KV4.3 channels

Channel name KV4.31,2,3,4,5,6
Description Voltage-gated potassium channel, A-type potassium current
Other names None
Molecular information Human: 655aa, NM_004980 (transcript variant 1), chr. 1p13.3, KCND3 (see “Comments”), GeneID: 3752, PMID: 87346152
Mouse: 655aa, NM_019931, chr. 3
Rat: 636aa, NM_031739, chr. 2q34
Associated subunits KChIP1 increases KV4.3 current densities, accelerates inactivation time course and recovery from inactivation, and shifts steady-state inactivation to more depolarized potentials; KChIP4a abolishes fast inactivation7; expression of K2 in brain increases current density and protein expression8; KChAP acts as a chaperone for KV4.39; KV4.3 may associate preferentially with DPP10 in native neurons that predominantly express this subunit20
Functional assays Patch-clamp, two-electrode voltage-clamp
Current Ito current in the heart is a heteromultimer of KV4.2 and KV4.3 subunits and KChIP210
Conductance ∼5pS (main unitary conductance under physiological conditions)7; association with DPPX increases single channel conductance21
Ion selectivity PNa/PK < 0.01
Activation Threshold for activation -30 mV, time course for activation 1.71 ms at 60 mV11
Inactivation Time course for inactivation fit by a biexponential function; τh1 = 27 ms at 60 mV, τh2 = 142 ms at 60 mV11 (see “Comments”)
Activators None
Gating inhibitors None
Blockers 4-Aminopyridine, bupivacaine (31 μM),11 PaTX1,2, (2–70 nM), nicotine (40 nM)12
Radioligands None
Channel distribution Heart, brain, smooth muscle1,2,3,4,5,6,13,14
Physiological functions Repolarization of the cardiac action potential (notch phase)
Mutations and pathophysiology KV4.3 mRNA levels are decreased in patients with paroxysmal atrial fibrillation15
Pharmacological significance Not established
Comments The Kv4.3 (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; kinetic properties depend on the expression system, recording configuration, and the presence of auxiliary subunits (KChIPs)16,17,18; KV4.3 currents expressed in Xenopus oocytes are suppressed in response to protein kinase C activation19; mammalian Shal-related family
  • aa, amino acids; chr., chromosome.

  • 1. Serodio P, Kentros C, and Rudy B (1994) Identification of molecular components of A-type channels activating at subthreshold potentials. J Neurophysiol 72:1516-1529

  • 2. Serodio P, Vega-Saenz de Miera E, and 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 75:2174-2179

  • 3. Dixon JE, Shi W, Wang HS, McDonald C, Yu H, Wymore RS, Cohen IS, and McKinnon D (1996) Role of the Kv4.3 K+ channel in ventricular muscle: a molecular correlate for the transient outward current. Circ Res 79:659-668

  • 4. Tsaur ML, Chou CC, Shih YH, and Wang HL (1997) Cloning, expression and CNS distribution of Kv4.3, an A-type K+ channel α subunit. FEBS Lett 400:215-220

  • 5. Ohya S, Tanaka M, Oku T, Asai Y, Watanabe M, Giles WR, and Imaizumi Y (1997) Molecular cloning and tissue distribution of an alternatively spliced variant of an A-type K+ channel α-subunit, Kv4.3 in the rat. FEBS Lett 420:47-53

  • 6. Dilks D, Ling HP, Cockett M, Sokol P, and Numann R (1999) Cloning and expression of the human Kv4.3 potassium channel. J Neurophysiol 81:1974-1977

  • 7. 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 99:1035-1040

  • 8. Yang EK, Alvira MR, Levitan ES, and Takimoto K (2001) Kvβ subunits increase expression of Kv4.3 channels by interacting with their C termini. J Biol Chem 276:4839-4844

  • 9. Kuryshev YA, Wible BA, Gudz TI, Ramirez AN, and Brown AM (2001) KChAP/Kvβ1.2 interactions and their effects on cardiac Kv channel expression. Am J Physiol Cell Physiol 281:C290-C299

  • 10. Guo W, Li H, Aimond F, Johns DC, Rhodes KJ, Trimmer JS, and Nerbonne JM (2002) Role of heteromultimers in the generation of myocardial transient outward K+ currents. Circ Res 90:586-593

  • 11. Franqueza L, Valenzuela C, Eck J, Tamkun MM, Tamargo J, and Snyders DJ (1999) Functional expression of an inactivating potassium channel (Kv4.3) in a mammalian cell line. Cardiovasc Res 41:212-219

  • 12. Wang H, Shi H, and Wang Z (1999) Nicotine depresses the functions of multiple cardiac potassium channels. Life Sci 65:PL143–PL149

  • 13. Wickenden AD, Jegla TJ, Kaprielian R, and 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:H1599-H1568

  • 14. Hoppe UC, Marban E, and Johns DC (2000) Molecular dissection of cardiac repolarization by in vivo Kv4.3 gene transfer. J Clin Invest 105:1077-1084

  • 15. Brundel BJ, Van Gelder IC, Henning RH, Tuinenburg AE, Wietses M, Grandjean JG, Wilde AA, Van Gilst WH, and 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 37:926-932

  • 16. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, et al. (2000) Modulation of A-type potassium channels by a family of calcium sensors. Nature (Lond) 403:553-556

  • 17. Beck EJ, Bowlby M, An WF, Rhodes KJ, and Covarrubias M (2002) Remodelling inactivation gating of Kv4 channels by KChIP1, a small-molecular-weight calcium-binding protein. J Physiol 538:691-706

  • 18. Beck E and Covarrubias M (2001) Preferential modulation of closed-state inactivation in Kv4 K+ channels. Biophys J 81:867-883

  • 19. Nakamura T, Coetzee WA, Vega-Saenz de Miera E, Artman M, and Rudy B (1997). Modulation of Kv4 channels, key components of rat ventricular transient K+ current, by PKC. Am J Physiol 273:H1775-H1786

  • 20. Zagha E, Ozaita A, Chang SY, Nadal MS, Lin U, Saganich MJ, McCormack T, Akinsanya KO, Qi SY, and Rudy B (2005) DPP10 modulates Kv4-mediated A-type potassium channels. J Biol Chem 280:18853-18861

  • 21. Rocha CA, Nadal M, Rudy B, and Covarrubias M. (2004) Inactivation gating of Kv4 K+ channels interacting with the dipeptidyl-aminopeptidase-like protein (DPPX), in Proceedings of the 48th Annual Meeting of the Biophysical Society; 2004 14–18 Feb; Baltimore, Md. Presentation 2780-Pos