K<SUB>v</SUB>4.3 | Voltage-gated potassium channels | IUPHAR/BPS Guide to PHARMACOLOGY

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Target not currently curated in GtoImmuPdb

Target id: 554

Nomenclature: Kv4.3

Family: Voltage-gated potassium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 655 1p13.3 KCND3 potassium voltage-gated channel subfamily D member 3 8
Mouse 6 1 655 3 F3 Kcnd3 potassium voltage-gated channel, Shal-related family, member 3 20
Rat 6 1 611 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
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
DPP6, DPP10 29,39
KChIP 1-4 7,36,40-41
Other Associated Proteins
Name References
KCNE 1, 2, 3 30-31
KChAP 29
Semaphorin 3A 3
Functional Characteristics
Ion Selectivity and Conductance
Species:  None
Rank order:  K+ [5.0 pS] > Na+ [0.05 pS]
References:  18
Species:  Rat
Macroscopic current rectification:  A-Type current
References:  18,46
Ion Selectivity and Conductance Comments
Association with DPPX increases single channel conductance.
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  6.0 - 48 Xenopus laevis oocytes Rat
Inactivation  -50.0 - 48
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  - 10.7 28 Xenopus laevis oocytes Rat
Inactivation  -43.4 89.1 28
Comments  Above values at 50mV.
At -20mV; τ activation (low) = 53.9 msec, τ inactivation (low) = 240msec.
Kv4.3 inactivation is both modulated by DPP10 and KChIP2b on different activation states.
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
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
riluzole Rn - 3.9 pIC50 - - 1
pIC50 3.9 [1]
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
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
phrixotoxin 1 Rn - 7.1 – 8.7 pIC50 - - 48
pIC50 7.1 – 8.7 [48]
phrixotoxin 2 Rn - 7.1 – 8.7 pIC50 - - 48
pIC50 7.1 – 8.7 [48]
nicotine Rn - 7.4 pIC50 - - 48
pIC50 7.4 [48]
phrixotoxin 2 Mm - 7.0 pIC50 - - 38,50
pIC50 7.0 [38,50]
sibutramine Rn - 4.7 pIC50 - - 23
pIC50 4.7 [23]
bupivacaine Mm - 4.0 – 4.5 pIC50 - - 38,50
pIC50 4.5 [50]
pIC50 4.0 [38]
fampridine Mm - 2.4 pIC50 - - 50
pIC50 2.4 [50]
View species-specific channel blocker tables
Channel Blocker Comments
Rabbit Kv4.3 channels are blocked by heteropodatoxin [47].
Tissue Distribution
Brain, heart
Species:  Human
Technique:  Northern Blot
References:  8,24
Species:  Mouse
Technique:  Laser capture microdissection
References:  45
Species:  Rat
Technique:  RNase protection assay
References:  22
Heart, brain (cortex, cerebellum, amygdala. caudate nucleus), smooth muscle, lower levels in the liver, skeletal muscle, kidney, lung and pancreas.
Species:  Rat
Technique:  RT-PCR
References:  9,22,26,33,42,49
Functional Assays
Molecular clone and voltage current
Species:  Rat
Tissue:  Xenopus laevis oocytes
Response measured:  Transient outward current, ITO
References:  46
Patch clamp
Species:  Human
Tissue:  HEK293 cells
Response measured:  Time and voltage dependent outward potassium current
References:  11,17
Species:  Rat
Tissue:  CHO (Chinese Hamster Ovary) cells
Response measured:  A robust ITO
References:  19
Physiological Functions
A-type potassium channels. Repolarization of the cardiac action potential (notch phase).
Mediate ITO current in the heart, and ISA current in neurons.
Species:  Human
Tissue:  Brain, heart
References:  43,51
Mediation of IA currents
Species:  Mouse
Tissue:  Brain. heart
References:  5,32
Clinically-Relevant Mutations and Pathophysiology
Disease:  Brugada syndrome 9; BRGDA9
Synonyms: Brugada syndrome [Orphanet: ORPHA130] [Disease Ontology: DOID:0050451]
Disease Ontology: DOID:0050451
OMIM: 616399
Orphanet: ORPHA130
References:  16,51
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human L450F Causes gain of function in the protein 16,51
Missense Human G600R Causes gain of function in the protein 16,51
Disease:  Early Onset Cerebellar Ataxia, Intellectual Disability and Epilepsy
References:  43
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
In-frame duplication Human R293_F295dup c.877_885dupCGCGTCTTC This de novo mutation leads to gain of function in the protein 43
Disease:  Lone Atrial Fibrillation
References:  35
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human A545P Causes gain of function in the protein 35
Disease:  Spinocerebellar ataxia 19; SCA19
Synonyms: Spinocerebellar ataxia 22; SCA22
Spinocerebellar ataxia type 19/22 [Orphanet: ORPHA98772]
OMIM: 607346
Orphanet: ORPHA98772
References:  10,27,37
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human T352P Causes loss of function in the protein 10,27,37
Missense Human M373I Causes loss of function in the protein 10,27,37
Missense Human S390N Causes loss of function in the protein 10,27,37
Disease:  Sudden unexplained death
References:  15
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human V392I Causes gain of function in the protein 15
Missense Human S530P Causes gain of function in the protein 15
Missense Human G600R Causes gain of function in the protein 15
Gene Expression and Pathophysiology
Decrease in Kv4.3 mRNA levels in paroxysmal atrial fibrillation
Tissue or cell type:  Atria
Pathophysiology:  Atrial Fibrillation, Valvular heart disease
Species:  Human
Technique:  Semi-quantitave PCR, Western Blotting
References:  4,14
Downregulation of the long splice variant of Kv4.3 in heart failure
Tissue or cell type:  Myocardium
Pathophysiology:  Heart failure
Species:  Human
Technique:  Ribonuclease protection assays, whole-cell electrophysiological recordings
References:  25
Reduction of expression of Kv4.3 mRNA in ventricular myocytes
Tissue or cell type:  Myocardium
Pathophysiology:  Hypertension
Species:  Rat
Technique:  RNase protection assays
References:  44
Biologically Significant Variants
Type:  Splice variants
Species:  Rat
Description:  Multiple variants (a-c) differentially expressed in brain
References:  34
Type:  Splice variant
Species:  Human
Description:  Long splice variant encodes the longer isoform mediating A-type K+ current.
Amino acids:  655
Nucleotide accession: 
Protein accession: 
References:  20,24
Type:  Splice variant
Species:  Human
Description:  The shorter splice variant, lacks an in-frame exon in the 3' coding region compared to variant 1. It encodes an isoform 2 which is shorter than isoform 1.
Amino acids:  636
Nucleotide accession: 
Protein accession: 
References:  24
Biologically Significant Variant Comments
Other human SNPs: Base pairs 264, 375, 669, IVS2 + 15, and IVS5 + 26 [12,21].
General Comments
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.


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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]

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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. U.S.A., 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]

35. Olesen MS, Refsgaard L, Holst AG, Larsen AP, Grubb S, Haunsø S, Svendsen JH, Olesen SP, Schmitt N, Calloe K. (2013) A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation. Cardiovasc. Res., 98 (3): 488-95. [PMID:23400760]

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]

37. Pulst SM, Otis TS. (2012) Repolarization matters: mutations in the Kv4.3 potassium channel cause SCA19/22. Ann. Neurol., 72 (6): 829-31. [PMID:23280833]

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]

46. Tsaur ML, Chou CC, Shih YH, Wang HL. (1997) Cloning, expression and CNS distribution of Kv4.3, an A-type K+ channel alpha subunit. FEBS Lett., 400 (2): 215-20. [PMID:9001401]

47. Wang D, Schreurs BG. (2006) Characteristics of IA currents in adult rabbit cerebellar Purkinje cells. Brain Res., 1096 (1): 85-96. [PMID:16716270]

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]


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