title: Nuclear localization and functional characteristics of voltage-gated potassium channel Kv1.3.
abstract: It is widely known that ion channels are expressed in the plasma membrane. However, a few studies have suggested that several ion channels including voltage-gated K(+) (Kv) channels also exist in intracellular organelles where they are involved in the biochemical events associated with cell signaling. In the present study, Western blot analysis using fractionated protein clearly indicates that Kv1.3 channels are expressed in the nuclei of MCF7, A549, and SNU-484 cancer cells and human brain tissues. In addition, Kv1.3 is located in the plasma membrane and the nucleus of Jurkat T cells. Nuclear membrane hyperpolarization after treatment with margatoxin (MgTX), a specific blocker of Kv1.3 channels, provides evidence for functional channels at the nuclear membrane of A549 cells. MgTX-induced hyperpolarization is abolished in the nuclei of Kv1.3 silenced cells, and the effects of MgTX are dependent on the magnitude of the K(+) gradient across the nuclear membrane. Selective Kv1.3 blockers induce the phosphorylation of cAMP response element-binding protein (CREB) and c-Fos activation. Moreover, Kv1.3 is shown to form a complex with the upstream binding factor 1 in the nucleus. Chromatin immunoprecipitation assay reveals that Sp1 transcription factor is directly bound to the promoter region of the Kv1.3 gene, and the Sp1 regulates Kv1.3 expression in the nucleus of A549 cells. These results demonstrate that Kv1.3 channels are primarily localized in the nucleus of several types of cancer cells and human brain tissues where they are capable of regulating nuclear membrane potential and activation of transcription factors, such as phosphorylated CREB and c-Fos.
authors.affiliation: From the Laboratories of Veterinary Pharmacology and the Biomedical Research Center, School of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
authors.forename: Soo Hwa
authors.initials: SH
authors.lastname: Jang
authors.affiliation: From the Laboratories of Veterinary Pharmacology and.
authors.forename: Jun Kyu
authors.initials: JK
authors.lastname: Byun
authors.affiliation: From the Laboratories of Veterinary Pharmacology and.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeon
authors.affiliation: From the Laboratories of Veterinary Pharmacology and.
authors.forename: Seon Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: the Department of Chemistry, Soongsil University, Seoul 156-743, Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Park
authors.affiliation: From the Laboratories of Veterinary Pharmacology and.
authors.forename: Bo Hyung
authors.initials: BH
authors.lastname: Lee
authors.affiliation: From the Laboratories of Veterinary Pharmacology and.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Yang
authors.affiliation: the Department of Physiology, School of Medicine, Chungnam National University, Daejeon 305-764, Korea, and.
authors.forename: Jin Bong
authors.initials: JB
authors.lastname: Park
authors.affiliation: the Department of Animal Science and Integrative Biology and Physiology, University of Minnesota, St. Paul, Minnesota 55455.
authors.forename: Scott M
authors.initials: SM
authors.lastname: O'Grady
authors.affiliation: Veterinary Pathology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Korea.
authors.forename: Dae-Yong
authors.initials: DY
authors.lastname: Kim
authors.affiliation: From the Laboratories of Veterinary Pharmacology and.
authors.forename: Pan Dong
authors.initials: PD
authors.lastname: Ryu
authors.affiliation: the Department of Chemistry, Soongsil University, Seoul 156-743, Korea.
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Joo
authors.affiliation: From the Laboratories of Veterinary Pharmacology and leeso@snu.ac.kr.
authors.forename: So Yeong
authors.initials: SY
authors.lastname: Lee
mesh_terms: D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D012604:Scorpion Venoms / Q000494:pharmacology; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D051664:Kv1.3 Potassium Channel; D012604:Scorpion Venoms; D026362:Serum Response Factor; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C077910:margatoxin
keywords: Kv channels; UBF1; c-Fos; cAMP response element-binding protein (CREB); cell fractionation; ion channel; nuclear membrane potential; nucleus; specificity protein 1 (Sp1)
references.citation: Cell Motil Cytoskeleton. 1993;25(2):111-28
references.pmid: 7686821
references.citation: Trends Cell Biol. 2005 Sep;15(9):457-9
references.pmid: 16084096
references.citation: Oncogene. 1995 Aug 3;11(3):455-65
references.pmid: 7630629
references.citation: Pflugers Arch. 1995 May;430(1):148-50
references.pmid: 7667076
references.citation: J Membr Biol. 1997 Jul 15;158(2):159-66
references.pmid: 9230093
references.citation: Biochem J. 1998 Mar 1;330 ( Pt 2):1015-21
references.pmid: 9480924
references.citation: Blood. 1999 Feb 1;93(3):816-25
references.pmid: 9920830
references.citation: Ann N Y Acad Sci. 1999 Apr 30;868:344-55
references.pmid: 10414304
references.citation: J Neurochem. 1999 Aug;73(2):849-58
references.pmid: 10428084
references.citation: J Biol Chem. 2005 Apr 1;280(13):12790-8
references.pmid: 15632141
references.citation: Oncogene. 2005 Nov 10;24(49):7310-9
references.pmid: 16158061
references.citation: J Membr Biol. 2005 Jun;205(3):159-73
references.pmid: 16362504
references.citation: Pharmacol Rev. 2005 Dec;57(4):473-508
references.pmid: 16382104
references.citation: Cell. 2006 Nov 3;127(3):591-606
references.pmid: 17081980
references.citation: J Physiol. 2007 Aug 1;582(Pt 3):1219-38
references.pmid: 17525115
references.citation: J Neurochem. 2007 Nov;103(4):1608-27
references.pmid: 17854350
references.citation: Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H2719-25
references.pmid: 17660393
references.citation: Cell Mol Life Sci. 2008 Jul;65(14):2215-31
references.pmid: 18408887
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14861-6
references.pmid: 18818304
references.citation: Immunity. 2008 Oct 17;29(4):602-14
references.pmid: 18835197
references.citation: Can J Physiol Pharmacol. 2009 Feb;87(2):108-19
references.pmid: 19234574
references.citation: J Cell Sci. 2009 Oct 15;122(Pt 20):3738-48
references.pmid: 19773357
references.citation: J Exp Zool A Ecol Genet Physiol. 2009 Dec 1;311(10):763-75
references.pmid: 19658087
references.citation: Biochem Biophys Res Commun. 2010 Jul 2;397(3):614-20
references.pmid: 20570656
references.citation: J Neurochem. 2011 Jan;116(1):1-9
references.pmid: 21044077
references.citation: Eur J Pharmacol. 2011 Jan 25;651(1-3):26-32
references.pmid: 21087602
references.citation: J Vet Sci. 2011 Mar;12(1):35-40
references.pmid: 21368561
references.citation: PLoS One. 2011;6(5):e19257
references.pmid: 21559285
references.citation: Cell Physiol Biochem. 2011;28(2):199-208
references.pmid: 21865727
references.citation: J Biol Chem. 2012 Jan 6;287(2):1261-8
references.pmid: 22110135
references.citation: Biochem J. 2012 Feb 1;441(3):859-67
references.pmid: 22023388
references.citation: EMBO Mol Med. 2012 Jul;4(7):577-93
references.pmid: 22496117
references.citation: J Biol Chem. 1983 Feb 25;258(4):2710-9
references.pmid: 6218170
references.citation: J Cell Sci. 2000 Feb;113 ( Pt 3):439-50
references.pmid: 10639331
references.citation: Biophys J. 2000 Jul;79(1):202-14
references.pmid: 10866948
references.citation: Amino Acids. 2000;19(1):23-31
references.pmid: 11026470
references.citation: J Physiol. 2000 Dec 15;529 Pt 3:541-52
references.pmid: 11195932
references.citation: Physiol Rev. 2001 Jan;81(1):1-19
references.pmid: 11152752
references.citation: Nat Genet. 2002 Apr;30(4):416-20
references.pmid: 11925568
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9544-9
references.pmid: 12089327
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2592-7
references.pmid: 12604782
references.citation: J Mol Neurosci. 2003 Apr;20(2):189-94
references.pmid: 12794312
references.citation: Biochem Pharmacol. 2003 Nov 1;66(9):1861-70
references.pmid: 14563496
references.citation: Glia. 2004 Apr 1;46(1):63-73
references.pmid: 14999814
references.citation: J Biol Chem. 2004 Apr 23;279(17):17772-84
references.pmid: 14754893
references.citation: Nature. 1990 Feb 22;343(6260):764-7
references.pmid: 2304551
references.citation: J Membr Biol. 1991 Apr;121(2):189-98
references.pmid: 1715405
references.citation: Acta Neurobiol Exp (Wars). 1990;50(4-5):173-9
references.pmid: 2130639
references.citation: Pflugers Arch. 1992 Aug;421(5):473-85
references.pmid: 1281311
references.citation: Int J Biochem Cell Biol. 2005 Aug;37(8):1578-94
references.pmid: 15882958
references.citation: J Biol Chem. 2005 Aug 19;280(33):29506-12
references.pmid: 15964838
references.citation: Biophys J. 1993 Jun;64(6):1735-49
references.pmid: 7690256