TABLE 17

KV4.2 channels

Channel name KV4.2
Description Voltage-gated potassium channel, A-type potassium current
Other names Shall, RK51,2,3
Molecular information Human: 630aa, NM_012281, chr. 7q31, KCND2 (see “Comments”), GeneID: 3751, PMID: 1055127024
Mouse: 630aa, NM_019697, chr. 6
Rat: 490aa, NM_031730, chr. 4q22
Associated subunits Coexpression of KChIP1 results in increased current densities, slowed onset of inactivation, and accelerated recovery from inactivation4; KChIP4/CALP interacts with KV4.2 and presenilin 25; frequenin, a calcium-binding protein, enhances KV4.2 current amplitudes, slows inactivation time course and accelerates recovery from inactivation6; PSD95, a PDZ domain protein, associates with KV4.2 and is involved in trafficking of the channel7; a number of proteins have been shown to interact and modify Kv4 proteins, including KChIPs, DPPX, DPP10, frequenin, PSD95, and filamin–most of these studies have used Kv4.2 and sometimes Kv4.3 proteins, but it is likely that these interactions also occur with Kv4.1; the physiological role of these proteins in native channels remains to be studied in most cases
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 KChIP28; ISA current in somatic recordings from neurons9
Conductance Not established
Ion selectivity PNa/PK < 0.01
Activation Midpoint of activation = 1 mV2
Inactivation Rapid inactivation with time constants of 15 and 60 ms2
Activators None
Gating inhibitors None
Blockers 4-Aminopyridine (5 mM),1,10 heteropodatoxins,11 PaTX1,2 (2–70 nM), arachidonic acid (2 μM)12
Radioligands None
Channel distribution Brain [cerebellum (granular cells) > hippocampus, thalamus, medial habenular nucleus > cerebral cortex; basal ganglia and forebrain13; concentrated in dendrites and soma14], cochlear nucleus,15 atrium, ventricle1,2,3,16; in situ hybridization has shown that many neuronal populations preferentially express KV4.2 or KV4.323–for example, CA1 hippocampal neurons express KV4.2 but not KV4.3–on the other hand, Purkinje cells and cortical interneurons express KV4.3 preferentially; in cerebellar granule cells, there is a reciprocal anterior-posterior gradient of expression
Physiological functions Repolarization of the cardiac action potential (notch phase), dampening back-propagating action potentials in CA1 hippocampal neurons
Mutations and pathophysiology KChIP2–/– mice lack the Ito current and are susceptible to ventricular tachycardia17; seizure activity reduces KV4.2 expression in the dentate granule cells of the hippocampus18
Pharmacological significance Not established
Comments The Kv4.2 (KCND2) gene, like KCND1 and KCND3, contains six exons– however, the introns are significantly longer19; kinetic properties depend on the expression system, recording configuration, and the presence of auxiliary subunits (KChIPs)20,21; KV4.2 currents expressed in Xenopus oocytes are suppressed in response to protein kinase C activation22; mammalian Shal-related family

  • aa, amino acids; chr., chromosome.

  • ↵1. Roberds SL and Tamkun MM (1991) Cloning and tissue-specific expression of five voltage-gated potassium channel cDNAs expressed in rat heart. Proc Natl Acad Sci USA 88:1798-1802

  • ↵2. Blair TA, Roberds SL, Tamkun MM, and Hartshorne RP (1991) Functional characterization of RK5, a voltage-gated K+ channel cloned from the rat cardiovascular system. FEBS Lett 295:211-213

  • ↵3. Roberds SL and Tamkun MM (1991) Develo pMental expression of cloned cardiac potassium channels. FEBS Lett 284:152-154

  • ↵4. Nakamura TY, Nandi S, Pountney DJ, Artman M, Rudy B, and Coetzee WA (2001) Different effects of the Ca2+-binding protein, KChIP1, on two Kv4 subfamily members, Kv4.1 and Kv4.2. FEBS Lett 499:205-209

  • ↵5. Morohashi Y, Hatano N, Ohya S, Takikawa R, Watabiki T, Takasugi N, Imaizumi Y, Tomita T, and Iwatsubo T (2002) Molecular cloning and characterization of CALP/KChIP4, a novel EF-hand protein interacting with presenilin 2 and voltage-gated potassium channel subunit Kv4. J Biol Chem 277:14965-14975

  • ↵6. Nakamura TY, Pountney DJ, Ozaita A, Nandi S, Ueda S, Rudy B, and Coetzee WA (2001) A role for frequenin, a Ca2+ binding protein, as a regulator of Kv4 K+-currents. Proc Natl Acad Sci USA 98:12808-12813

  • ↵7. Wong W, Newell E, Jugloff DG, Jones OT, and Schlichter LC (2002) Cell-surface targeting and clustering interactions between heterologously expressed PSD-95 and the Shal voltage-gated potassium channel, Kv4.2. J Biol Chem 277:20423-20430

  • ↵8. 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

  • ↵9. 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

  • ↵10. Tseng GN, Jiang M, and Yao JA (1996) Reverse use dependence of Kv4.2 blockade by 4-aminopyridine. J Pharmacol Exp Ther 279:865-876

  • ↵11. Sanguinetti MC, Johnson JH, Hammerland LG, Kelbaugh PR, Volkmann RA, Saccomano NA, and Mueller AL (1997) Heteropodatoxins: peptides isolated from spider venom that block Kv4.2 potassium channels. Mol Pharmacol 51:491-498

  • ↵12. Villarroel A and Schwarz TL (1996) Inhibition of the Kv4 (Shal) family of transient K+ currents by arachidonic acid. J Neurosci 16:2522-2532

  • ↵13. Tkatch T, Baranauskas G, and Surmeier DJ (2000) Kv4.2 mRNA abundance and A-type K+ current amplitude are linearly related in basal ganglia and basal forebrain neurons. J Neurosci 20:579-588

  • ↵14. Sheng M, Tsaur ML, Jan YN, and Jan LY (1992) Subcellular segregation of two A-type K+ channel proteins in rat central neurons. Neuron 9:271-284

  • ↵15. Fitzakerley JL, Star KV, Rinn JL, and Elmquist BJ (2000) Expression of Shal potassium channel subunits in the adult and developing cochlear nucleus of the mouse. Hear Res 147:31-45

  • ↵16. Dixon JE and McKinnon D (1994) Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. Circ Res 75:252-260

  • ↵17. Kuo HC, Cheng CF, Clark RB, Lin JJ, Lin JL, Hoshijima M, Nguyen-Tran VT, Gu Y, Ikeda Y, Chu PH, et al. (2001) A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of Ito and confers susceptibility to ventricular tachycardia. Cell 107:801-813

  • ↵18. Tsaur ML, Sheng M, Lowenstein DH, Jan YN, and Jan LY (1992) Differential expression of K+ channel mRNAs in the rat brain and down-regulation in the hippocampus following seizures. Neuron 8:1055-1067

  • ↵19. Isbrandt D, Leicher T, Waldschutz R, Zhu X, Luhmann U, Michel U, Sauter K and Pongs O (2000) Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents ITO and ISA. Genomics 64:144-154

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

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

  • ↵22. 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

  • ↵23. Serodio P and Rudy B (1998) Differential expression of Kv4 K+ channel subunits mediating subthreshold transient K+ (A-type) currents in rat brain. J Neurophysiol 79:1081-1091

  • ↵24. Zhu XR, Wulf A, Schwarz M, Isbrandt D, and Pongs O (1999) Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current. Receptors Channels 6:387-400