KCNA3: Difference between revisions

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{{Infobox_gene}}
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'''Potassium voltage-gated channel, shaker-related subfamily, member 3''', also known as '''KCNA3''' or '''K<sub>v</sub>1.3''', is a [[protein]] that in humans is encoded by the ''KCNA3'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: KCNA3 potassium voltage-gated channel, shaker-related subfamily, member 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3738| accessdate = }}</ref><ref name="Grissmer_1990">{{cite journal |vauthors=Grissmer S, Dethlefs B, Wasmuth JJ, Goldin AL, Gutman GA, Cahalan MD, Chandy KG | title = Expression and chromosomal localization of a lymphocyte K<sup>+</sup> channel gene | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 23 | pages = 9411–5 |date=December 1990 | pmid = 2251283 | pmc = 55175 | doi = 10.1073/pnas.87.23.9411| url = }}</ref><ref name="Gutman_2005">{{cite journal |vauthors=Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stühmer W, Wang X | title = International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels | journal = Pharmacol. Rev. | volume = 57 | issue = 4 | pages = 473–508 |date=December 2005 | pmid = 16382104 | doi = 10.1124/pr.57.4.10 | url =  }}</ref>
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[[Potassium channel]]s represent the most complex class of [[voltage-gated ion channel]]s 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).
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This gene encodes a member of the potassium channel, voltage-gated, [[shaker gene|shaker]]-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the [[Voltage-gated potassium channel#Delayed rectifier|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 [[intron]]less and is clustered together with [[KCNA2]] and [[KCNA10]] genes on chromosome 1.<ref name="entrez"/>
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== Function ==
 
''KCNA3'' encodes the voltage-gated K<sub>v</sub>1.3 channel, which is expressed in [[T cell|T]] and [[B cell|B lymphocytes]].<ref name="Grissmer_1990"/><ref name="DeCoursey_1984">{{cite journal |vauthors=DeCoursey TE, Chandy KG, Gupta S, Cahalan MD | title = Voltage-gated K<sup>+</sup> channels in human T lymphocytes: a role in mitogenesis? | journal = Nature | volume = 307 | issue = 5950 | pages = 465–8 | year = 1984 | pmid = 6320007 | doi = 10.1038/307465a0| url =  }}</ref><ref name="Matteson_1984">{{cite journal |vauthors=Matteson DR, Deutsch C | title = K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion | journal = Nature | volume = 307 | issue = 5950 | pages = 468–71 | year = 1984 | pmid = 6320008 | doi = 10.1038/307468a0| url =  }}</ref><ref name="Chandy_1984">{{cite journal |vauthors=Chandy KG, DeCoursey TE, Cahalan MD, McLaughlin C, Gupta S | title = Voltage-gated potassium channels are required for human T lymphocyte activation | journal = J. Exp. Med. | volume = 160 | issue = 2 | pages = 369–85 |date=August 1984 | pmid = 6088661 | pmc = 2187449 | doi = 10.1084/jem.160.2.369| url =  }}</ref><ref name="Chandy_1990">{{cite journal |vauthors=Chandy KG, Williams CB, Spencer RH, Aguilar BA, Ghanshani S, Tempel BL, Gutman GA | title = A family of three mouse potassium channel genes with intronless coding regions | journal = Science | volume = 247 | issue = 4945 | pages = 973–5 |date=February 1990 | pmid = 2305265 | doi = 10.1126/science.2305265 | url = | issn = }}</ref><ref name="Douglass_1990">{{cite journal |vauthors=Douglass J, Osborne PB, Cai YC, Wilkinson M, Christie MJ, Adelman JP | title = Characterization and functional expression of a rat genomic DNA clone encoding a lymphocyte potassium channel | journal = J. Immunol. | volume = 144 | issue = 12 | pages = 4841–50 |date=June 1990 | pmid = 2351830 | doi = | url = http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=2351830 | issn = }}</ref><ref name="Cai_1992">{{cite journal |vauthors=Cai YC, Osborne PB, North RA, Dooley DC, Douglass J | title = Characterization and functional expression of genomic DNA encoding the human lymphocyte type n potassium channel | journal = DNA Cell Biol. | volume = 11 | issue = 2 | pages = 163–72 |date=March 1992 | pmid = 1547020 | doi = 10.1089/dna.1992.11.163| url = | issn = }}</ref>  All human T cells express roughly 300 K<sub>v</sub>1.3 channels per cell along with 10-20 calcium-activated [[KCNN4|K<sub>Ca</sub>3.1 channel]]s.<ref name="Chandy_2004">{{cite journal |vauthors=Chandy KG, Wulff H, Beeton C, Pennington M, Gutman GA, Cahalan MD | title = K<sup>+</sup> channels as targets for specific immunomodulation | journal = Trends Pharmacol. Sci. | volume = 25 | issue = 5 | pages = 280–9 |date=May 2004 | pmid = 15120495 | doi = 10.1016/j.tips.2004.03.010 | url = | pmc = 2749963  }}</ref><ref name="Wulff_2003">{{cite journal |vauthors=Wulff H, Calabresi PA, Allie R, Yun S, Pennington M, Beeton C, Chandy KG | title = The voltage-gated K<sub>v</sub>1.3 K<sup>+</sup> channel in effector memory T cells as new target for MS | journal = J. Clin. Invest. | volume = 111 | issue = 11 | pages = 1703–13 |date=June 2003 | pmid = 12782673 | pmc = 156104 | doi = 10.1172/JCI16921 | url =  }}</ref> Upon activation, [[naive T cell|naive]] and central [[memory T cell]]s increase expression of the K<sub>Ca</sub>3.1 channel to approximately 500 channels per cell, while effector-memory T cells increase expression of the K<sub>v</sub>1.3 channel.<ref name="Chandy_2004"/><ref name="Wulff_2003"/> Among human B cells, naive and early memory B cells express small numbers of K<sub>v</sub>1.3 and K<sub>Ca</sub>3.1 channels when they are quiescent, and augment K<sub>Ca</sub>3.1 expression after activation.<ref name="Wulff_2004">{{cite journal |vauthors=Wulff H, Knaus HG, Pennington M, Chandy KG | title = K<sup>+</sup> channel expression during B cell differentiation: implications for immunomodulation and autoimmunity | journal = J. Immunol. | volume = 173 | issue = 2 | pages = 776–86 |date=July 2004 | pmid = 15240664 | doi = 10.4049/jimmunol.173.2.776| url = http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=15240664 | issn = }}</ref> In contrast, class-switched memory B cells express high numbers of K<sub>v</sub>1.3 channels per cell (about 1500/cell) and this number increases after activation.<ref name="Wulff_2004"/>
 
K<sub>v</sub>1.3 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]].<ref name="Panyi_2004">{{cite journal |vauthors=Panyi G, Vámosi G, Bacsó Z, Bagdány M, Bodnár A, Varga Z, Gáspár R, Mátyus L, Damjanovich S | title = K<sub>v</sub>1.3 potassium channels are localized in the immunological synapse formed between cytotoxic and target cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 5 | pages = 1285–90 |date=February 2004 | pmid = 14745040 | pmc = 337045 | doi = 10.1073/pnas.0307421100 | url =  }}</ref><ref name="Beeton_2006">{{cite journal |vauthors=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 | title = K<sub>v</sub>1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 46 | pages = 17414–9 |date=November 2006 | pmid = 17088564 | pmc = 1859943 | doi = 10.1073/pnas.0605136103 | url =  }}</ref> However, blockade of the channel does not prevent immune synapse formation.<ref name="Beeton_2006"/>  K<sub>v</sub>1.3 and K<sub>Ca</sub>3.1 regulate [[membrane potential]] and [[calcium signaling]] of T cells.<ref name="Chandy_2004"/> Calcium entry through the [[TMEM142A|CRAC channel]] is promoted by potassium efflux through the K<sub>v</sub>1.3 and K<sub>Ca</sub>3.1 potassium channels.<ref name="Beeton_2006"/><ref name="Matheu_2008"/>
 
Blockade of K<sub>v</sub>1.3 channels in effector-memory T cells suppresses calcium signaling, [[cytokine]] production ([[interferon-gamma]], [[interleukin 2]]) and cell proliferation.<ref name="Chandy_2004"/><ref name="Wulff_2003"/><ref name="Beeton_2006"/> In vivo, K<sub>v</sub>1.3 blockers paralyze effector-memory T cells at the sites of inflammation and prevent their reactivation in inflamed tissues.<ref name="Matheu_2008">{{cite journal |vauthors=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 | title = Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by K<sub>v</sub>1.3 channel block | journal = Immunity | volume = 29 | issue = 4 | pages = 602–14 |date=October 2008 | pmid = 18835197 | doi = 10.1016/j.immuni.2008.07.015 | url = | pmc = 2732399  }}</ref>  In contrast, K<sub>v</sub>1.3 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 K<sub>Ca</sub>3.1 channel and are, therefore, protected from the effect of K<sub>v</sub>1.3 blockade.<ref name="Matheu_2008"/>
 
K<sub>v</sub>1.3 has been reported to be expressed in the [[inner mitochondrial membrane]] in lymphocytes.<ref name= "Szabo_2005">{{cite journal |vauthors=Szabò I, Bock J, Jekle A, Soddemann M, Adams C, Lang F, Zoratti M, Gulbins E | title = A novel potassium channel in lymphocyte mitochondria | journal = J. Biol. Chem. | volume = 280 | issue = 13 | pages = 12790–8 |date=April 2005 | pmid = 15632141 | doi = 10.1074/jbc.M413548200 | url = | issn = }}</ref> The apoptotic protein [[Bcl-2-associated X protein|Bax]] has been suggested to insert into the [[outer mitochondrial membrane]] and occlude the pore of K<sub>v</sub>1.3 via a [[lysine]] residue.<ref name="Szabo_2008">{{cite journal |vauthors=Szabó I, Bock J, Grassmé H, Soddemann M, Wilker B, Lang F, Zoratti M, Gulbins E | title = Mitochondrial potassium channel K<sub>v</sub>1.3 mediates Bax-induced apoptosis in lymphocytes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 39 | pages = 14861–6 |date=September 2008 | pmid = 18818304 | doi = 10.1073/pnas.0804236105 | url = | issn = | pmc = 2567458 }}</ref> Thus, K<sub>v</sub>1.3 modulation may be one of many mechanisms that contribute to apoptosis.<ref name= "Szabo_2005" /><ref name= "Szabo_2008" /><ref name="Szabo_1996">{{cite journal |vauthors=Szabò I, Gulbins E, Apfel H, Zhang X, Barth P, Busch AE, Schlottmann K, Pongs O, Lang F | title = Tyrosine phosphorylation-dependent suppression of a voltage-gated K<sup>+</sup> channel in T lymphocytes upon Fas stimulation | journal = J. Biol. Chem. | volume = 271 | issue = 34 | pages = 20465–9 |date=August 1996 | pmid = 8702786 | doi = 10.1074/jbc.271.34.20465 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8702786 | issn = }}</ref><ref name="Story_2003">{{cite journal |vauthors=Storey NM, Gómez-Angelats M, Bortner CD, Armstrong DL, Cidlowski JA | title = Stimulation of K<sub>v</sub>1.3 potassium channels by death receptors during apoptosis in Jurkat T lymphocytes | journal = J. Biol. Chem. | volume = 278 | issue = 35 | pages = 33319–26 |date=August 2003 | pmid = 12807917 | doi = 10.1074/jbc.M300443200 | url = | issn = }}</ref><ref name="Franco_2008">{{cite journal |vauthors=Franco R, Dehaven WI, Sifre MI, Bortner CD, Cidlowski JA | title = Glutathione depletion and disruption of intracellular ionic homeostasis regulate lymphoid cell apoptosis | journal = J. Biol. Chem. | volume = 283 | issue = 52 | pages = 36071–87 |date=December 2008 | pmid = 18940791 | doi = 10.1074/jbc.M807061200 | url = | issn = | pmc = 2605975 }}</ref>
 
== Clinical significance ==
 
=== Autoimmune ===
 
In patients with [[multiple sclerosis]] (MS), disease-associated myelin-specific T cells from the blood are predominantly co-stimulation-independent<ref name="Markovic-Plese_2001">{{cite journal |vauthors=Markovic-Plese S, Cortese I, Wandinger KP, McFarland HF, Martin R | title = CD4<sup>+</sup>/CD28<sup>−</sup> costimulation-independent T cells in multiple sclerosis | journal = J. Clin. Invest. | volume = 108 | issue = 8 | pages = 1185–94 |date=October 2001 | pmid = 11602626 | pmc = 209525 | doi = 10.1172/JCI12516 | url =  }}</ref> effector-memory T cells that express high numbers of K<sub>v</sub>1.3 channels.<ref name="Wulff_2003"/><ref name="Beeton_2006"/> T cells in MS lesions in postmortem brain lesions are also predominantly effector-memory T cells that express high levels of the K<sub>v</sub>1.3 channel.<ref name="Rus_2005">{{cite journal |vauthors=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 | title = The voltage-gated potassium channel K<sub>v</sub>1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 102 | issue = 31 | pages = 11094–9 |date=August 2005 | pmid = 16043714 | pmc = 1182417 | doi = 10.1073/pnas.0501770102 | url =  }}</ref>  In children with type-1 [[diabetes mellitus]], the disease-associated insulin- and [[GAD2|GAD65]]-specific T cells isolated from the blood are effector-memory T cells that express high numbers of K<sub>v</sub>1.3 channels, and the same is true of T cells from the synovial joint fluid of patients with [[rheumatoid arthritis]].<ref name="Beeton_2006"/> T cells with other antigen specificities in these patients were naive or central memory T cells that upregulate the K<sub>Ca</sub>3.1 channel upon activation.<ref name="Beeton_2006"/> Consequently, it should be possible to selectively suppress effector-memory T cells with a K<sub>v</sub>1.3-specific blocker and thereby ameliorate many [[autoimmune disease]]s without compromising the protective immune response. In proof-of-concept studies, K<sub>v</sub>1.3 blockers have prevented and treated disease in rat models of multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, contact dermatitis, and delayed-type hypersensitivity.<ref name="Beeton_2006"/><ref name="Beeton_2001">{{cite journal |vauthors=Beeton C, Wulff H, Barbaria J, Clot-Faybesse O, Pennington M, Bernard D, Cahalan MD, Chandy KG, Béraud E | title = Selective blockade of T lymphocyte K<sup>+</sup> channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 24 | pages = 13942–7 |date=November 2001 | pmid = 11717451 | pmc = 61146 | doi = 10.1073/pnas.241497298 | url =  }}</ref><ref name="Beeton_2005">{{cite journal |vauthors=Beeton C, Pennington MW, Wulff H, Singh S, Nugent D, Crossley G, Khaytin I, Calabresi PA, Chen CY, Gutman GA, Chandy KG | title = Targeting effector memory T cells with a selective peptide inhibitor of K<sub>v</sub>1.3 channels for therapy of autoimmune diseases | journal = Mol. Pharmacol. | volume = 67 | issue = 4 | pages = 1369–81 |date=April 2005 | pmid = 15665253 | doi = 10.1124/mol.104.008193 | url =  }}</ref><ref name="ref_18">{{cite journal |vauthors=Beeton C, Smith BJ, Sabo JK, Crossley G, Nugent D, Khaytin I, Chi V, Chandy KG, Pennington MW, Norton RS | title = The D-diastereomer of ShK toxin selectively blocks voltage-gated K<sup>+</sup> channels and inhibits T lymphocyte proliferation | journal = J. Biol. Chem. | volume = 283 | issue = 2 | pages = 988–97 |date=January 2008 | pmid = 17984097 | doi = 10.1074/jbc.M706008200 | url =  }}</ref><ref name="Azam_2007">{{cite journal |vauthors=Azam P, Sankaranarayanan A, Homerick D, Griffey S, Wulff H | title = Targeting effector memory T cells with the small molecule K<sub>v</sub>1.3 blocker PAP-1 suppresses allergic contact dermatitis | journal = J. Invest. Dermatol. | volume = 127 | issue = 6 | pages = 1419–29 |date=June 2007 | pmid = 17273162 | pmc = 1929164 | doi = 10.1038/sj.jid.5700717 | url =  }}</ref>
 
At therapeutic concentrations, the blockers did not cause any clinically evident toxicity in rodents,<ref name="Beeton_2006"/><ref name="Beeton_2001"/> and it did not compromise the protective immune response to acute [[influenza]] viral infection and acute [[Chlamydia infection|chlamydia]] bacterial infection.<ref name="Matheu_2008"/> Many groups are developing K<sub>v</sub>1.3 blockers for the treatment of autoimmune diseases.<ref name="Wulff_2003b">{{cite journal |vauthors=Wulff H, Beeton C, Chandy KG | title = Potassium channels as therapeutic targets for autoimmune disorders | journal = Curr Opin Drug Discov Dev | volume = 6 | issue = 5 | pages = 640–7 |date=September 2003 | pmid = 14579513 | doi = | url = | issn = }}</ref>
 
=== Metabolic ===
 
K<sub>v</sub>1.3 is also considered a therapeutic target for the treatment of obesity,<ref name="Tucker_2008">{{cite journal |vauthors=Tucker K, Overton JM, Fadool DA | title = K<sub>v</sub>1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice | journal = Int J Obes (Lond) | volume = 32 | issue = 8 | pages = 1222–32 |date=August 2008 | pmid = 18542083 | doi = 10.1038/ijo.2008.77 | url = | pmc = 2737548  }}</ref><ref name="Xu_2003">{{cite journal |vauthors=Xu J, Koni PA, Wang P, Li G, Kaczmarek L, Wu Y, Li Y, Flavell RA, Desir GV | title = The voltage-gated potassium channel K<sub>v</sub>1.3 regulates energy homeostasis and body weight | journal = Hum. Mol. Genet. | volume = 12 | issue = 5 | pages = 551–9 |date=March 2003 | pmid = 12588802 | doi =10.1093/hmg/ddg049 }}</ref> for enhancing peripheral [[insulin sensitivity]] in patients with [[diabetes mellitus type 2|type-2 diabetes mellitus]],<ref name="Xu_2004">{{cite journal |vauthors=Xu J, Wang P, Li Y, Li G, Kaczmarek LK, Wu Y, Koni PA, Flavell RA, Desir GV | title = The voltage-gated potassium channel K<sub>v</sub>1.3 regulates peripheral insulin sensitivity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 9 | pages = 3112–7 |date=March 2004 | pmid = 14981264 | pmc = 365752 | doi = 10.1073/pnas.0308450100 | url =  }}</ref> and for preventing [[bone resorption]] in [[periodontitis|periodontal disease]].<ref name="Valverde_2005">{{cite journal |vauthors=Valverde P, Kawai T, Taubman MA | title = Potassium channel-blockers as therapeutic agents to interfere with bone resorption of periodontal disease | journal = J. Dent. Res. | volume = 84 | issue = 6 | pages = 488–99 |date=June 2005 | pmid = 15914584 | doi = 10.1177/154405910508400603| url = }}</ref> A genetic variation in the K<sub>v</sub>1.3 promoter region is associated with low insulin sensitivity and [[impaired glucose tolerance]].<ref name="Tschritter_2006">{{cite journal |vauthors=Tschritter O, Machicao F, Stefan N, Schäfer S, Weigert C, Staiger H, Spieth C, Häring HU, Fritsche A | title = A new variant in the human K<sub>v</sub>1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance | journal = J. Clin. Endocrinol. Metab. | volume = 91 | issue = 2 | pages = 654–8 |date=February 2006 | pmid = 16317062 | doi = 10.1210/jc.2005-0725 | url = | issn = }}</ref>


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== Blockers==
{{GNF_Protein_box
| image = PBB_Protein_KCNA3_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1dsx.
| PDB = {{PDB2|1dsx}}, {{PDB2|1qdv}}, {{PDB2|1qdw}}
| Name = Potassium voltage-gated channel, shaker-related subfamily, member 3
| HGNCid = 6221
| Symbol = KCNA3
| AltSymbols =; PCN3; HGK5; HLK3; HPCN3; HUKIII; KV1.3; MK3
| OMIM = 176263
| ECnumber = 
| Homologene = 20513
| MGIid = 96660
| GeneAtlas_image1 = PBB_GE_KCNA3_207237_at_tn.png
| Function = {{GNF_GO|id=GO:0005251 |text = delayed rectifier potassium channel activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0030955 |text = potassium ion binding}}
| Component = {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0008076 |text = voltage-gated potassium channel complex}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006811 |text = ion transport}} {{GNF_GO|id=GO:0006813 |text = potassium ion transport}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3738
    | Hs_Ensembl = ENSG00000177272
    | Hs_RefseqProtein = NP_002223
    | Hs_RefseqmRNA = NM_002232
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 1
    | Hs_GenLoc_start = 111016610
    | Hs_GenLoc_end = 111019178
    | Hs_Uniprot = P22001
    | Mm_EntrezGene = 16491
    | Mm_Ensembl = ENSMUSG00000047959
    | Mm_RefseqmRNA = NM_008418
    | Mm_RefseqProtein = NP_032444
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 3
    | Mm_GenLoc_start = 107164479
    | Mm_GenLoc_end = 107166065
    | Mm_Uniprot = P16390
  }}
}}
'''Potassium voltage-gated channel, shaker-related subfamily, member 3''', also known as '''KCNA3''' or '''K<sub>v</sub>1.3''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: KCNA3 potassium voltage-gated channel, shaker-related subfamily, member 3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3738| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
K<sub>v</sub>1.3 is blocked<ref name="Valverde_2005"/> by several peptides from venomous creatures including scorpions (ADWX1, OSK1,<ref name="pmid16234482">{{cite journal |vauthors=Mouhat S, Teodorescu G, Homerick D, Visan V, Wulff H, Wu Y, Grissmer S, Darbon H, De Waard M, Sabatier JM | title = Pharmacological profiling of Orthochirus scrobiculosus toxin 1 analogs with a trimmed N-terminal domain | journal = Mol. Pharmacol. | volume = 69 | issue = 1 | pages = 354–62 |date=January 2006 | pmid = 16234482 | doi = 10.1124/mol.105.017210 | url = }}</ref> [[margatoxin]],<ref name="pmid9164927">{{cite journal |vauthors=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 | title = Blockade of the voltage-gated potassium channel K<sub>v</sub>1.3 inhibits immune responses in vivo | journal = J. Immunol. | volume = 158 | issue = 11 | pages = 5120–8 |date=June 1997 | pmid = 9164927 | doi = | url = http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=9164927 | issn = }}</ref> [[kaliotoxin]], [[charybdotoxin]], [[noxiustoxin]], anuroctoxin)<ref name="pmid7576659">{{cite journal |vauthors=Aiyar J, Withka JM, Rizzi JP, Singleton DH, Andrews GC, Lin W, Boyd J, Hanson DC, Simon M, Dethlefs B | title = Topology of the pore-region of a K<sup>+</sup> channel revealed by the NMR-derived structures of scorpion toxins | journal = Neuron | volume = 15 | issue = 5 | pages = 1169–81 |date=November 1995 | pmid = 7576659 | doi = 10.1016/0896-6273(95)90104-3| url =  }}</ref><ref name="pmid15615696">{{cite journal |vauthors=Bagdány M, Batista CV, Valdez-Cruz NA, Somodi S, Rodriguez de la Vega RC, Licea AF, Varga Z, Gáspár R, Possani LD, Panyi G | title = Anuroctoxin, a new scorpion toxin of the alpha-KTx 6 subfamily, is highly selective for K<sub>v</sub>1.3 over IKCa1 ion channels of human T lymphocytes | journal = Mol. Pharmacol. | volume = 67 | issue = 4 | pages = 1034–44 |date=April 2005 | pmid = 15615696 | doi = 10.1124/mol.104.007187 | url =  }}</ref> and sea anemone ([[Stichodactyla toxin|ShK]],<ref name="ref_24">{{cite journal |vauthors=Pennington MW, Mahnir VM, Krafte DS, Zaydenberg I, Byrnes ME, Khaytin I, Crowley K, Kem WR | title = Identification of three separate binding sites on SHK toxin, a potent inhibitor of voltage-dependent potassium channels in human T-lymphocytes and rat brain | journal = Biochem. Biophys. Res. Commun. | volume = 219 | issue = 3 | pages = 696–701 |date=February 1996 | pmid = 8645244 | doi = 10.1006/bbrc.1996.0297 | url =  }}</ref><ref name="pmid8599755">{{cite journal |vauthors=Tudor JE, Pallaghy PK, Pennington MW, Norton RS | title = Solution structure of ShK toxin, a novel potassium channel inhibitor from a sea anemone | journal = Nat. Struct. Biol. | volume = 3 | issue = 4 | pages = 317–20 |date=April 1996 | pmid = 8599755 | doi = 10.1038/nsb0496-317| url =  }}</ref><ref name="pmid9830012">{{cite journal |vauthors=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 | title = ShK-Dap22, a potent K<sub>v</sub>1.3-specific immunosuppressive polypeptide | journal = J. Biol. Chem. | volume = 273 | issue = 49 | pages = 32697–707 |date=December 1998 | pmid = 9830012 | doi = 10.1074/jbc.273.49.32697| url = }}</ref><ref name="pmid10419508">{{cite journal |vauthors=Rauer H, Pennington M, Cahalan M, Chandy KG | title = Structural conservation of the pores of calcium-activated and voltage-gated potassium channels determined by a sea anemone toxin | journal = J. Biol. Chem. | volume = 274 | issue = 31 | pages = 21885–92 |date=July 1999 | pmid = 10419508 | doi = 10.1074/jbc.274.31.21885| url = }}</ref><ref name="pmid18480054">{{cite journal |vauthors=Han S, Yi H, Yin SJ, Chen ZY, Liu H, Cao ZJ, Wu YL, Li WX | title = Structural basis of a potent peptide inhibitor designed for K<sub>v</sub>1.3 channel, a therapeutic target of autoimmune disease | journal = J. Biol. Chem. | volume = 283 | issue = 27 | pages = 19058–65 |date=July 2008 | pmid = 18480054 | doi = 10.1074/jbc.M802054200 | url =  }}</ref> ShK-F6CA, ShK-186, ShK-192,<ref name="pmid19122005">{{cite journal |vauthors=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 | title = Engineering a stable and selective peptide blocker of the K<sub>v</sub>1.3 channel in T lymphocytes | journal = Mol. Pharmacol. | volume = 75| issue = 4| pages = 762–73|date=January 2009 | pmid = 19122005 | doi = 10.1124/mol.108.052704 | url = | pmc = 2684922  }}</ref>  BgK<ref name="pmid9063464">{{cite journal |vauthors=Cotton J, Crest M, Bouet F, Alessandri N, Gola M, Forest E, Karlsson E, Castañeda O, Harvey AL, Vita C, Ménez A | title = A potassium-channel toxin from the sea anemone Bunodosoma granulifera, an inhibitor for K<sub>v</sub>1 channels. Revision of the amino acid sequence, disulfide-bridge assignment, chemical synthesis, and biological activity | journal = Eur. J. Biochem. | volume = 244 | issue = 1 | pages = 192–202 |date=February 1997 | pmid = 9063464 | doi = 10.1111/j.1432-1033.1997.00192.x| url = }}</ref>), and by [[small molecule]] compounds (e.g., PAP-1,<ref name="pmid16099841">{{cite journal |vauthors=Schmitz A, Sankaranarayanan A, Azam P, Schmidt-Lassen K, Homerick D, Hänsel W, Wulff H | title = Design of PAP-1, a selective small molecule K<sub>v</sub>1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases | journal = Mol. Pharmacol. | volume = 68 | issue = 5 | pages = 1254–70 |date=November 2005 | pmid = 16099841 | doi = 10.1124/mol.105.015669 | url =  }}</ref> correolide,<ref name="pmid10607427">{{cite journal |vauthors=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 | title = Correolide and derivatives are novel immunosuppressants blocking the lymphocyte K<sub>v</sub>1.3 potassium channels | journal = Cell. Immunol. | volume = 197 | issue = 2 | pages = 99–107 |date=November 1999 | pmid = 10607427 | doi = 10.1006/cimm.1999.1569 | url =  }}</ref> benzamides,<ref name="pmid12643934">{{cite journal |vauthors=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 | title = Benzamide derivatives as blockers of K<sub>v</sub>1.3 ion channel | journal = Bioorg. Med. Chem. Lett. | volume = 13 | issue = 6 | pages = 1161–4 |date=March 2003 | pmid = 12643934 | doi = 10.1016/S0960-894X(03)00014-3| url = }}</ref> CP339818,<ref name="pmid8967992">{{cite journal |vauthors=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 | title = Novel nonpeptide agents potently block the C-type inactivated conformation of K<sub>v</sub>1.3 and suppress T cell activation | journal = Mol. Pharmacol. | volume = 50 | issue = 6 | pages = 1672–9 |date=December 1996 | pmid = 8967992 | doi = | url = | issn = }}</ref> progesterone<ref name= "Ehring">{{cite journal |vauthors=Ehring GR, Kerschbaum HH, Eder C, Neben AL, Fanger CM, Khoury RM, Negulescu PA, Cahalan MD | year = 1998 | title = A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K<sup>+</sup> channels, Ca2+ signaling, and gene expression in T lymphocytes | url = | journal = J Exp Med | volume = 188 | issue = 9| pages = 1593–1602 | pmid = 9802971 | pmc=2212508 | doi=10.1084/jem.188.9.1593}}</ref> and the anti-lepromatous drug [[clofazimine]]<ref name="pmid19104661">{{cite journal | vauthors = Ren YR, Pan F, Parvez S, Fleig A, Chong CR, Xu J, Dang Y, Zhang J, Jiang H, Penner R, Liu JO | editor1-last = Alberola-Ila | editor1-first = Jose | title = Clofazimine inhibits human K<sub>v</sub>1.3 potassium channel by perturbing calcium oscillation in T lymphocytes | journal = PLoS ONE | volume = 3 | issue = 12 | pages = e4009 | year = 2008 | pmid = 19104661 | pmc = 2602975 | doi = 10.1371/journal.pone.0004009 | url =  }}</ref>). Interestingly, the K<sub>v</sub>1.3 blocker clofazimine has been reported to be effective in the treatment of chronic [[graft-versus-host disease]],<ref name="pmid9116272">{{cite journal |vauthors=Lee SJ, Wegner SA, McGarigle CJ, Bierer BE, Antin JH | title = Treatment of chronic graft-versus-host disease with clofazimine | journal = Blood | volume = 89 | issue = 7 | pages = 2298–302 |date=April 1997 | pmid = 9116272 | doi = | url = http://bloodjournal.hematologylibrary.org/cgi/content/abstract/ | issn = }} {{dead link|date=May 2010}}</ref> [[systemic lupus erythematosus|cutaneous lupus]],<ref name="pmid16200586">{{cite journal |vauthors=Bezerra EL, Vilar MJ, da Trindade Neto PB, Sato EI | title = Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus | journal = Arthritis Rheum. | volume = 52 | issue = 10 | pages = 3073–8 |date=October 2005 | pmid = 16200586 | doi = 10.1002/art.21358 | url = | issn = }}</ref><ref name="pmid4851057">{{cite journal |vauthors=Mackey JP, Barnes J | title = Clofazimine in the treatment of discoid lupus erythematosus | journal = Br. J. Dermatol. | volume = 91 | issue = 1 | pages = 93–6 |date=July 1974 | pmid = 4851057 | doi = 10.1111/j.1365-2133.1974.tb06723.x| url = | issn = }}</ref> and [[generalized pustular psoriasis|pustular psoriasis]]<ref name="pmid708598">{{cite journal |vauthors=Chuaprapaisilp T, Piamphongsant T | title = Treatment of pustular psoriasis with clofazimine | journal = Br. J. Dermatol. | volume = 99 | issue = 3 | pages = 303–5 |date=September 1978 | pmid = 708598 | doi = 10.1111/j.1365-2133.1978.tb02001.x| url = | issn = }}</ref><ref name="pmid7829710">{{cite journal |vauthors=Arbiser JL, Moschella SL | title = Clofazimine: a review of its medical uses and mechanisms of action | journal = J. Am. Acad. Dermatol. | volume = 32 | issue = 2 Pt 1 | pages = 241–7 |date=February 1995 | pmid = 7829710 | doi = 10.1016/0190-9622(95)90134-5| url = | issn = }}</ref> 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 [[antimycobacterial|anti-mycobacterial]] activity, but could well have been an [[immunomodulator]]y effect by clofazimine.<ref name="Selby_2007">{{cite journal |vauthors=Selby W, Pavli P, Crotty B, Florin T, Radford-Smith G, Gibson P, Mitchell B, Connell W, Read R, Merrett M, Ee H, Hetzel D | title = Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease | journal = Gastroenterology | volume = 132 | issue = 7 | pages = 2313–9 |date=June 2007 | pmid = 17570206 | doi = 10.1053/j.gastro.2007.03.031 | url = | issn = }}</ref>
{{PBB_Summary
| section_title =  
| summary_text = 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 it is clustered together with KCNA2 and KCNA10 genes on chromosome 1.<ref name="entrez">{{cite web | title = Entrez Gene: KCNA3 potassium voltage-gated channel, shaker-related subfamily, member 3| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3738| accessdate = }}</ref>
}}


==See also==
==See also==
Line 58: Line 36:


==References==
==References==
{{reflist|2}}
{{reflist|30em}}
 
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Gutman GA, Chandy KG, Grissmer S, ''et al.'' |title=International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. |journal=Pharmacol. Rev. |volume=57 |issue= 4 |pages= 473-508 |year= 2006 |pmid= 16382104 |doi= 10.1124/pr.57.4.10 }}
*{{cite journal  | author=Attali B, Romey G, Honoré E, ''et al.'' |title=Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes. |journal=J. Biol. Chem. |volume=267 |issue= 12 |pages= 8650-7 |year= 1992 |pmid= 1373731 |doi=  }}
*{{cite journal  | author=Cai YC, Osborne PB, North RA, ''et al.'' |title=Characterization and functional expression of genomic DNA encoding the human lymphocyte type n potassium channel. |journal=DNA Cell Biol. |volume=11 |issue= 2 |pages= 163-72 |year= 1992 |pmid= 1547020 |doi=  }}
*{{cite journal  | author=Philipson LH, Hice RE, Schaefer K, ''et al.'' |title=Sequence and functional expression in Xenopus oocytes of a human insulinoma and islet potassium channel. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue= 1 |pages= 53-7 |year= 1991 |pmid= 1986382 |doi=  }}
*{{cite journal  | author=Grissmer S, Dethlefs B, Wasmuth JJ, ''et al.'' |title=Expression and chromosomal localization of a lymphocyte K+ channel gene. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=87 |issue= 23 |pages= 9411-5 |year= 1991 |pmid= 2251283 |doi=  }}
*{{cite journal  | author=Folander K, Douglass J, Swanson R |title=Confirmation of the assignment of the gene encoding Kv1.3, a voltage-gated potassium channel (KCNA3) to the proximal short arm of human chromosome 1. |journal=Genomics |volume=23 |issue= 1 |pages= 295-6 |year= 1995 |pmid= 7829094 |doi= 10.1006/geno.1994.1500 }}
*{{cite journal  | author=Bock J, Szabó I, Jekle A, Gulbins E |title=Actinomycin D-induced apoptosis involves the potassium channel Kv1.3. |journal=Biochem. Biophys. Res. Commun. |volume=295 |issue= 2 |pages= 526-31 |year= 2002 |pmid= 12150982 |doi=  }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  | author=Panyi G, Bagdány M, Bodnár A, ''et al.'' |title=Colocalization and nonrandom distribution of Kv1.3 potassium channels and CD3 molecules in the plasma membrane of human T lymphocytes. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue= 5 |pages= 2592-7 |year= 2003 |pmid= 12604782 |doi= 10.1073/pnas.0438057100 }}
*{{cite journal  | author=Hajdú P, Varga Z, Pieri C, ''et al.'' |title=Cholesterol modifies the gating of Kv1.3 in human T lymphocytes. |journal=Pflugers Arch. |volume=445 |issue= 6 |pages= 674-82 |year= 2003 |pmid= 12632187 |doi= 10.1007/s00424-002-0974-y }}
*{{cite journal  | author=Storey NM, Gómez-Angelats M, Bortner CD, ''et al.'' |title=Stimulation of Kv1.3 potassium channels by death receptors during apoptosis in Jurkat T lymphocytes. |journal=J. Biol. Chem. |volume=278 |issue= 35 |pages= 33319-26 |year= 2003 |pmid= 12807917 |doi= 10.1074/jbc.M300443200 }}
*{{cite journal  | author=Preussat K, Beetz C, Schrey M, ''et al.'' |title=Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas. |journal=Neurosci. Lett. |volume=346 |issue= 1-2 |pages= 33-6 |year= 2003 |pmid= 12850541 |doi=  }}
*{{cite journal  | author=Mackenzie AB, Chirakkal H, North RA |title=Kv1.3 potassium channels in human alveolar macrophages. |journal=Am. J. Physiol. Lung Cell Mol. Physiol. |volume=285 |issue= 4 |pages= L862-8 |year= 2003 |pmid= 12909584 |doi= 10.1152/ajplung.00095.2003 }}
*{{cite journal  | author=Grunnet M, Rasmussen HB, Hay-Schmidt A, ''et al.'' |title=KCNE4 is an inhibitory subunit to Kv1.1 and Kv1.3 potassium channels. |journal=Biophys. J. |volume=85 |issue= 3 |pages= 1525-37 |year= 2004 |pmid= 12944270 |doi=  }}
*{{cite journal  | author=Panyi G, Vámosi G, Bacsó Z, ''et al.'' |title=Kv1.3 potassium channels are localized in the immunological synapse formed between cytotoxic and target cells. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 5 |pages= 1285-90 |year= 2004 |pmid= 14745040 |doi= 10.1073/pnas.0307421100 }}
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Szabò I, Bock J, Jekle A, ''et al.'' |title=A novel potassium channel in lymphocyte mitochondria. |journal=J. Biol. Chem. |volume=280 |issue= 13 |pages= 12790-8 |year= 2005 |pmid= 15632141 |doi= 10.1074/jbc.M413548200 }}
*{{cite journal  | author=Rus H, Pardo CA, Hu L, ''et al.'' |title=The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue= 31 |pages= 11094-9 |year= 2005 |pmid= 16043714 |doi= 10.1073/pnas.0501770102 }}
*{{cite journal  | author=Mullen KM, Rozycka M, Rus H, ''et al.'' |title=Potassium channels Kv1.3 and Kv1.5 are expressed on blood-derived dendritic cells in the central nervous system. |journal=Ann. Neurol. |volume=60 |issue= 1 |pages= 118-27 |year= 2006 |pmid= 16729292 |doi= 10.1002/ana.20884 }}
}}
{{refend}}


== External links ==
== External links ==
* {{MeshName|Kv1.1+Potassium+Channel}}
* {{MeshName|KCNA1+protein,+human}}
* {{MeshName|KCNA1+protein,+human}}
* {{MeshName|K<sub>v</sub>1.1+Potassium+Channel}}


{{membrane-protein-stub}}
{{PDB_Gallery|geneid=3738}}
{{Ion channels|g3}}
{{NLM content}}
{{NLM content}}
{{Ion channels}}
 
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[[Category:Ion channels]]
[[Category:Ion channels]]
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Revision as of 23:01, 25 November 2017

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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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]

Blockers

Kv1.3 is blocked[31] by several peptides from venomous creatures including scorpions (ADWX1, OSK1,[33] margatoxin,[34] kaliotoxin, charybdotoxin, noxiustoxin, anuroctoxin)[35][36] and sea anemone (ShK,[37][38][39][40][41] ShK-F6CA, ShK-186, ShK-192,[42] BgK[43]), and by small molecule compounds (e.g., PAP-1,[44] correolide,[45] benzamides,[46] CP339818,[47] progesterone[48] and the anti-lepromatous drug clofazimine[49]). Interestingly, the Kv1.3 blocker clofazimine has been reported to be effective in the treatment of chronic graft-versus-host disease,[50] cutaneous lupus,[51][52] and pustular psoriasis[53][54] 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.[55]

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". Proc. Natl. Acad. Sci. U.S.A. 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". Pharmacol. Rev. 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". J. Exp. Med. 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". J. Immunol. 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 Cell Biol. 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 Pharmacol. Sci. 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". J. Clin. Invest. 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". J. Immunol. 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". Proc. Natl. Acad. Sci. U.S.A. 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". Proc. Natl. Acad. Sci. U.S.A. 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". J. Biol. Chem. 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". Proc. Natl. Acad. Sci. U.S.A. 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". J. Biol. Chem. 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". J. Biol. Chem. 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". J. Biol. Chem. 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". J. Clin. Invest. 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". Proc. Natl. Acad. Sci. U.S.A. 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". Proc. Natl. Acad. Sci. U.S.A. 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". Mol. Pharmacol. 67 (4): 1369–81. doi:10.1124/mol.104.008193. 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". J. Biol. Chem. 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". J. Invest. Dermatol. 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". Curr Opin Drug Discov Dev. 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". Int J Obes (Lond). 32 (8): 1222–32. doi:10.1038/ijo.2008.77. PMC 2737548. PMID 18542083.
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  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". Proc. Natl. Acad. Sci. U.S.A. 101 (9): 3112–7. doi:10.1073/pnas.0308450100. PMC 365752. PMID 14981264.
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