz B, et al. Modulation of Kv channel expression and function by TCR and costimulatory signals during peripheral CD4 + lymphocyte differentiation. J Exp Med 2002;196(7):897-909
43. Jager H, Adelman JP, Grissmer S. SK2 encodes the apamin-sensitive Ca2 + -activated K + channels in the human leukemic T cell line, Jurkat. FEBS Lett 2000;469(2-3):196-202
44. Fanger CM, Neben AL, Cahalan MD. Differential Ca2 + influx, KCa channel activity, and Ca2 + clearance distinguish Th1 and Th2 lymphocytes. J Immunol 2000;164(3):1153-1160
45. Pottosin II, Bonales-Alatorre E, Valencia-Cruz G, et al. TRESK-like potassium channels in leukemic T cells. Pflugers Arch 2008;456(6):1037-1048
46. Lee SC, Levy DI, Deutsch C. Diverse K + channels in primary human T lymphocytes. J Gen Physiol 1992;99(5):771-793
47. Meuth SG, Bittner S, Meuth P, et al. TWIK-related acid-sensitive K + channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions. J Biol Chem 2008;283(21):14559-14570
48. Kim Y, Bang H, Kim D. TASK-3, a new member of the tandem pore K + channel family. J Biol Chem 2000;275(13):9340-9347 (Pubitemid 30185157)
49. Poling JS, Rogawski MA, Salem N Jr, Vicini S. Anandamide, an endogenous cannabinoid, inhibits Shaker-related voltage-gated K + channels. Neuropharmacology 1996;35(7):983-991 (Pubitemid 26377684)
50. + -dependent potassium channels in in vitro anandamide-mediated mesenteric vasorelaxation in rats with biliary cirrhosis. Liver Int 2007;27(8):1045-1055
51. Calloway N, Vig M, Kinet JP, et al. Molecular clustering of STIM1 with Orai1/CRACM1 at the plasma membrane depends dynamically on depletion of Ca2 + stores and on electrostatic interactions. Mol Biol Cell 2009;20(1):389-399
52. Cahalan MD, Wulff H, Chandy KG. Molecular properties and physiological roles of ion channels in the immune system. J Clin Immunol 2001;21(4):235-252 (Pubitemid 32652595)
53. Oh-Hora M, Rao A. Calcium signaling in lymphocytes. Curr Opin Immunol 2008;20(3):250-258
54. Vig M, Kinet JP. Calcium signaling in immune cells. Nat Immunol 2009;10(1):21-27
55. Lioudyno MI, Kozak JA, Penna A, et al. Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. Proc Natl Acad Sci USA 2008;105(6):2011-2016
56. Roos J, DiGregorio PJ, Yeromin AV, et al. STIM1, an essential and conserved component of store-operated Ca2 + channel function. J Cell Biol 2005;169(3):435-445 (Pubitemid 40686694)
57. Zhang SL, Yu Y, Roos J, et al. STIM1 is a Ca2 + sensor that activates CRAC channels and migrates from the Ca2 + store to the plasma membrane. Nature 2005;437(7060):902-905 (Pubitemid 41486767)
58. Prakriya M, Feske S, Gwack Y, et al. Orai1 is an essential pore subunit of the CRAC channel. Nature 2006;443(7108):230-233 (Pubitemid 44387613)
59. + entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J Cell Biol 2006;174(6):815-825
60. Peinelt C, Vig M, Koomoa DL, et al. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 2006;8(7):771-773
61. Vig M, Beck A, Billingsley JM, et al. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol 2006;16(20):2073-2079 (Pubitemid 44573821)
62. Luik RM, Wang B, Prakriya M, et al. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 2008;454(7203):538-542
63. Chandy KG, Wulff H, Beeton C, et al. Kv1.3 Potassium channel: physiology, pharmacology and therapeutic indications. In: Triggle DJ, Gopalakrishnan M, Rampe D, Zheng W, editors, Voltage-gated ion channels as drug targets. Weinheim: Wiley-VCH Verlag GmbH & co. KGaA. 2006. p. 214-274
64. Tatham PE, O'Flynn K, Linch DC. The relationship between mitogen-induced membrane potential changes and intracellular free calcium in human T-lymphocytes. Biochim Biophys Acta 1986;856(2):202-211 (Pubitemid 16067472)
65. Ishida Y, Chused TM. Heterogeneity of lymphocyte calcium metabolism is caused by T cell-specific calcium-sensitive potassium channel and sensitivity of the calcium ATPase pump to membrane potential. J Exp Med 1988;168(3):839-852 (Pubitemid 18244114)
66. Hess SD, Oortgiesen M, Cahalan MD. Calcium oscillations in human T and natural killer cells depend upon membrane potential and calcium influx. J Immunol 1993;150(7):2620-2633 (Pubitemid 23127511)
67. Leonard RJ, Garcia ML, Slaughter RS, Reuben JP. Selective blockers of voltage-gated K + channels depolarize human T lymphocytes: mechanism of the antiproliferative effect of charybdotoxin. Proc Natl Acad Sci USA 1992;89(21):10094-10098
68. + -activated K + channels in intact human T lymphocytes. Noninvasive measurements of membrane currents, membrane potential, and intracellular calcium. J Gen Physiol 1995;105(6):765-794
69. + signaling. Cell Calcium 1995;17(4):287-300
70. Mello de Queiroz F, Ponte CG, Bonomo A, et al. Study of membrane potential in T lymphocytes subpopulations using flow cytometry. BMC Immunol 2008;9:63. Published online3 November 2008, doi:10.1186/1471-2172-9-63
71. Panyi G, Bagdány M, Bodnár A, et al. Colocalization and nonrandom distribution of Kv1.3 potassium channels and CD3 molecules in the plasma membrane of human T lymphocytes. Proc Natl Acad Sci USA 2003;100(5):2592-2597 (Pubitemid 36297543)
72. Panyi G, Vámosi G, Bacsó Z, et al. Kv1.3 potassium channels are localized in the immunological synapse formed between cytotoxic and target cells. Proc Natl Acad Sci USA 2004;101(5):1285-1290 (Pubitemid 38182681)
73. Nicolaou SA, Neumeier L, Peng Y, et al. The Ca2+ -activated K + channel KCa3.1 compartmentalizes in the immunological synapse of human T lymphocytes. Am J Physiol Cell Physiol 2007;292(4):C1431-9 (Pubitemid 46631716)
74. + channel in effector memory T cells as new target for MS. J Clin Invest 2003;111(11):1703-1713
75. Sallusto F, Langenkamp A, Geginat J, Lanzavecchia A. Functional subsets of memory T cells identified by CCR7 expression. Curr Top Microbiol Immunol 2000;251:167-171 (Pubitemid 30691267)
76. Mullen KM, Rozycka M, Rus H, et al. Potassium channels Kv1.3 and Kv1.5 are expressed on blood-derived dendritic cells in the central nervous system. Ann Neurol 2006;60(1):118-127
77. + channel in macrophages. J Biol Chem 2006;281(49):37675-37685
78. Vicente R, Villalonga N, Calvo M, et al. Kv1.5 association modifies Kv1.3 traffic and membrane localization. J Biol Chem 2008;283(13):8756-8764
79. Villalonga N, Escalada A, Vicente R, et al. Kv1.3/Kv1.5 heteromeric channels compromise pharmacological responses in macrophages. Biochem Biophys Res Commun 2007;352(4):913-918 (Pubitemid 44894372)
80. Matzner N, Zemtsova IM, Nguyen TX, et al. Ion channels modulating mouse dendritic cell functions. J Immunol 2008;181(10):6803-6809
81. Fordyce CB, Jagasia R, Zhu X, Schlichter LC. Microglia Kv1.3 channels contribute to their ability to kill neurons. J Neurosci 2005;25(31):7139-7149 (Pubitemid 41113930)
82. Pannasch U, Färber K, Nolte C, et al. The potassium channels Kv1.5 and Kv1.3 modulate distinct functions of microglia. Mol Cell Neurosci 2006;33(4):401-411 (Pubitemid 44820855)
83. Breland AE, Currier RD. Scorpion venom and multiple sclerosis. Lancet 1983;2(8357):1021
84. Sands SB, Lewis RS, Cahalan MD. Charybdotoxin blocks voltage-gated K + channels in human and murine T lymphocytes. J Gen Physiol 1989;93(6):1061-1074
85. Deutsch C, Price M, Lee S, et al. Characterization of high affinity binding sites for charybdotoxin in human T lymphocytes. Evidence for association with the voltage-gated K + channel. J Biol Chem 1991;266(6):3668-3674 (Pubitemid 21909264)
86. Price M, Lee SC, Deutsch C. Charybdotoxin inhibits proliferation and interleukin 2 production in human peripheral blood lymphocytes. Proc Natl Acad Sci USA 1989;86(24):10171-10175 (Pubitemid 20030801)
87. Koo GC, Blake JT, Talento A, et al. Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo. J Immunol 1997;158(11):5120-5128 (Pubitemid 127681213)
88. Beeton C, Wulff H, Barbaria J, et al. Selective blockade of T lymphocyte K + channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Proc Natl Acad Sci USA 2001;98(24):13942-13947 (Pubitemid 33116003)
89. Aiyar J, Withka JM, Rizzi JP, et al. Topology of the pore-region of a K + channel revealed by the NMR-derived structures of scorpion toxins. Neuron 1995;15(5):1169-1181
90. Aiyar J, Rizzi JP, Gutman GA, Chandy KG. The signature sequence of voltage-gated potassium channels projects into the external vestibule. J Biol Chem 1996;271(49):31013-31016 (Pubitemid 26408534)
91. Rauer H, Pennington M, Cahalan M, Chandy KG. Structural conservation of the pores of calcium-activated and voltage-gated potassium channels determined by a sea anemone toxin. J Biol Chem 1999;274(31):21885-21892 (Pubitemid 129519740)
92. Doyle DA, Morais Cabral J, Pfuetzner RA. The structure of the potassium channel: molecular basis of K + conduction and selectivity. Science 1998;280(5360):69-77
93. MacKinnon R, Cohen SL, Kuo A, et al. Structural conservation in prokaryotic and eukaryotic potassium channels. Science 1998;280(5360):106-109 (Pubitemid 28169092)
94. Long SB, Campbell EB, Mackinnon R. Crystal structure of a mammalian voltage-dependent Shaker family K + channel. Science 2005;309(5736):897-903
95. Castaneda O, Sotolongo V, Amor AM, et al. Characterization of a potassium channel toxin from the Caribbean Sea anemone Stichodactyla helianthus. Toxicon 1995;33(5):603-613
96. Cotton J, Crest M, Bouet F, et al. A potassium-channel toxin from the sea anemone Bunodosoma granulifera, an inhibitor for Kv1 channels. Revision of the amino acid sequence, disulfide-bridge assignment, chemical synthesis, and biological activity. Eur J Biochem 1997;244(1):192-202 (Pubitemid 27079714)
97. Alessandri-Haber N, Lecoq A, Gasparini S, et al. Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. Clues to design analogs with enhanced selectivity. J Biol Chem 1999;274(50):35653-35661 (Pubitemid 129512865)
98. Kalman K, Pennington MW, Lanigan MD, et al. ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide. J Biol Chem 1998;273(49):32697- 32707 (Pubitemid 28557654)
99. Beeton C, Wulff H, Singh S, et al. A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes. J Biol Chem 2003;278(11):9928-9937 (Pubitemid 36800497)
100. Pennington MW, Beeton C, Galea CA, et al. Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes. Mol Pharmacol 2009;75(4):762-773
101. Michne WF, Guiles JW, Treasurywala AM, et al. Novel inhibitors of potassium ion channels on human T lymphocytes. J Med Chem 1995;38(11):1877-1883
102. + channels in human T lymphocytes. Mol Pharmacol 1995;48(1):98-104
103. Nguyen A, Kath JC, Hanson DC, et al. Novel nonpeptide agents potently block the C-type inactivated conformation of Kv1.3 and suppress T cell activation. Mol Pharmacol 1996;50(6):1672-1679 (Pubitemid 26425126)
104. Wanner SG, Glossmann H, Knaus HG, et al. WIN 17317-3, a new high-affinity probe for voltage-gated sodium channels. Biochemistry 1999;38(34):11137-11146 (Pubitemid 29411605)
105. Hanson DC, Nguyen A, Mather RJ, et al. UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation. Br J Pharmacol 1999;126(8):1707-1716
106. Koo GC, Blake JT, Shah K, et al. Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels. Cell Immunol 1999;197(2):99-107 (Pubitemid 30000730)
107. Bohuslavizki KH, Hänsel W, Kneip A, et al. Potassium channel blockers from Ruta-a new approach for the treatment of multiple sclerosis. Gen Physiol Biophys 1992;11(5):507-512
108. Bohuslavizki KH, Hinck-Kneip C, Kneip A. Koppenh reduction of MS-related scotomata by a new class of potassium channel blockers from Ruta graveolens. Neuro Opthalmol 1993;13:191-198 (Pubitemid 23286078)
109. Vennekamp J, Wulff H, Beeton C, et al. Kv1.3-blocking 5-phenylalkoxypsoralens: a new class of immunomodulators. Mol Pharmacol 2004;65(6):1364-1374 (Pubitemid 38668295)
110. Ren YR, Pan F, Parvez S, et al. Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. PLoS ONE 2008;3(12):e4009. Publiashed online 23 December 2008, doi:10.1371/journal.pone. 0004009
111. Available from: http://www.bionomics.com.au
112. Merck Serono and Bionomics Announce Multiple Sclerosis Development and Licensing Agreement. Pharmalicensing Ltd 2008. Available from: http://pharmalicensing.com/public/news/viewNewsML/1237/Merck%20Serono-and- Bionomics-Announce-Multiple-Sclerosis-Development-and-Licensing-Agreement [Last accessed 14 May 2009]
113. Lin CS, Boltz RC, Blake JT, et al. Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation. J Exp Med 1993;177(3):637-645
114. Verheugen JA, Le Deist F, Devignot V, Korn H. Enhancement of calcium signaling and proliferation responses in activated human T lymphocytes. Inhibitory effects of K + channel block by charybdotoxin depend on the T cell activation state. Cell Calcium 1997;21(1):1-17
115. Matheu MP, Beeton C, Garcia A, et al. Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block. Immunity 2008;29(4):602-614
116. Hu L, Pennington M, Jiang Q, et al. Characterization of the functional properties of the voltage-gated potassium channel Kv1.3 in human CD4 + T lymphocytes. J Immunol 2007;179(7):4563-4570
117. Matheu MP, Beeton C, Garcia A, et al. Effector memory T cell in contact with an antigen presenting cell 3 hours after antigen challenge during DTH. Veomed 2008. Available from: http://www.veomed.com/?q = node/8647 [Last accessed 14 May 2009]
118. Matheu MP, Beeton C, Garcia A, et al. Effector memory T cells moving in inflamed tissue 24 hours after antigen challenge during delayed type hypersensitivity. Veomed 2008. Available from: http://www.veomed.com/?q = node/8580 [Last accessed 14 May 2009]
119. Matheu MP, Beeton C, Garcia A, et al. Effector memory T cells paralyzed in inflamed tissue by ShK-186 treatment: visualization by two-photon imaging. Veomed 2008. Available from: http://www.veomed.com/?q = node/8159 [Last accessed 14 May 2009]
120. Matheu MP, Beeton C, Garcia A, et al. Effector memory T cells moving along collagen fibers in inflamed tissue 24 hours after antigen challenge during DTH. Veomed 2008. Available from: http://www.veomed.com/?q = node/2843 [Last accessed 14 May 2009]
121. Fdez-Freire LR, Serrano Gotarredona A, Bernabeu Wittel J, et al. Clofazimine as elective treatment for granulomatous cheilitis. J Drugs Dermatol 2005;4(3):374-377
122. Bezerra EL, Vilar MJ, da Trindade Neto PB, Sato EI et al. Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus. Arthritis Rheum 2005;52(10):3073-3078
123. Nair LV, Shereef PH. Successful treatment of generalized pustular psoriasis with clofazimine. Int J Dermatol 1991;30(2):151
124. Chuaprapaisilp T. Piamphongsant T. Treatment of pustular psoriasis with clofazimine. Br J Dermatol 1978;99(3):303-305
125. Lee SJ, Wegner SA, McGarigle CJ, et al. Treatment of chronic graft-versus-host disease with clofazimine. Blood 1997;89(7):2298-2302 (Pubitemid 27143275)
126. Matheu MP, Beeton C, Garcia A, et al. Chronic relapsing-remitting experimental autoimmune encephalomyelitis (CR-EAE) in Dark Agouti rats Treatment of chronic relapsing-remitting experimental autoimmune encephalomyelitis by ShK-186. Veomed 2009; Available from: http://www.veomed.com/?q = node/8896 [Last accessed 14 May 2009]
127. Matheu MP, Beeton C, Garcia A, et al. Treatment of chronic relapsing-remitting EAE in rats with ShK-186, an inhibitor of Kv1.3 channels in effector memory T cells. Available from: http://www.veomed.com/?q = node/2841 [Last accessed 14 May 2009]
128. Azam P, Sankaranarayanan A, Homerick D, et al. Targeting effector memory T cells with the small molecule Kv1.3 blocker PAP-1 suppresses allergic contact dermatitis. J Invest Dermatol 2007;127(6):1419-1429 (Pubitemid 46762978)
129. Valverde P, Kawai T, Taubman MA. Selective blockade of voltage-gated potassium channels reduces inflammatory bone resorption in experimental periodontal disease. J Bone Miner Res 2004;19(1):155-164 (Pubitemid 41295148)
130. Taubman MA, Valverde P, Han X, Kawai T. Immune response: the key to bone resorption in periodontal disease. J Periodontol 2005;76(11 Suppl):2033-2041 (Pubitemid 41748950)
131. Arkett S, Dixon J, Yang JN, et al. Mammalian osteoclasts express a transient potassium channel with properties of Kv1.3. Receptors Channels 1994;2(4):281-293
132. Jacob A, Hurley IR, Goodwin LO, et al. Molecular characterization of a voltage-gated potassium channel expressed in rat testis. Mol Hum Reprod 2000;6(4):303-313 (Pubitemid 30171516)
133. Manabe I, Tsuboi M, Ahmmed GU, et al. Expression of Shaker-type voltage-gated potassium channel genes in the guinea-pig. Res Commun Mol Pathol Pharmacol 1998;99(1):33-40 (Pubitemid 28110415)
134. Vautier F, Belachew S, Chittajallu R, Gallo V. Shaker-type potassium channel subunits differentially control oligodendrocyte progenitor proliferation. Glia 2004;48(4):337-345 (Pubitemid 39578034)
135. Grunnet M, Rasmussen HB, Hay-Schmidt A, Klaerke DA. The voltage-gated potassium channel subunit, Kv1.3, is expressed in epithelia. Biochim Biophys Acta 2003;1616(1):85-94 (Pubitemid 37272116)
136. Xu J, Koni PA, Wang P, et al. The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight. Hum Mol Genet 2003;12(5):551-559 (Pubitemid 36305593)
137. Xu J, Wang P, Li Y, et al. The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity. Proc Natl Acad Sci USA 2004;101(9):3112-3117 (Pubitemid 38327743)
138. Parizhskaya M, Youssef NN, Di Lorenzo C, Goyal RK. Clofazimine enteropathy in a pediatric bone marrow transplant recipient. J Pediatr 2001;138(4):574-576 (Pubitemid 32319734)
139. Mathew BS, Pulimood AB, Prasanna CG, et al. Clofazimine induced enteropathy-a case highlighting the importance of drug induced disease in differential diagnosis. Trop Gastroenterol 2006;27(2):87-88
140. Craythorn JM, Swartz M, Creel DJ. Clofazimine-induced bull's-eye retinopathy. Retina 1986;6(1):50-52
141. McDougall AC, Horsfall WR, Hede JE, Chaplin AJ. Splenic infarction and tissue accumulation of crystals associated with the use of clofazimine (Lamprene; B663) in the treatment of pyoderma gangrenosum. Br J Dermatol 1980;102(2):227-230
142. Gegg CV, Walker KW, Miranda LP, Xiong F. Modified Fc molecules. USPTO Application Number 20070269369; 2007
143. Markovic-Plese S, Cortese I, Wandinger KP, et al. CD4+CD28- costimulation-independent T cells in multiple sclerosis. J Clin Invest 2001;108:1185-1194
144. Viglietta V, Kent SC, Orban T, et al. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. J Clin Invest 2002;109:895-903 (Pubitemid 34275110)
145. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001;345:248-255
146. Chamian F, Lin SL, Lee E, et al. Alefacept (anti-CD2) causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis. J Transl Med 2007;5:27 (Pubitemid 47054427)
147. Abdulahad WH, Stegeman CA, Limburg PC, et al. CD4-positive effector memory T cells participate in disease expression in ANCA-associated vasculitis. Ann N Y Acad Sci 2007;1107:22-31
148. Lamprecht P, Mueller A, Gross WL. CD28- T cells display features of effector memory T cells in Wegener's granulomatosis. Kidney Int 2004;65:1113; author reply -4
149. Abdulahad WH, van der Geld YM, Stegeman CA, et al. Persistent expansion of CD4+ effector memory T cells in Wegener's granulomatosis. Kidney Int 2006;70:938-947
150. Capraru D, Muller A, Csernok E, et al. Expansion of circulating NKG2D+ effector memory T-cells and expression of NKG2D-ligand MIC in granulomaous lesions in Wegener's granulomatosis. Clin Immunol 2008;127:144-150
151. Guida G, Vallario A, Stella S, et al. Clonal CD8+ TCR-Vbeta expanded populations with effector memory phenotype in Churg Strauss syndrome. Clin Immunol 2008;128:94-102
152. Mizuno K, Yachie A, Nagaoki S, et al. Oligoclonal expansion of circulating and tissue-infiltrating CD8+ T cells with killer/effector phenotypes in juvenile dermatomyositis syndrome. Clin Exp Immunol 2004;137:187-194 (Pubitemid 38869795)
153. Minetti C, Gattorno M, Repetto S, et al. Chemokine receptor CCR7 is expressed in muscle fibers in juvenile dermatomyositis. Biochem Biophys Res Commun 2005;333:540-543 (Pubitemid 40848324)
154. Warrington KJ, Nair U, Carbone LD, et al. Characterisation of the immune response to type I collagen in scleroderma. Arthritis Res Ther 2006;8:R136
155. Wells AU, Lorimer S, Majumdar S, et al. Fibrosing alveolitis in systemic sclerosis: increase in memory T-cells in lung interstitium. Eur Respir J 1995;8:266-271
156. Lin MS, Fu CL, Aoki V, et al. Desmoglein-1-specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem). J Clin Invest 2000;105:207-213 (Pubitemid 30054360)
157. Valverde P, Kawai T, Taubman MA. Potassium channel-blockers as therapeutic agents to interfere with bone resorption of periodontal disease. J Dent Res 2005;84:488-499 (Pubitemid 43827855)
158. Yamashita K, Choi U, Woltz PC, et al. Severe chronic graft-versus-host disease is characterized by a preponderance of CD4(+) effector memory cells relative to central memory cells. Blood 2004;103:3986-3988 (Pubitemid 38596324)