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Gene Review

KCNIP2  -  Kv channel interacting protein 2

Homo sapiens

Synonyms: A-type potassium channel modulatory protein 2, Cardiac voltage-gated potassium channel modulatory subunit, KCHIP2, KChIP2, Kv channel-interacting protein 2, ...
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Disease relevance of KCNIP2

  • As a result hKChIP2 might play a role in cardiac diseases, where a contribution of I(to1) has been shown [1].
  • Overexpression of constitutively active Cn in NRVMs induced hypertrophy and caused profound increases in I(to,f) density as well as Kv4.2 mRNA and protein expression and promoter activity, without affecting Kv4.3 or KChIP2 levels [2].

High impact information on KCNIP2

  • Here, we analyzed the function of DREAM and the related protein KChIP-2 in the immune system using transgenic (tg) mice expressing a cross-dominant active mutant (EFmDREAM) for DREAM and KChIPs Ca2+-dependent transcriptional derepression [3].
  • Despite activating Cn and inducing hypertrophy in NRVMs, PE resulted in profound down-regulation of I(to,f) densities as well as Kv4.2, Kv4.3, and KChIP2 expression [2].
  • Co-immunoprecipitation and competitive glutathione S-transferase-binding assays indicate a direct interaction between KChIP2 and the Kv4.2 C terminus with a relative binding affinity comparable with that of the N terminus [4].
  • The angiotensin receptor type 1 also co-immunoprecipitates with Kv4.3 from canine ventricle or when co-expressed with Kv4.3 and its beta-subunit KChIP2 in human embryonic kidney 293 cells [5].
  • Analysis with chimeric proteins between KChIP2 and NCS-1 reveals that the three regions of KChIP2 (the linker between the first and second EF hands, the one between the third and fourth EF hands, and the C-terminal peptide after the fourth EF hand) are necessary and sufficient for its effective binding to Kv4.3 protein [6].

Biological context of KCNIP2

  • In the course of this work we mapped the hKCNIP2 gene to chromosome 10q24 [1].
  • METHODS AND RESULTS: We describe the cloning and tissue distribution of hKChIP2, as well as its functional interaction with hKv4.3 after expression in Xenopus oocytes [1].
  • Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle [7].
  • Elucidating KChIP effects on Kv4.3 inactivation and recovery kinetics with a minimal KChIP2 isoform [8].
  • Since Itof is one of the essential currents contributing to the shape of the cardiac action potential in the rat, ferret, dog, and human heart, an important implication of this concept is that all ventricular cardiac myocytes from these species express members of the Kv4 and the KChIP2 gene family [9].

Anatomical context of KCNIP2

  • Compared to I(to) in native human myocytes, none of the combination of KChIP2 and KCNE produced an ideal congruency in current characteristics, suggesting that additional factors contribute to the regulation of the native I(to) channel [10].
  • Transmural gradients were detected only for KChIP2 in left and right ventricles [10].
  • Northern blot analyses revealed that hKChIP2 is expressed in the human heart and occurs in the adult atria and ventricles but not in the fetal heart [1].
  • KChIP2 mRNA was 25-fold more abundant in the epicardium than in the endocardium, and this gradient paralleled the gradient in transient outward current (Ito) expression [7].
  • Wild-type and mutant Kv4.2 channels were coexpressed with KChIP2 isoforms in mammalian cell lines [11].

Associations of KCNIP2 with chemical compounds

  • 2. Bupivacaine inhibition of Kv4.3V401I resembled Kv4.3wt and was not changed by coexpression of KChIP2 [12].
  • Here we show that KChIP2 mRNA and protein levels are dramatically decreased to 10% to 30% of control levels in the left ventricle of aorta-constricted rats in vivo and phenylephrine (PE)-treated myocytes in vitro [13].
  • Inhibition of protein kinase Cs (PKCs) does not affect the PE-induced reduction in KChIP2 mRNA level, whereas activation of PKC with phorbol ester (phorbol myristate [PMA]) causes a marked reduction in KChIP2 mRNA level [13].

Physical interactions of KCNIP2

  • KCNE3 also inhibits currents generated by Kv4.3 in complex with the accessory subunit KChIP2 [14].

Other interactions of KCNIP2

  • 1. The real-time RT-PCR analysis showed that the relative abundance of the encoding genes of I(A) alpha-subunit and K(V) channel-interacting proteins (KChIPs) was K(V)4.2 > K(V)3.4 > K(V)4.3 (long) > K(V)4.1, and KChIP3 >> KChIP2, respectively [15].
  • In the canine heart, the expression of Kv4.3, Kv1.4, KChIP2 and KvLQT1 was significantly higher, and that of Nav1.5 and MinK much lower, in EPI than in MID [16].
  • In addition, a constitutively active MEK1 decreases the basal KChIP2 mRNA level, and PMA causes no further reduction in auxiliary subunit mRNA level in active MEK1-expressing cells [13].

Analytical, diagnostic and therapeutic context of KCNIP2


  1. hKChIP2 is a functional modifier of hKv4.3 potassium channels: cloning and expression of a short hKChIP2 splice variant. Decher, N., Uyguner, O., Scherer, C.R., Karaman, B., Yüksel-Apak, M., Busch, A.E., Steinmeyer, K., Wollnik, B. Cardiovasc. Res. (2001) [Pubmed]
  2. Calcineurin Increases Cardiac Transient Outward K+ Currents via Transcriptional Up-regulation of Kv4.2 Channel Subunits. Gong, N., Bodi, I., Zobel, C., Schwartz, A., Molkentin, J.D., Backx, P.H. J. Biol. Chem. (2006) [Pubmed]
  3. Transcriptional repressor DREAM regulates T-lymphocyte proliferation and cytokine gene expression. Savignac, M., Pintado, B., Gutierrez-Adan, A., Palczewska, M., Mellström, B., Naranjo, J.R. EMBO J. (2005) [Pubmed]
  4. C-terminal Domain of Kv4.2 and Associated KChIP2 Interactions Regulate Functional Expression and Gating of Kv4.2. Han, W., Nattel, S., Noguchi, T., Shrier, A. J. Biol. Chem. (2006) [Pubmed]
  5. Angiotensin receptor type 1 forms a complex with the transient outward potassium channel Kv4.3 and regulates its gating properties and intracellular localization. Doronin, S.V., Potapova, I.A., Lu, Z., Cohen, I.S. J. Biol. Chem. (2004) [Pubmed]
  6. Effective association of Kv channel-interacting proteins with Kv4 channel is mediated with their unique core peptide. Ren, X., Shand, S.H., Takimoto, K. J. Biol. Chem. (2003) [Pubmed]
  7. Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle. Rosati, B., Pan, Z., Lypen, S., Wang, H.S., Cohen, I., Dixon, J.E., McKinnon, D. J. Physiol. (Lond.) (2001) [Pubmed]
  8. Elucidating KChIP effects on Kv4.3 inactivation and recovery kinetics with a minimal KChIP2 isoform. Patel, S.P., Campbell, D.L., Strauss, H.C. J. Physiol. (Lond.) (2002) [Pubmed]
  9. Kv4.2 and KChIP2 transcription in individual cardiomyocytes from the rat left ventricular free wall. Schultz, J.H., Janzen, C., Volk, T., Ehmke, H. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  10. Functional modulation of the transient outward current Ito by KCNE beta-subunits and regional distribution in human non-failing and failing hearts. Radicke, S., Cotella, D., Graf, E.M., Banse, U., Jost, N., Varró, A., Tseng, G.N., Ravens, U., Wettwer, E. Cardiovasc. Res. (2006) [Pubmed]
  11. Contribution of N- and C-terminal channel domains to Kv4.2 domains to KChIP interaction [corrected]. Callsen, B., Isbrandt, D., Sauter, K., Hartmann, L.S., Pongs, O., Bähring, R. J. Physiol. (Lond.) (2005) [Pubmed]
  12. Inhibition of Kv4.3/KChIP2.2 channels by bupivacaine and its modulation by the pore mutation Kv4.3V401I. Solth, A., Siebrands, C.C., Friederich, P. Anesthesiology (2005) [Pubmed]
  13. Mitogen-activated protein kinases control cardiac KChIP2 gene expression. Jia, Y., Takimoto, K. Circ. Res. (2006) [Pubmed]
  14. KCNE3 is an inhibitory subunit of the Kv4.3 potassium channel. Lundby, A., Olesen, S.P. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  15. Molecular and pharmacological characteristics of transient voltage-dependent K+ currents in cultured human pulmonary arterial smooth muscle cells. Iida, H., Jo, T., Iwasawa, K., Morita, T., Hikiji, H., Takato, T., Toyo-Oka, T., Nagai, R., Nakajima, T. Br. J. Pharmacol. (2005) [Pubmed]
  16. Asymmetrical distribution of ion channels in canine and human left-ventricular wall: epicardium versus midmyocardium. Szabó, G., Szentandrássy, N., Bíró, T., Tóth, B.I., Czifra, G., Magyar, J., Bányász, T., Varró, A., Kovács, L., Nánási, P.P. Pflugers Arch. (2005) [Pubmed]
  17. Three-dimensional structure of I(to); Kv4.2-KChIP2 ion channels by electron microscopy at 21 Angstrom resolution. Kim, L.A., Furst, J., Gutierrez, D., Butler, M.H., Xu, S., Goldstein, S.A., Grigorieff, N. Neuron (2004) [Pubmed]
  18. Regulation of Kv4.3 current by KChIP2 splice variants: a component of native cardiac I(to)? Deschênes, I., DiSilvestre, D., Juang, G.J., Wu, R.C., An, W.F., Tomaselli, G.F. Circulation (2002) [Pubmed]
  19. Novel KChIP2 isoforms increase functional diversity of transient outward potassium currents. Decher, N., Barth, A.S., Gonzalez, T., Steinmeyer, K., Sanguinetti, M.C. J. Physiol. (Lond.) (2004) [Pubmed]
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