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Gene and Protein Information  |
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| Species | TM | P Loops | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 6 | 1 | 655 | 1p13.2 | KCND3 | potassium voltage-gated channel subfamily D member 3 | 8 |
| Mouse | 6 | 1 | 655 | 3 F2.2 | Kcnd3 | potassium voltage-gated channel, Shal-related family, member 3 | 20 |
| Rat | 6 | 1 | 655 | 2q34 | Kcnd3 | potassium voltage-gated channel subfamily D member 3 | 42 |
| Previous and Unofficial Names |
| KCND3L | KCND3S | KSHIVB | Potassium voltage-gated channel subfamily D member 3 | potassium voltage-gated channel, Shal-related subfamily, member 3 | potassium channel, voltage gated Shal related subfamily D, member 3 | potassium channel, voltage-gated Shal-related subfamily D, member 3 | potassium voltage-gated channel, Shal-related family, member 3 | potassium voltage-gated channel |
| Database Links |
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| Alphafold | Q9UK17 (Hs), Q9Z0V1 (Mm), Q62897 (Rn) |
| ChEMBL Target | CHEMBL1964 (Hs) |
| DrugBank Target | Q9UK17 (Hs) |
| Ensembl Gene | ENSG00000171385 (Hs), ENSMUSG00000040896 (Mm), ENSRNOG00000014686 (Rn) |
| Entrez Gene | 3752 (Hs), 56543 (Mm), 65195 (Rn) |
| Human Protein Atlas | ENSG00000171385 (Hs) |
| KEGG Gene | hsa:3752 (Hs), mmu:56543 (Mm), rno:65195 (Rn) |
| OMIM | 605411 (Hs) |
| Orphanet | ORPHA302951 (Hs) |
| Pharos | Q9UK17 (Hs) |
| RefSeq Nucleotide | NM_004980 (Hs), NM_172198 (Hs), NM_019931 (Mm), NM_031739 (Rn) |
| RefSeq Protein | NP_004971 (Hs), NP_751948 (Hs), NP_064315 (Mm), NP_113927 (Rn) |
| UniProtKB | Q9UK17 (Hs), Q9Z0V1 (Mm), Q62897 (Rn) |
| Wikipedia | KCND3 (Hs) |
| Associated Proteins |
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| Functional Characteristics |
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| KA | |
| Ion Selectivity and Conductance |
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| Ion Selectivity and Conductance Comments | ||||||
| Association with DPPX increases single channel conductance. |
| Voltage Dependence |
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| Voltage Dependence Comments | ||||||||||||||||||||||
| Voltage Dependence data for dog available [13]. | ||||||||||||||||||||||
| Associated subunits |
| KChIP 1-4, DPP6 and DPP10, MinK, MiRPs |
Download all structure-activity data for this target as a CSV file 
| Gating inhibitors
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Gating Inhibitor Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DPP10 (dipeptyl peptidase related ancilliary subunit) accelerates the forward processes of activation and inactivation, as well as a reverse process, recovery from inactivation, suggesting DPP10 lowers the energy barrier in both forward and reverse transitions [28]. CaMKII associates with Kv4.3 even at low [Ca2+] [2,6]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Channel Blockers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Channel Blocker Comments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rabbit Kv4.3 channels are blocked by heteropodatoxin [47]. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tissue Distribution
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| Functional Assays
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| Physiological Functions
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| Clinically-Relevant Mutations and Pathophysiology
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| Gene Expression and Pathophysiology
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| Biologically Significant Variants
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| Biologically Significant Variant Comments | ||||||||||||||
| Other human SNPs: Base pairs 264, 375, 669, IVS2 + 15, and IVS5 + 26 [12,21]. |
| General Comments |
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In the basal state, the basic biophysical properties of both splice variants are identical. The Kv3.4 (KCND3) gene contains six exons analogous to those found in KCND1 and KCND2, and an additional exon L between exons 4 and 5. Relative to KCND1, the introns are significantly longer. The kinetic properties depend on the expression system, recording configuration, and the presence of auxiliary subunits (KChIPs). Kv4.3 currents expressed in Xenopus laevis oocytes are suppressed in response to protein kinase C activation. It is a member of the mammalian Shal-related family. |
1. Ahn HS, Kim SE, Jang HJ, Kim MJ, Rhie DJ, Yoon SH, Jo YH, Kim MS, Sung KW, Hahn SJ. (2006) Interaction of riluzole with the closed inactivated state of Kv4.3 channels. J Pharmacol Exp Ther, 319 (1): 323-31. [PMID:16815868]
2. Anderson ME. (2005) Calmodulin kinase signaling in heart: an intriguing candidate target for therapy of myocardial dysfunction and arrhythmias. Pharmacol Ther, 106 (1): 39-55. [PMID:15781121]
3. Boczek NJ, Ye D, Johnson EK, Wang W, Crotti L, Tester DJ, Dagradi F, Mizusawa Y, Torchio M, Alders M et al.. (2014) Characterization of SEMA3A-encoded semaphorin as a naturally occurring Kv4.3 protein inhibitor and its contribution to Brugada syndrome. Circ Res, 115 (4): 460-9. [PMID:24963029]
4. Brundel BJ, Van Gelder IC, Henning RH, Tuinenburg AE, Wietses M, Grandjean JG, Wilde AA, Van Gilst WH, Crijns HJ. (2001) Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K+ channels. J Am Coll Cardiol, 37 (3): 926-32. [PMID:11693772]
5. Carrasquillo Y, Burkhalter A, Nerbonne JM. (2012) A-type K+ channels encoded by Kv4.2, Kv4.3 and Kv1.4 differentially regulate intrinsic excitability of cortical pyramidal neurons. J Physiol (Lond.), 590 (Pt 16): 3877-90. [PMID:22615428]
6. Colinas O, Gallego M, Setién R, López-López JR, Pérez-García MT, Casis O. (2006) Differential modulation of Kv4.2 and Kv4.3 channels by calmodulin-dependent protein kinase II in rat cardiac myocytes. Am J Physiol Heart Circ Physiol, 291 (4): H1978-87. [PMID:16648177]
7. Deschênes I, Tomaselli GF. (2002) Modulation of Kv4.3 current by accessory subunits. FEBS Lett, 528 (1-3): 183-8. [PMID:12297301]
8. Dilks D, Ling HP, Cockett M, Sokol P, Numann R. (1999) Cloning and expression of the human kv4.3 potassium channel. J Neurophysiol, 81 (4): 1974-7. [PMID:10200233]
9. Dixon JE, Shi W, Wang HS, McDonald C, Yu H, Wymore RS, Cohen IS, McKinnon D. (1996) Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. Circ Res, 79 (4): 659-68. [PMID:8831489]
10. Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, van Dijk F, Verschuuren-Bemelmans C, Hageman G, van de Vlies P et al.. (2012) Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol, 72 (6): 870-80. [PMID:23280838]
11. Faivre JF, Calmels TP, Rouanet S, Javré JL, Cheval B, Bril A. (1999) Characterisation of Kv4.3 in HEK293 cells: comparison with the rat ventricular transient outward potassium current. Cardiovasc Res, 41 (1): 188-99. [PMID:10325966]
12. Frank-Hansen R, Larsen LA, Andersen P, Jespersgaard C, Christiansen M. (2005) Mutations in the genes KCND2 and KCND3 encoding the ion channels Kv4.2 and Kv4.3, conducting the cardiac fast transient outward current (ITO,f), are not a frequent cause of long QT syndrome. Clin Chim Acta, 351 (1-2): 95-100. [PMID:15563876]
13. Franqueza L, Valenzuela C, Eck J, Tamkun MM, Tamargo J, Snyders DJ. (1999) Functional expression of an inactivating potassium channel (Kv4.3) in a mammalian cell line. Cardiovasc Res, 41 (1): 212-9. [PMID:10325968]
14. Gaborit N, Steenman M, Lamirault G, Le Meur N, Le Bouter S, Lande G, Léger J, Charpentier F, Christ T, Dobrev D et al.. (2005) Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation. Circulation, 112 (4): 471-81. [PMID:16027256]
15. Giudicessi JR, Ye D, Kritzberger CJ, Nesterenko VV, Tester DJ, Antzelevitch C, Ackerman MJ. (2012) Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death. Hum Mutat, 33 (6): 989-97. [PMID:22457051]
16. Giudicessi JR, Ye D, Tester DJ, Crotti L, Mugione A, Nesterenko VV, Albertson RM, Antzelevitch C, Schwartz PJ, Ackerman MJ. (2011) Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm, 8 (7): 1024-32. [PMID:21349352]
17. Hatano N, Ohya S, Imaizumi Y. (2002) Functional interaction between KChIP1 and GFP-fused Kv4.3L co-expressed in HEK293 cells. Pflugers Arch, 444 (1-2): 80-8. [PMID:11976919]
18. Holmqvist MH, Cao J, Hernandez-Pineda R, Jacobson MD, Carroll KI, Sung MA, Betty M, Ge P, Gilbride KJ, Brown ME et al.. (2002) Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain. Proc Natl Acad Sci USA, 99 (2): 1035-40. [PMID:11805342]
19. Hoppe UC, Johns DC, Marbán E, O'Rourke B. (1999) Manipulation of cellular excitability by cell fusion: effects of rapid introduction of transient outward K+ current on the guinea pig action potential. Circ Res, 84 (8): 964-72. [PMID:10222344]
20. Isbrandt D, Leicher T, Waldschütz R, Zhu X, Luhmann U, Michel U, Sauter K, Pongs O. (2000) Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(TO) and I(SA). Genomics, 64 (2): 144-54. [PMID:10729221]
21. Iwasa H, Kurabayashi M, Nagai R, Nakamura Y, Tanaka T. (2001) Multiple single-nucleotide polymorphisms (SNPs) in the Japanese population in six candidate genes for long QT syndrome. J Hum Genet, 46 (3): 158-62. [PMID:11310586]
22. Iwasaki YK, Yamashita T, Sekiguchi A, Hatano S, Sagara K, Iinuma H, Fu LT, Kobayashi Y, Katoh T, Takano T. (2006) A method for the simultaneous analysis of mRNA levels of multiple cardiac ion channels with a multi-probe RNase protection assay. Europace, 8 (11): 1011-5. [PMID:17005589]
23. Kim SE, Ahn HS, Choi BH, Jang HJ, Kim MJ, Rhie DJ, Yoon SH, Jo YH, Kim MS, Sung KW, Hahn SJ. (2007) Open channel block of A-type, kv4.3, and delayed rectifier K+ channels, Kv1.3 and Kv3.1, by sibutramine. J Pharmacol Exp Ther, 321 (2): 753-62. [PMID:17312186]
24. Kong W, Po S, Yamagishi T, Ashen MD, Stetten G, Tomaselli GF. (1998) Isolation and characterization of the human gene encoding Ito: further diversity by alternative mRNA splicing. Am J Physiol, 275 (6 Pt 2): H1963-70. [PMID:9843794]
25. Kääb S, Dixon J, Duc J, Ashen D, Näbauer M, Beuckelmann DJ, Steinbeck G, McKinnon D, Tomaselli GF. (1998) Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation, 98 (14): 1383-93. [PMID:9760292]
26. Lee SY, Maniak PJ, Ingbar DH, O'Grady SM. (2003) Adult alveolar epithelial cells express multiple subtypes of voltage-gated K+ channels that are located in apical membrane. Am J Physiol, Cell Physiol, 284 (6): C1614-24. [PMID:12606310]
27. Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, Tsai PC, Ichikawa Y, Goto J, Monin ML et al.. (2012) Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol, 72 (6): 859-69. [PMID:23280837]
28. Li HL, Qu YJ, Lu YC, Bondarenko VE, Wang S, Skerrett IM, Morales MJ. (2006) DPP10 is an inactivation modulatory protein of Kv4.3 and Kv1.4. Am J Physiol, Cell Physiol, 291 (5): C966-76. [PMID:16738002]
29. Li Y, Um SY, McDonald TV. (2006) Voltage-gated potassium channels: regulation by accessory subunits. Neuroscientist, 12 (3): 199-210. [PMID:16684966]
30. Liu J, Deng JX, Pan BX, Huang QB. (2006) [KCNE2 modulates the function of Kv4.3 channel]. Nan Fang Yi Ke Da Xue Xue Bao, 26 (12): 1754-6. [PMID:17259113]
31. Lundby A, Olesen SP. (2006) KCNE3 is an inhibitory subunit of the Kv4.3 potassium channel. Biochem Biophys Res Commun, 346 (3): 958-67. [PMID:16782062]
32. Norris AJ, Nerbonne JM. (2010) Molecular dissection of I(A) in cortical pyramidal neurons reveals three distinct components encoded by Kv4.2, Kv4.3, and Kv1.4 alpha-subunits. J Neurosci, 30 (14): 5092-101. [PMID:20371829]
33. Ohya S, Tanaka M, Oku T, Asai Y, Watanabe M, Giles WR, Imaizumi Y. (1997) Molecular cloning and tissue distribution of an alternatively spliced variant of an A-type K+ channel alpha-subunit, Kv4.3 in the rat. FEBS Lett, 420 (1): 47-53. [PMID:9450548]
34. Ohya S, Tanaka M, Oku T, Furuyama T, Mori N, Giles WR, Watanabe M, Imaizumi Y. (2001) Regional expression of the splice variants of Kv4.3 in rat brain and effects of C-terminus deletion on expressed K+ currents. Life Sci, 68 (15): 1703-16. [PMID:11270617]
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36. Patel SP, Parai R, Parai R, Campbell DL. (2004) Regulation of Kv4.3 voltage-dependent gating kinetics by KChIP2 isoforms. J Physiol (Lond.), 557 (Pt 1): 19-41. [PMID:14724186]
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38. Qu YJ, Bondarenko VE, Xie C, Wang S, Awayda MS, Strauss HC, Morales MJ. (2007) W-7 modulates Kv4.3: pore block and Ca2+-calmodulin inhibition. Am J Physiol Heart Circ Physiol, 292 (5): H2364-77. [PMID:17220193]
39. Radicke S, Cotella D, Graf EM, Ravens U, Wettwer E. (2005) Expression and function of dipeptidyl-aminopeptidase-like protein 6 as a putative beta-subunit of human cardiac transient outward current encoded by Kv4.3. J Physiol (Lond.), 565 (Pt 3): 751-6. [PMID:15890703]
40. Rhodes KJ, Carroll KI, Sung MA, Doliveira LC, Monaghan MM, Burke SL, Strassle BW, Buchwalder L, Menegola M, Cao J et al.. (2004) KChIPs and Kv4 alpha subunits as integral components of A-type potassium channels in mammalian brain. J Neurosci, 24 (36): 7903-15. [PMID:15356203]
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42. Serôdio P, Vega-Saenz de Miera E, Rudy B. (1996) Cloning of a novel component of A-type K+ channels operating at subthreshold potentials with unique expression in heart and brain. J Neurophysiol, 75 (5): 2174-9. [PMID:8734615]
43. Smets K, Duarri A, Deconinck T, Ceulemans B, van de Warrenburg BP, Züchner S, Gonzalez MA, Schüle R, Synofzik M, Van der Aa N et al.. (2015) First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy. BMC Med Genet, 16: 51. [PMID:26189493]
44. Takimoto K, Li D, Hershman KM, Li P, Jackson EK, Levitan ES. (1997) Decreased expression of Kv4.2 and novel Kv4.3 K+ channel subunit mRNAs in ventricles of renovascular hypertensive rats. Circ Res, 81 (4): 533-9. [PMID:9314834]
45. Teutsch C, Kondo RP, Dederko DA, Chrast J, Chien KR, Giles WR. (2007) Spatial distributions of Kv4 channels and KChip2 isoforms in the murine heart based on laser capture microdissection. Cardiovasc Res, 73 (4): 739-49. [PMID:17289005]
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48. Wang H, Shi H, Zhang L, Pourrier M, Yang B, Nattel S, Wang Z. (2000) Nicotine is a potent blocker of the cardiac A-type K(+) channels. Effects on cloned Kv4.3 channels and native transient outward current. Circulation, 102 (10): 1165-71. [PMID:10973847]
49. Wickenden AD, Jegla TJ, Kaprielian R, Backx PH. (1999) Regional contributions of Kv1.4, Kv4.2, and Kv4.3 to transient outward K+ current in rat ventricle. Am J Physiol, 276 (5): H1599-607. [PMID:10330244]
50. Yeung SY, Ohya S, Sergeant GP, Pucovský V, Greenwood IA. (2006) Pharmacological and molecular evidence for the involvement of Kv4.3 in ultra-fast activating K+ currents in murine portal vein myocytes. Br J Pharmacol, 149 (6): 676-86. [PMID:17016508]
51. You T, Mao W, Cai B, Li F, Xu H. (2015) Two novel Brugada syndrome-associated mutations increase KV4.3 membrane expression and function. Int J Mol Med, 36 (1): 309-15. [PMID:26016905]
