KCNA3

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Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the KCNA3 gene.[1][2][3]

Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes – shaker, shaw, shab, and shal – have been identified in Drosophila, and each has been shown to have human homolog(s).

This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. It plays an essential role in T cell proliferation and activation. This gene appears to be intronless and is clustered together with KCNA2 and KCNA10 genes on chromosome 1.[1]

Function

KCNA3 encodes the voltage-gated Kv1.3 channel, which is expressed in T and B lymphocytes.[2][4][5][6][7][8][9] All human T cells express roughly 300 Kv1.3 channels per cell along with 10-20 calcium-activated KCa3.1 channels.[10][11] Upon activation, naive and central memory T cells increase expression of the KCa3.1 channel to approximately 500 channels per cell, while effector-memory T cells increase expression of the Kv1.3 channel.[10][11] Among human B cells, naive and early memory B cells express small numbers of Kv1.3 and KCa3.1 channels when they are quiescent, and augment KCa3.1 expression after activation.[12] In contrast, class-switched memory B cells express high numbers of Kv1.3 channels per cell (about 1500/cell) and this number increases after activation.[12]

Kv1.3 is physically coupled through a series of adaptor proteins to the T-cell receptor signaling complex and it traffics to the immunological synapse during antigen presentation.[13][14] However, blockade of the channel does not prevent immune synapse formation.[14] Kv1.3 and KCa3.1 regulate membrane potential and calcium signaling of T cells.[10] Calcium entry through the CRAC channel is promoted by potassium efflux through the Kv1.3 and KCa3.1 potassium channels.[14][15]

Blockade of Kv1.3 channels in effector-memory T cells suppresses calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation.[10][11][14] In vivo, Kv1.3 blockers paralyze effector-memory T cells at the sites of inflammation and prevent their reactivation in inflamed tissues.[15] In contrast, Kv1.3 blockers do not affect the homing to and motility within lymph nodes of naive and central memory T cells, most likely because these cells express the KCa3.1 channel and are, therefore, protected from the effect of Kv1.3 blockade.[15]

Kv1.3 has been reported to be expressed in the inner mitochondrial membrane in lymphocytes.[16] The apoptotic protein Bax has been suggested to insert into the outer mitochondrial membrane and occlude the pore of Kv1.3 via a lysine residue.[17] Thus, Kv1.3 modulation may be one of many mechanisms that contribute to apoptosis.[16][17][18][19][20]

Clinical significance

Autoimmune

In patients with multiple sclerosis (MS), disease-associated myelin-specific T cells from the blood are predominantly co-stimulation-independent[21] effector-memory T cells that express high numbers of Kv1.3 channels.[11][14] T cells in MS lesions in postmortem brain lesions are also predominantly effector-memory T cells that express high levels of the Kv1.3 channel.[22] In children with type-1 diabetes mellitus, the disease-associated insulin- and GAD65-specific T cells isolated from the blood are effector-memory T cells that express high numbers of Kv1.3 channels, and the same is true of T cells from the synovial joint fluid of patients with rheumatoid arthritis.[14] T cells with other antigen specificities in these patients were naive or central memory T cells that upregulate the KCa3.1 channel upon activation.[14] Consequently, it should be possible to selectively suppress effector-memory T cells with a Kv1.3-specific blocker and thereby ameliorate many autoimmune diseases without compromising the protective immune response. In proof-of-concept studies, Kv1.3 blockers have prevented and treated disease in rat models of multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, contact dermatitis, and delayed-type hypersensitivity.[14][23][24][25][26]

At therapeutic concentrations, the blockers did not cause any clinically evident toxicity in rodents,[14][23] and it did not compromise the protective immune response to acute influenza viral infection and acute chlamydia bacterial infection.[15] Many groups are developing Kv1.3 blockers for the treatment of autoimmune diseases.[27]

Metabolic

Kv1.3 is also considered a therapeutic target for the treatment of obesity,[28][29] for enhancing peripheral insulin sensitivity in patients with type-2 diabetes mellitus,[30] and for preventing bone resorption in periodontal disease.[31] A genetic variation in the Kv1.3 promoter region is associated with low insulin sensitivity and impaired glucose tolerance.[32]

Neurodegeneration

Kv1.3 channels have been found to be highly expressed by activated and plaque-associated microglia in human Alzheimer’s disease (AD) post-mortem brains [33] as well as in mouse models of AD pathology.[34] Patch-clamp recordings and flow cytometric studies performed on acutely isolated mouse microglia have confirmed upregulation of Kv1.3 channels with disease progression in mouse AD models.[34][35] The Kv1.3 channel gene has also been found to be a regulator of pro-inflammatory microglial responses.[36] Selective blockade of Kv1.3 channels by the small molecule Pap1 as well as a peptide sea anemone toxin-based peptide ShK-223 have been found to limit amyloid beta plaque burden in mouse AD models, potentially via augmented clearance by microglia.[34][35]

Blockers

Kv1.3 is blocked[31] by several peptides from venomous creatures including scorpions (ADWX1, OSK1,[37] margatoxin,[38] kaliotoxin, charybdotoxin, noxiustoxin, anuroctoxin)[39][40] and sea anemone (ShK,[41][42][43][44][45] ShK-F6CA, ShK-186, ShK-192,[46] BgK[47]), and by small molecule compounds (e.g., PAP-1,[48] Psora-4,[49] correolide,[50] benzamides,[51] CP339818,[52] progesterone[53] and the anti-lepromatous drug clofazimine[54]). The Kv1.3 blocker clofazimine has been reported to be effective in the treatment of chronic graft-versus-host disease,[55] cutaneous lupus,[56][57] and pustular psoriasis[58][59] in humans. Furthermore, clofazimine in combination with the antibiotics clarithromycin and rifabutin induced remission for about 2 years in patients with Crohn's disease, but the effect was temporary; the effect was thought to be due to anti-mycobacterial activity, but could well have been an immunomodulatory effect by clofazimine.[60]

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: KCNA3 potassium voltage-gated channel, shaker-related subfamily, member 3".
  2. ↑ 2.0 2.1 Grissmer S, Dethlefs B, Wasmuth JJ, Goldin AL, Gutman GA, Cahalan MD, Chandy KG (December 1990). "Expression and chromosomal localization of a lymphocyte K + channel gene". Proceedings of the National Academy of Sciences of the United States of America. 87 (23): 9411–5. doi:10.1073/pnas.87.23.9411. PMC 55175. PMID 2251283.
  3. ↑ Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stühmer W, Wang X (December 2005). "International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels". Pharmacological Reviews. 57 (4): 473–508. doi:10.1124/pr.57.4.10. PMID 16382104.
  4. ↑ DeCoursey TE, Chandy KG, Gupta S, Cahalan MD (1984). "Voltage-gated K + channels in human T lymphocytes: a role in mitogenesis?". Nature. 307 (5950): 465–8. doi:10.1038/307465a0. PMID 6320007.
  5. ↑ Matteson DR, Deutsch C (1984). "K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion". Nature. 307 (5950): 468–71. doi:10.1038/307468a0. PMID 6320008.
  6. ↑ Chandy KG, DeCoursey TE, Cahalan MD, McLaughlin C, Gupta S (August 1984). "Voltage-gated potassium channels are required for human T lymphocyte activation". The Journal of Experimental Medicine. 160 (2): 369–85. doi:10.1084/jem.160.2.369. PMC 2187449. PMID 6088661.
  7. ↑ Chandy KG, Williams CB, Spencer RH, Aguilar BA, Ghanshani S, Tempel BL, Gutman GA (February 1990). "A family of three mouse potassium channel genes with intronless coding regions". Science. 247 (4945): 973–5. doi:10.1126/science.2305265. PMID 2305265.
  8. ↑ Douglass J, Osborne PB, Cai YC, Wilkinson M, Christie MJ, Adelman JP (June 1990). "Characterization and functional expression of a rat genomic DNA clone encoding a lymphocyte potassium channel". Journal of Immunology. 144 (12): 4841–50. PMID 2351830.
  9. ↑ Cai YC, Osborne PB, North RA, Dooley DC, Douglass J (March 1992). "Characterization and functional expression of genomic DNA encoding the human lymphocyte type n potassium channel". DNA and Cell Biology. 11 (2): 163–72. doi:10.1089/dna.1992.11.163. PMID 1547020.
  10. ↑ 10.0 10.1 10.2 10.3 Chandy KG, Wulff H, Beeton C, Pennington M, Gutman GA, Cahalan MD (May 2004). "K + channels as targets for specific immunomodulation". Trends in Pharmacological Sciences. 25 (5): 280–9. doi:10.1016/j.tips.2004.03.010. PMC 2749963. PMID 15120495.
  11. ↑ 11.0 11.1 11.2 11.3 Wulff H, Calabresi PA, Allie R, Yun S, Pennington M, Beeton C, Chandy KG (June 2003). "The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS". The Journal of Clinical Investigation. 111 (11): 1703–13. doi:10.1172/JCI16921. PMC 156104. PMID 12782673.
  12. ↑ 12.0 12.1 Wulff H, Knaus HG, Pennington M, Chandy KG (July 2004). "K + channel expression during B cell differentiation: implications for immunomodulation and autoimmunity". Journal of Immunology. 173 (2): 776–86. doi:10.4049/jimmunol.173.2.776. PMID 15240664.
  13. ↑ Panyi G, Vámosi G, Bacsó Z, Bagdány M, Bodnár A, Varga Z, Gáspár R, Mátyus L, Damjanovich S (February 2004). "Kv1.3 potassium channels are localized in the immunological synapse formed between cytotoxic and target cells". Proceedings of the National Academy of Sciences of the United States of America. 101 (5): 1285–90. doi:10.1073/pnas.0307421100. PMC 337045. PMID 14745040.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 Beeton C, Wulff H, Standifer NE, Azam P, Mullen KM, Pennington MW, Kolski-Andreaco A, Wei E, Grino A, Counts DR, Wang PH, LeeHealey CJ, S Andrews B, Sankaranarayanan A, Homerick D, Roeck WW, Tehranzadeh J, Stanhope KL, Zimin P, Havel PJ, Griffey S, Knaus HG, Nepom GT, Gutman GA, Calabresi PA, Chandy KG (November 2006). "Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases". Proceedings of the National Academy of Sciences of the United States of America. 103 (46): 17414–9. doi:10.1073/pnas.0605136103. PMC 1859943. PMID 17088564.
  15. ↑ 15.0 15.1 15.2 15.3 Matheu MP, Beeton C, Garcia A, Chi V, Rangaraju S, Safrina O, Monaghan K, Uemura MI, Li D, Pal S, de la Maza LM, Monuki E, Flügel A, Pennington MW, Parker I, Chandy KG, Cahalan MD (October 2008). "Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block". Immunity. 29 (4): 602–14. doi:10.1016/j.immuni.2008.07.015. PMC 2732399. PMID 18835197.
  16. ↑ 16.0 16.1 Szabò I, Bock J, Jekle A, Soddemann M, Adams C, Lang F, Zoratti M, Gulbins E (April 2005). "A novel potassium channel in lymphocyte mitochondria". The Journal of Biological Chemistry. 280 (13): 12790–8. doi:10.1074/jbc.M413548200. PMID 15632141.
  17. ↑ 17.0 17.1 Szabó I, Bock J, Grassmé H, Soddemann M, Wilker B, Lang F, Zoratti M, Gulbins E (September 2008). "Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytes". Proceedings of the National Academy of Sciences of the United States of America. 105 (39): 14861–6. doi:10.1073/pnas.0804236105. PMC 2567458. PMID 18818304.
  18. ↑ Szabò I, Gulbins E, Apfel H, Zhang X, Barth P, Busch AE, Schlottmann K, Pongs O, Lang F (August 1996). "Tyrosine phosphorylation-dependent suppression of a voltage-gated K + channel in T lymphocytes upon Fas stimulation". The Journal of Biological Chemistry. 271 (34): 20465–9. doi:10.1074/jbc.271.34.20465. PMID 8702786.
  19. ↑ Storey NM, Gómez-Angelats M, Bortner CD, Armstrong DL, Cidlowski JA (August 2003). "Stimulation of Kv1.3 potassium channels by death receptors during apoptosis in Jurkat T lymphocytes". The Journal of Biological Chemistry. 278 (35): 33319–26. doi:10.1074/jbc.M300443200. PMID 12807917.
  20. ↑ Franco R, DeHaven WI, Sifre MI, Bortner CD, Cidlowski JA (December 2008). "Glutathione depletion and disruption of intracellular ionic homeostasis regulate lymphoid cell apoptosis". The Journal of Biological Chemistry. 283 (52): 36071–87. doi:10.1074/jbc.M807061200. PMC 2605975. PMID 18940791.
  21. ↑ Markovic-Plese S, Cortese I, Wandinger KP, McFarland HF, Martin R (October 2001). "CD4+CD28- costimulation-independent T cells in multiple sclerosis". The Journal of Clinical Investigation. 108 (8): 1185–94. doi:10.1172/JCI12516. PMC 209525. PMID 11602626.
  22. ↑ Rus H, Pardo CA, Hu L, Darrah E, Cudrici C, Niculescu T, Niculescu F, Mullen KM, Allie R, Guo L, Wulff H, Beeton C, Judge SI, Kerr DA, Knaus HG, Chandy KG, Calabresi PA (August 2005). "The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain". Proceedings of the National Academy of Sciences of the United States of America. 102 (31): 11094–9. doi:10.1073/pnas.0501770102. PMC 1182417. PMID 16043714.
  23. ↑ 23.0 23.1 Beeton C, Wulff H, Barbaria J, Clot-Faybesse O, Pennington M, Bernard D, Cahalan MD, Chandy KG, Béraud E (November 2001). "Selective blockade of T lymphocyte K(+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis". Proceedings of the National Academy of Sciences of the United States of America. 98 (24): 13942–7. doi:10.1073/pnas.241497298. PMC 61146. PMID 11717451.
  24. ↑ Beeton C, Pennington MW, Wulff H, Singh S, Nugent D, Crossley G, Khaytin I, Calabresi PA, Chen CY, Gutman GA, Chandy KG (April 2005). "Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases". Molecular Pharmacology. 67 (4): 1369–81. doi:10.1124/mol.104.008193. PMC 4275123. PMID 15665253.
  25. ↑ Beeton C, Smith BJ, Sabo JK, Crossley G, Nugent D, Khaytin I, Chi V, Chandy KG, Pennington MW, Norton RS (January 2008). "The D-diastereomer of ShK toxin selectively blocks voltage-gated K + channels and inhibits T lymphocyte proliferation". The Journal of Biological Chemistry. 283 (2): 988–97. doi:10.1074/jbc.M706008200. PMID 17984097.
  26. ↑ Azam P, Sankaranarayanan A, Homerick D, Griffey S, Wulff H (June 2007). "Targeting effector memory T cells with the small molecule Kv1.3 blocker PAP-1 suppresses allergic contact dermatitis". The Journal of Investigative Dermatology. 127 (6): 1419–29. doi:10.1038/sj.jid.5700717. PMC 1929164. PMID 17273162.
  27. ↑ Wulff H, Beeton C, Chandy KG (September 2003). "Potassium channels as therapeutic targets for autoimmune disorders". Current Opinion in Drug Discovery & Development. 6 (5): 640–7. PMID 14579513.
  28. ↑ Tucker K, Overton JM, Fadool DA (August 2008). "Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice". International Journal of Obesity. 32 (8): 1222–32. doi:10.1038/ijo.2008.77. PMC 2737548. PMID 18542083.
  29. ↑ Xu J, Koni PA, Wang P, Li G, Kaczmarek L, Wu Y, Li Y, Flavell RA, Desir GV (March 2003). "The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight". Human Molecular Genetics. 12 (5): 551–9. doi:10.1093/hmg/ddg049. PMID 12588802.
  30. ↑ Xu J, Wang P, Li Y, Li G, Kaczmarek LK, Wu Y, Koni PA, Flavell RA, Desir GV (March 2004). "The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity". Proceedings of the National Academy of Sciences of the United States of America. 101 (9): 3112–7. doi:10.1073/pnas.0308450100. PMC 365752. PMID 14981264.
  31. ↑ 31.0 31.1 Valverde P, Kawai T, Taubman MA (June 2005). "Potassium channel-blockers as therapeutic agents to interfere with bone resorption of periodontal disease". Journal of Dental Research. 84 (6): 488–99. doi:10.1177/154405910508400603. PMID 15914584.
  32. ↑ Tschritter O, Machicao F, Stefan N, Schäfer S, Weigert C, Staiger H, Spieth C, Häring HU, Fritsche A (February 2006). "A new variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance". The Journal of Clinical Endocrinology and Metabolism. 91 (2): 654–8. doi:10.1210/jc.2005-0725. PMID 16317062.
  33. ↑ Rangaraju S, Gearing M, Jin LW, Levey A (2015-02-06). "Potassium channel Kv1.3 is highly expressed by microglia in human Alzheimer's disease". Journal of Alzheimer's Disease. 44 (3): 797–808. doi:10.3233/jad-141704. PMC 4402159. PMID 25362031.
  34. ↑ 34.0 34.1 34.2 Maezawa I, Nguyen HM, Di Lucente J, Jenkins DP, Singh V, Hilt S, Kim K, Rangaraju S, Levey AI, Wulff H, Jin LW (February 2018). "Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer's disease: preclinical proof of concept". Brain. 141 (2): 596–612. doi:10.1093/brain/awx346. PMC 5837198. PMID 29272333.
  35. ↑ 35.0 35.1 Rangaraju S, Dammer EB, Raza SA, Rathakrishnan P, Xiao H, Gao T, Duong DM, Pennington MW, Lah JJ, Seyfried NT, Levey AI (May 2018). "Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease". Molecular Neurodegeneration. 13 (1): 24. doi:10.1186/s13024-018-0254-8. PMID 29784049.
  36. ↑ Rangaraju S, Raza SA, Pennati A, Deng Q, Dammer EB, Duong D, Pennington MW, Tansey MG, Lah JJ, Betarbet R, Seyfried NT, Levey AI (June 2017). "A systems pharmacology-based approach to identify novel Kv1.3 channel-dependent mechanisms in microglial activation". Journal of Neuroinflammation. 14 (1): 128. doi:10.1186/s12974-017-0906-6. PMC 5485721. PMID 28651603.
  37. ↑ Mouhat S, Teodorescu G, Homerick D, Visan V, Wulff H, Wu Y, Grissmer S, Darbon H, De Waard M, Sabatier JM (January 2006). "Pharmacological profiling of Orthochirus scrobiculosus toxin 1 analogs with a trimmed N-terminal domain". Molecular Pharmacology. 69 (1): 354–62. doi:10.1124/mol.105.017210. PMID 16234482.
  38. ↑ Koo GC, Blake JT, Talento A, Nguyen M, Lin S, Sirotina A, Shah K, Mulvany K, Hora D, Cunningham P, Wunderler DL, McManus OB, Slaughter R, Bugianesi R, Felix J, Garcia M, Williamson J, Kaczorowski G, Sigal NH, Springer MS, Feeney W (June 1997). "Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo". Journal of Immunology. 158 (11): 5120–8. PMID 9164927.
  39. ↑ Aiyar J, Withka JM, Rizzi JP, Singleton DH, Andrews GC, Lin W, Boyd J, Hanson DC, Simon M, Dethlefs B (November 1995). "Topology of the pore-region of a K + channel revealed by the NMR-derived structures of scorpion toxins". Neuron. 15 (5): 1169–81. doi:10.1016/0896-6273(95)90104-3. PMID 7576659.
  40. ↑ Bagdány M, Batista CV, Valdez-Cruz NA, Somodi S, Rodriguez de la Vega RC, Licea AF, Varga Z, Gáspár R, Possani LD, Panyi G (April 2005). "Anuroctoxin, a new scorpion toxin of the alpha-KTx 6 subfamily, is highly selective for Kv1.3 over IKCa1 ion channels of human T lymphocytes". Molecular Pharmacology. 67 (4): 1034–44. doi:10.1124/mol.104.007187. PMID 15615696.
  41. ↑ Pennington MW, Mahnir VM, Krafte DS, Zaydenberg I, Byrnes ME, Khaytin I, Crowley K, Kem WR (February 1996). "Identification of three separate binding sites on SHK toxin, a potent inhibitor of voltage-dependent potassium channels in human T-lymphocytes and rat brain". Biochemical and Biophysical Research Communications. 219 (3): 696–701. doi:10.1006/bbrc.1996.0297. PMID 8645244.
  42. ↑ Tudor JE, Pallaghy PK, Pennington MW, Norton RS (April 1996). "Solution structure of ShK toxin, a novel potassium channel inhibitor from a sea anemone". Nature Structural Biology. 3 (4): 317–20. doi:10.1038/nsb0496-317. PMID 8599755.
  43. ↑ Kalman K, Pennington MW, Lanigan MD, Nguyen A, Rauer H, Mahnir V, Paschetto K, Kem WR, Grissmer S, Gutman GA, Christian EP, Cahalan MD, Norton RS, Chandy KG (December 1998). "ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide". The Journal of Biological Chemistry. 273 (49): 32697–707. doi:10.1074/jbc.273.49.32697. PMID 9830012.
  44. ↑ Rauer H, Pennington M, Cahalan M, Chandy KG (July 1999). "Structural conservation of the pores of calcium-activated and voltage-gated potassium channels determined by a sea anemone toxin". The Journal of Biological Chemistry. 274 (31): 21885–92. doi:10.1074/jbc.274.31.21885. PMID 10419508.
  45. ↑ Han S, Yi H, Yin SJ, Chen ZY, Liu H, Cao ZJ, Wu YL, Li WX (July 2008). "Structural basis of a potent peptide inhibitor designed for Kv1.3 channel, a therapeutic target of autoimmune disease". The Journal of Biological Chemistry. 283 (27): 19058–65. doi:10.1074/jbc.M802054200. PMID 18480054.
  46. ↑ Pennington MW, Beeton C, Galea CA, Smith BJ, Chi V, Monaghan KP, Garcia A, Rangaraju S, Giuffrida A, Plank D, Crossley G, Nugent D, Khaytin I, Lefievre Y, Peshenko I, Dixon C, Chauhan S, Orzel A, Inoue T, Hu X, Moore RV, Norton RS, Chandy KG (April 2009). "Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes". Molecular Pharmacology. 75 (4): 762–73. doi:10.1124/mol.108.052704. PMC 2684922. PMID 19122005.
  47. ↑ Cotton J, Crest M, Bouet F, Alessandri N, Gola M, Forest E, Karlsson E, Castañeda O, Harvey AL, Vita C, Ménez A (February 1997). "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". European Journal of Biochemistry. 244 (1): 192–202. doi:10.1111/j.1432-1033.1997.00192.x. PMID 9063464.
  48. ↑ Schmitz A, Sankaranarayanan A, Azam P, Schmidt-Lassen K, Homerick D, Hänsel W, Wulff H (November 2005). "Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases". Molecular Pharmacology. 68 (5): 1254–70. doi:10.1124/mol.105.015669. PMID 16099841.
  49. ↑ Zhou YY, Hou GQ, He SW, Xiao Z, Xu HJ, Qiu YT, Jiang S, Zheng H, Li ZY (July 2015). "Psora-4, a Kv1.3 Blocker, Enhances Differentiation and Maturation in Neural Progenitor Cells". CNS Neuroscience & Therapeutics. 21 (7): 558–67. doi:10.1111/cns.12402. PMID 25976092.
  50. ↑ Koo GC, Blake JT, Shah K, Staruch MJ, Dumont F, Wunderler D, Sanchez M, McManus OB, Sirotina-Meisher A, Fischer P, Boltz RC, Goetz MA, Baker R, Bao J, Kayser F, Rupprecht KM, Parsons WH, Tong XC, Ita IE, Pivnichny J, Vincent S, Cunningham P, Hora D, Feeney W, Kaczorowski G (November 1999). "Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels". Cellular Immunology. 197 (2): 99–107. doi:10.1006/cimm.1999.1569. PMID 10607427.
  51. ↑ Miao S, Bao J, Garcia ML, Goulet JL, Hong XJ, Kaczorowski GJ, Kayser F, Koo GC, Kotliar A, Schmalhofer WA, Shah K, Sinclair PJ, Slaughter RS, Springer MS, Staruch MJ, Tsou NN, Wong F, Parsons WH, Rupprecht KM (March 2003). "Benzamide derivatives as blockers of Kv1.3 ion channel". Bioorganic & Medicinal Chemistry Letters. 13 (6): 1161–4. doi:10.1016/S0960-894X(03)00014-3. PMID 12643934.
  52. ↑ Nguyen A, Kath JC, Hanson DC, Biggers MS, Canniff PC, Donovan CB, Mather RJ, Bruns MJ, Rauer H, Aiyar J, Lepple-Wienhues A, Gutman GA, Grissmer S, Cahalan MD, Chandy KG (December 1996). "Novel nonpeptide agents potently block the C-type inactivated conformation of Kv1.3 and suppress T cell activation". Molecular Pharmacology. 50 (6): 1672–9. PMID 8967992.
  53. ↑ Ehring GR, Kerschbaum HH, Eder C, Neben AL, Fanger CM, Khoury RM, Negulescu PA, Cahalan MD (November 1998). "A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K + channels, Ca2+ signaling, and gene expression in T lymphocytes". The Journal of Experimental Medicine. 188 (9): 1593–602. doi:10.1084/jem.188.9.1593. PMC 2212508. PMID 9802971.
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