Biology:KCNA3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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, OdK2[39])[40][41] and sea anemone (ShK,[42][43][44][45][46] ShK-F6CA, ShK-186, ShK-192,[47] BgK[48]), and by small molecule compounds (e.g., PAP-1,[49] Psora-4,[50] correolide,[51] benzamides,[52] CP339818,[53] progesterone[54] and the anti-lepromatous drug clofazimine[55]). The Kv1.3 blocker clofazimine has been reported to be effective in the treatment of chronic graft-versus-host disease,[56] cutaneous lupus,[57][58] and pustular psoriasis[59][60] 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.[61]

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: KCNA3 potassium voltage-gated channel, shaker-related subfamily, member 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3738. 
  2. ↑ 2.0 2.1 "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. December 1990. doi:10.1073/pnas.87.23.9411. PMID 2251283. Bibcode: 1990PNAS...87.9411G. 
  3. ↑ "International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels". Pharmacological Reviews 57 (4): 473–508. December 2005. doi:10.1124/pr.57.4.10. PMID 16382104. 
  4. ↑ "Voltage-gated K + channels in human T lymphocytes: a role in mitogenesis?". Nature 307 (5950): 465–8. 1984. doi:10.1038/307465a0. PMID 6320007. Bibcode: 1984Natur.307..465D. 
  5. ↑ "K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion". Nature 307 (5950): 468–71. 1984. doi:10.1038/307468a0. PMID 6320008. Bibcode: 1984Natur.307..468M. 
  6. ↑ "Voltage-gated potassium channels are required for human T lymphocyte activation". The Journal of Experimental Medicine 160 (2): 369–85. August 1984. doi:10.1084/jem.160.2.369. PMID 6088661. 
  7. ↑ "A family of three mouse potassium channel genes with intronless coding regions". Science 247 (4945): 973–5. February 1990. doi:10.1126/science.2305265. PMID 2305265. Bibcode: 1990Sci...247..973C. 
  8. ↑ "Characterization and functional expression of a rat genomic DNA clone encoding a lymphocyte potassium channel". Journal of Immunology 144 (12): 4841–50. June 1990. doi:10.4049/jimmunol.144.12.4841. PMID 2351830. http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=2351830. 
  9. ↑ "Characterization and functional expression of genomic DNA encoding the human lymphocyte type n potassium channel". DNA and Cell Biology 11 (2): 163–72. March 1992. doi:10.1089/dna.1992.11.163. PMID 1547020. 
  10. ↑ 10.0 10.1 10.2 10.3 "K + channels as targets for specific immunomodulation". Trends in Pharmacological Sciences 25 (5): 280–9. May 2004. doi:10.1016/j.tips.2004.03.010. PMID 15120495. 
  11. ↑ 11.0 11.1 11.2 11.3 "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. June 2003. doi:10.1172/JCI16921. PMID 12782673. 
  12. ↑ 12.0 12.1 "K + channel expression during B cell differentiation: implications for immunomodulation and autoimmunity". Journal of Immunology 173 (2): 776–86. July 2004. doi:10.4049/jimmunol.173.2.776. PMID 15240664. 
  13. ↑ "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. February 2004. doi:10.1073/pnas.0307421100. PMID 14745040. Bibcode: 2004PNAS..101.1285P. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 "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. November 2006. doi:10.1073/pnas.0605136103. PMID 17088564. Bibcode: 2006PNAS..10317414B. 
  15. ↑ 15.0 15.1 15.2 15.3 "Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block". Immunity 29 (4): 602–14. October 2008. doi:10.1016/j.immuni.2008.07.015. PMID 18835197. 
  16. ↑ 16.0 16.1 "A novel potassium channel in lymphocyte mitochondria". The Journal of Biological Chemistry 280 (13): 12790–8. April 2005. doi:10.1074/jbc.M413548200. PMID 15632141. 
  17. ↑ 17.0 17.1 "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. September 2008. doi:10.1073/pnas.0804236105. PMID 18818304. Bibcode: 2008PNAS..10514861S. 
  18. ↑ "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. August 1996. doi:10.1074/jbc.271.34.20465. PMID 8702786. 
  19. ↑ "Stimulation of Kv1.3 potassium channels by death receptors during apoptosis in Jurkat T lymphocytes". The Journal of Biological Chemistry 278 (35): 33319–26. August 2003. doi:10.1074/jbc.M300443200. PMID 12807917. 
  20. ↑ "Glutathione depletion and disruption of intracellular ionic homeostasis regulate lymphoid cell apoptosis". The Journal of Biological Chemistry 283 (52): 36071–87. December 2008. doi:10.1074/jbc.M807061200. PMID 18940791. 
  21. ↑ "CD4+CD28- costimulation-independent T cells in multiple sclerosis". The Journal of Clinical Investigation 108 (8): 1185–94. October 2001. doi:10.1172/JCI12516. PMID 11602626. 
  22. ↑ "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. August 2005. doi:10.1073/pnas.0501770102. PMID 16043714. Bibcode: 2005PNAS..10211094R. 
  23. ↑ 23.0 23.1 "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. November 2001. doi:10.1073/pnas.241497298. PMID 11717451. Bibcode: 2001PNAS...9813942B. 
  24. ↑ "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. April 2005. doi:10.1124/mol.104.008193. PMID 15665253. 
  25. ↑ "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. January 2008. doi:10.1074/jbc.M706008200. PMID 17984097. 
  26. ↑ "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. June 2007. doi:10.1038/sj.jid.5700717. PMID 17273162. 
  27. ↑ "Potassium channels as therapeutic targets for autoimmune disorders". Current Opinion in Drug Discovery & Development 6 (5): 640–7. September 2003. PMID 14579513. 
  28. ↑ "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. August 2008. doi:10.1038/ijo.2008.77. PMID 18542083. 
  29. ↑ "The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight". Human Molecular Genetics 12 (5): 551–9. March 2003. doi:10.1093/hmg/ddg049. PMID 12588802. 
  30. ↑ "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. March 2004. doi:10.1073/pnas.0308450100. PMID 14981264. Bibcode: 2004PNAS..101.3112X. 
  31. ↑ 31.0 31.1 "Potassium channel-blockers as therapeutic agents to interfere with bone resorption of periodontal disease". Journal of Dental Research 84 (6): 488–99. June 2005. doi:10.1177/154405910508400603. PMID 15914584. 
  32. ↑ "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. February 2006. doi:10.1210/jc.2005-0725. PMID 16317062. 
  33. ↑ "Potassium channel Kv1.3 is highly expressed by microglia in human Alzheimer's disease". Journal of Alzheimer's Disease 44 (3): 797–808. 2015-02-06. doi:10.3233/jad-141704. PMID 25362031. 
  34. ↑ 34.0 34.1 34.2 "Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer's disease: preclinical proof of concept". Brain 141 (2): 596–612. February 2018. doi:10.1093/brain/awx346. PMID 29272333. 
  35. ↑ 35.0 35.1 "Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease". Molecular Neurodegeneration 13 (1): 24. May 2018. doi:10.1186/s13024-018-0254-8. PMID 29784049. 
  36. ↑ "A systems pharmacology-based approach to identify novel Kv1.3 channel-dependent mechanisms in microglial activation". Journal of Neuroinflammation 14 (1): 128. June 2017. doi:10.1186/s12974-017-0906-6. PMID 28651603. 
  37. ↑ "Pharmacological profiling of Orthochirus scrobiculosus toxin 1 analogs with a trimmed N-terminal domain". Molecular Pharmacology 69 (1): 354–62. January 2006. doi:10.1124/mol.105.017210. PMID 16234482. 
  38. ↑ "Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo". Journal of Immunology 158 (11): 5120–8. June 1997. doi:10.4049/jimmunol.158.11.5120. PMID 9164927. http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=9164927. 
  39. ↑ Abdel-Mottaleb, Yousra; Vandendriessche, Thomas; Clynen, Elke; Landuyt, Bart; Jalali, Amir; Vatanpour, Hossein; Schoofs, Liliane; Tytgat, Jan (2008-06-15). "OdK2, a Kv1.3 channel-selective toxin from the venom of the Iranian scorpion Odonthobuthus doriae" (in en). Toxicon 51 (8): 1424–1430. doi:10.1016/j.toxicon.2008.03.027. ISSN 0041-0101. PMID 18471844. http://www.sciencedirect.com/science/article/pii/S0041010108001074. 
  40. ↑ "Topology of the pore-region of a K + channel revealed by the NMR-derived structures of scorpion toxins". Neuron 15 (5): 1169–81. November 1995. doi:10.1016/0896-6273(95)90104-3. PMID 7576659. 
  41. ↑ "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. April 2005. doi:10.1124/mol.104.007187. PMID 15615696. 
  42. ↑ "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. February 1996. doi:10.1006/bbrc.1996.0297. PMID 8645244. 
  43. ↑ "Solution structure of ShK toxin, a novel potassium channel inhibitor from a sea anemone". Nature Structural Biology 3 (4): 317–20. April 1996. doi:10.1038/nsb0496-317. PMID 8599755. 
  44. ↑ "ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide". The Journal of Biological Chemistry 273 (49): 32697–707. December 1998. doi:10.1074/jbc.273.49.32697. PMID 9830012. 
  45. ↑ "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. July 1999. doi:10.1074/jbc.274.31.21885. PMID 10419508. 
  46. ↑ "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. July 2008. doi:10.1074/jbc.M802054200. PMID 18480054. 
  47. ↑ "Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes". Molecular Pharmacology 75 (4): 762–73. April 2009. doi:10.1124/mol.108.052704. PMID 19122005. 
  48. ↑ "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. February 1997. doi:10.1111/j.1432-1033.1997.00192.x. PMID 9063464. 
  49. ↑ "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. November 2005. doi:10.1124/mol.105.015669. PMID 16099841. 
  50. ↑ "Psora-4, a Kv1.3 Blocker, Enhances Differentiation and Maturation in Neural Progenitor Cells". CNS Neuroscience & Therapeutics 21 (7): 558–67. July 2015. doi:10.1111/cns.12402. PMID 25976092. 
  51. ↑ "Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels". Cellular Immunology 197 (2): 99–107. November 1999. doi:10.1006/cimm.1999.1569. PMID 10607427. 
  52. ↑ "Benzamide derivatives as blockers of Kv1.3 ion channel". Bioorganic & Medicinal Chemistry Letters 13 (6): 1161–4. March 2003. doi:10.1016/S0960-894X(03)00014-3. PMID 12643934. 
  53. ↑ "Novel nonpeptide agents potently block the C-type inactivated conformation of Kv1.3 and suppress T cell activation". Molecular Pharmacology 50 (6): 1672–9. December 1996. PMID 8967992. 
  54. ↑ "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. November 1998. doi:10.1084/jem.188.9.1593. PMID 9802971. 
  55. ↑ Alberola-Ila, Jose, ed (2008). "Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes". PLOS ONE 3 (12): e4009. doi:10.1371/journal.pone.0004009. PMID 19104661. Bibcode: 2008PLoSO...3.4009R. 
  56. ↑ "Treatment of chronic graft-versus-host disease with clofazimine". Blood 89 (7): 2298–302. April 1997. doi:10.1182/blood.V89.7.2298. PMID 9116272. http://www.bloodjournal.org/content/89/7/2298.long. 
  57. ↑ "Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus". Arthritis and Rheumatism 52 (10): 3073–8. October 2005. doi:10.1002/art.21358. PMID 16200586. 
  58. ↑ "Clofazimine in the treatment of discoid lupus erythematosus". The British Journal of Dermatology 91 (1): 93–6. July 1974. doi:10.1111/j.1365-2133.1974.tb06723.x. PMID 4851057. 
  59. ↑ "Treatment of pustular psoriasis with clofazimine". The British Journal of Dermatology 99 (3): 303–5. September 1978. doi:10.1111/j.1365-2133.1978.tb02001.x. PMID 708598. 
  60. ↑ "Clofazimine: a review of its medical uses and mechanisms of action". Journal of the American Academy of Dermatology 32 (2 Pt 1): 241–7. February 1995. doi:10.1016/0190-9622(95)90134-5. PMID 7829710. 
  61. ↑ "Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease". Gastroenterology 132 (7): 2313–9. June 2007. doi:10.1053/j.gastro.2007.03.031. PMID 17570206. 

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