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Kcnd2  -  potassium channel, voltage-gated Shal...

Rattus norvegicus

Synonyms: Kv4.2, Potassium voltage-gated channel subfamily D member 2, RK5, Shal1, Voltage-gated potassium channel subunit Kv4.2
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Disease relevance of Kcnd2

  • The rat Kv4.2-coding sequence was truncated at a position just past the first transmembrane segment and subcloned into an adenoviral shuttle vector downstream of a cytomegalovirus promoter (pE1Kv4.2ST) [1].
  • Using a modified Sindbis virus, we expressed either the enhanced green fluorescence protein (EGFP)-tagged Kv4.2 or an EGFP-tagged dominant negative mutant of Kv4.2 (Kv4.2g(W362F)) in CA1 pyramidal neurones of organotypic slice cultures [2].
  • Although hypertrophy was not detected in diabetic rats at 12 wk after streptozocin treatment, ventricular Kv4.2 mRNA levels decreased 41% relative to nondiabetic controls [3].
  • Overexpression of Kv4.2 channels using adenovirus prevented the AP duration prolongation as well as the increases in Ca2+ influx and Ca2+-transient amplitude induced by PE [4].
  • RESULTS: MMI treatment induced hypothyroidism and resulted in a significant decrease in the mRNA levels of Kv1.5, Kv2.1 and Kv4.2 (19%, 77% and 61% of control value, respectively; n = 6, p < 0.05) [5].

Psychiatry related information on Kcnd2


High impact information on Kcnd2

  • It is necessary for dendritic targeting of potassium channel Kv4.2 and is sufficient to target the axonally localized channels Kv1.3 and Kv1.4 to the dendrites [7].
  • Here we report a 2.0 Angstrom crystal structure of the core domain of KChIP1 (KChIP1*) in complex with the N-terminal fragment of Kv4.2 (Kv4.2N30) [8].
  • As a result, the H10 of KChIP1 and alpha1 of Kv4.2 mediate interactions between these two molecules, structurally reminiscent of the interactions between calmodulin and its target peptides [8].
  • Manipulations that blocked Kv4.2 A-type K(+) channels, including a dominant-negative Kv4.2 construct and 4-aminopyridine, increased the amplitude of plateau potentials by allowing them to recruit neighboring dendrites [9].
  • Prolongation of plateau potentials or block of Kv4.2 channels at branch points facilitated the ability of dendritic excitation to trigger fast action potentials [9].

Chemical compound and disease context of Kcnd2

  • On the other hand, a 72-h treatment with cardiac non-myocyte cell (NMC)-conditioned growth medium (NCGM) or phenylephrine (20 microM) induced similar cell hypertrophy, but in sharp contrast to T3, both markedly suppressed the Kv4.2 channel protein level [10].
  • Kainic acid-induced generalized seizures alter the regional hippocampal expression of the rat Kv4.2 potassium channel gene [11].

Biological context of Kcnd2

  • KChIP co-expression also causes fundamental changes in Kv4.2 steady-state expression levels, phosphorylation, detergent solubility, and stability that reconstitute the molecular properties of Kv4.2 in native cells [12].
  • Suppression of neuronal and cardiac transient outward currents by viral gene transfer of dominant-negative Kv4.2 constructs [1].
  • KChIP proteins regulate Shal, Kv4.x, channel expression by binding to a conserved sequence at the N terminus of the subunit [13].
  • 2. Phrixotoxins specifically block Kv4.3 and Kv4.2 currents that underlie I(to1), with an 5 < IC50 < 70 nM, by altering the gating properties of these channels [14].
  • A cDNA clone encoding a K+ channel polypeptide with 72% amino acid sequence identity to Drosophila Shal was isolated from rat hippocampus [15].

Anatomical context of Kcnd2

  • There was a large gradient of Kv4.2 expression across the ventricular wall, and Kv4.2 expression in epicardial muscle was more than eight times higher than in papillary muscle [16].
  • Co-expression of KChIPs1-3 causes a dramatic redistribution of Kv4.2, releasing intrinsic endoplasmic reticulum retention and allowing for trafficking to the cell surface [12].
  • Immunofluorescence labeling revealed that KChIP1 and Kv4.2 are concentrated in somata of cerebellar granule cells and in synaptic glomeruli that surround synaptophysin-positive mossy fiber axon terminals [17].
  • In synaptic glomeruli, KChIP1 and Kv4.2 immunoreactivity is concentrated along the granule cell dendritic membrane, but is not concentrated at postsynaptic densities [17].
  • Taken together, these data suggest that A-type potassium channels containing Kv4.2 and KChIP1, and perhaps also KChIP3 and 4, play a critical role in regulating postsynaptic excitability at the cerebellar mossy-fiber/granule cell synapse [17].

Associations of Kcnd2 with chemical compounds

  • Recently we have shown that mutants of Kv4.2 lacking the ability to bind an intersubunit Zn(2+) between their T1 domains fail to form functional channels because they are unable to assemble to tetramers and remain trapped in the endoplasmic reticulum [13].
  • Furthermore, captopril administration to sham-operated rats significantly increased Kv4.2 mRNA [18].
  • As Ca(2)(+) influx occurs primarily during AP repolarization, Kv4.2 activity can regulate cellular processes involving Ca(2)(+)-dependent second messenger cascades such as gene expression and synaptic plasticity [2].
  • DiC8 also prevented the augmentation of Kv4.2 density by quinapril [19].
  • Kv4.2 overexpression also prohibited the PE-induced increases in cell size, protein/DNA ratio, atrial natriuretic factor expression, beta/alpha myosin mRNA ratio, and NFAT activation [4].

Enzymatic interactions of Kcnd2

  • We used this information to develop antibodies that recognize Kv4.2 phosphorylated by ERK2 [20].

Regulatory relationships of Kcnd2

  • Zn(2+)-less Kv4.2 channels expressed with KChIP3 demonstrate several distinct kinetic changes in channel gating, including a reduced time to peak and faster entry into the inactivated state as well as extending the time to recover from inactivation by 3-4 fold [13].
  • Immunocytochemical experiments also demonstrated that KChIP2 enhanced the trafficking of Kv4.2 channels to cell surface [21].
  • In addition, the trophic and the Kv4.2-downregulating effects of NCGM could be mimicked by exogenous endothelin-1 (0.1 microM), a paracrine factor secreted from cardiac NMCs [10].
  • Kv1.4 inactivated over more depolarized voltages than Kv4.2 (V(1/2)inact = -49.3 +/- 1.4 mV, n = 12) [22].

Other interactions of Kcnd2

  • Structural insights into the functional interaction of KChIP1 with Shal-type K(+) channels [8].
  • Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties [23].
  • By light microscopy, immunoperoxidase labeling showed that Kv4.2, Kv4.3, and KChIPs 1, 3, and 4 (but not KChIP2) were expressed at high levels in cerebellar granule cells (GCs) [17].
  • Voltage-gated potassium (Kv) channels from the Kv4, or Shal-related, gene family underlie a major component of the A-type potassium current in mammalian central neurons [24].
  • Immunoreactivity for KChIP2, KChIP4, and Kv4.2 is concentrated in the apical and basal dendrites of hippocampal and neocortical pyramidal cells [24].

Analytical, diagnostic and therapeutic context of Kcnd2


  1. Suppression of neuronal and cardiac transient outward currents by viral gene transfer of dominant-negative Kv4.2 constructs. Johns, D.C., Nuss, H.B., Marban, E. J. Biol. Chem. (1997) [Pubmed]
  2. Kv4 potassium channel subunits control action potential repolarization and frequency-dependent broadening in rat hippocampal CA1 pyramidal neurones. Kim, J., Wei, D.S., Hoffman, D.A. J. Physiol. (Lond.) (2005) [Pubmed]
  3. Altered K(+) channel gene expression in diabetic rat ventricle: isoform switching between Kv4.2 and Kv1.4. Nishiyama, A., Ishii, D.N., Backx, P.H., Pulford, B.E., Birks, B.R., Tamkun, M.M. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  4. Prevention of hypertrophy by overexpression of Kv4.2 in cultured neonatal cardiomyocytes. Zobel, C., Kassiri, Z., Nguyen, T.T., Meng, Y., Backx, P.H. Circulation (2002) [Pubmed]
  5. Effects of thyroid status on expression of voltage-gated potassium channels in rat left ventricle. Nishiyama, A., Kambe, F., Kamiya, K., Seo, H., Toyama, J. Cardiovasc. Res. (1998) [Pubmed]
  6. Differential effects of acute and chronic electroconvulsive shock on the abundance of messenger RNAs for voltage-dependent potassium channel subunits in the rat brain. Pei, Q., Burnet, P.W., Grahame-Smith, D.G., Zetterström, T.S. Neuroscience (1997) [Pubmed]
  7. An evolutionarily conserved dileucine motif in Shal K+ channels mediates dendritic targeting. Rivera, J.F., Ahmad, S., Quick, M.W., Liman, E.R., Arnold, D.B. Nat. Neurosci. (2003) [Pubmed]
  8. Structural insights into the functional interaction of KChIP1 with Shal-type K(+) channels. Zhou, W., Qian, Y., Kunjilwar, K., Pfaffinger, P.J., Choe, S. Neuron (2004) [Pubmed]
  9. Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Cai, X., Liang, C.W., Muralidharan, S., Muralidharan, S., Kao, J.P., Tang, C.M., Thompson, S.M. Neuron (2004) [Pubmed]
  10. Regulation of Kv4.2 and Kv1.4 K+ channel expression by myocardial hypertrophic factors in cultured newborn rat ventricular cells. Guo, W., Kamiya, K., Hojo, M., Kodama, I., Toyama, J. J. Mol. Cell. Cardiol. (1998) [Pubmed]
  11. Kainic acid-induced generalized seizures alter the regional hippocampal expression of the rat Kv4.2 potassium channel gene. Francis, J., Jugloff, D.G., Mingo, N.S., Wallace, M.C., Jones, O.T., Burnham, W.M., Eubanks, J.H. Neurosci. Lett. (1997) [Pubmed]
  12. A fundamental role for KChIPs in determining the molecular properties and trafficking of Kv4.2 potassium channels. Shibata, R., Misonou, H., Campomanes, C.R., Anderson, A.E., Schrader, L.A., Doliveira, L.C., Carroll, K.I., Sweatt, J.D., Rhodes, K.J., Trimmer, J.S. J. Biol. Chem. (2003) [Pubmed]
  13. KChIP3 rescues the functional expression of Shal channel tetramerization mutants. Kunjilwar, K., Strang, C., DeRubeis, D., Pfaffinger, P.J. J. Biol. Chem. (2004) [Pubmed]
  14. Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis. Diochot, S., Drici, M.D., Moinier, D., Fink, M., Lazdunski, M. Br. J. Pharmacol. (1999) [Pubmed]
  15. Characterization of a mammalian cDNA for an inactivating voltage-sensitive K+ channel. Baldwin, T.J., Tsaur, M.L., Lopez, G.A., Jan, Y.N., Jan, L.Y. Neuron (1991) [Pubmed]
  16. Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. Dixon, J.E., McKinnon, D. Circ. Res. (1994) [Pubmed]
  17. Light and electron microscopic analysis of KChIP and Kv4 localization in rat cerebellar granule cells. Strassle, B.W., Menegola, M., Rhodes, K.J., Trimmer, J.S. J. Comp. Neurol. (2005) [Pubmed]
  18. Decreased expression of Kv4.2 and novel Kv4.3 K+ channel subunit mRNAs in ventricles of renovascular hypertensive rats. Takimoto, K., Li, D., Hershman, K.M., Li, P., Jackson, E.K., Levitan, E.S. Circ. Res. (1997) [Pubmed]
  19. Role of PKC in autocrine regulation of rat ventricular K+ currents by angiotensin and endothelin. Shimoni, Y., Liu, X.F. Am. J. Physiol. Heart Circ. Physiol. (2003) [Pubmed]
  20. The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK. Adams, J.P., Anderson, A.E., Varga, A.W., Dineley, K.T., Cook, R.G., Pfaffinger, P.J., Sweatt, J.D. J. Neurochem. (2000) [Pubmed]
  21. Contribution of KChIP2 to the developmental increase in transient outward current of rat cardiomyocytes. Kobayashi, T., Yamada, Y., Nagashima, M., Seki, S., Tsutsuura, M., Ito, Y., Sakuma, I., Hamada, H., Abe, T., Tohse, N. J. Mol. Cell. Cardiol. (2003) [Pubmed]
  22. Effect of Cd2+ on Kv4.2 and Kv1.4 expressed in Xenopus oocytes and on the transient outward currents in rat and rabbit ventricular myocytes. Wickenden, A.D., Tsushima, R.G., Losito, V.A., Kaprielian, R., Backx, P.H. Cell. Physiol. Biochem. (1999) [Pubmed]
  23. Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties. Jerng, H.H., Kunjilwar, K., Pfaffinger, P.J. J. Physiol. (Lond.) (2005) [Pubmed]
  24. KChIPs and Kv4 alpha subunits as integral components of A-type potassium channels in mammalian brain. Rhodes, K.J., Carroll, K.I., Sung, M.A., Doliveira, L.C., Monaghan, M.M., Burke, S.L., Strassle, B.W., Buchwalder, L., Menegola, M., Cao, J., An, W.F., Trimmer, J.S. J. Neurosci. (2004) [Pubmed]
  25. Adult alveolar epithelial cells express multiple subtypes of voltage-gated K+ channels that are located in apical membrane. Lee, S.Y., Maniak, P.J., Ingbar, D.H., O'Grady, S.M. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  26. Cell surface targeting and clustering interactions between heterologously expressed PSD-95 and the Shal voltage-gated potassium channel, Kv4.2. Wong, W., Newell, E.W., Jugloff, D.G., Jones, O.T., Schlichter, L.C. J. Biol. Chem. (2002) [Pubmed]
  27. The role of Zn2+ in Shal voltage-gated potassium channel formation. Strang, C., Kunjilwar, K., DeRubeis, D., Peterson, D., Pfaffinger, P.J. J. Biol. Chem. (2003) [Pubmed]
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