title: Downregulation of KCNQ4 by Janus kinase 2.
abstract: Janus kinase-2 (JAK2) participates in the signaling of several hormones, growth factors and cytokines. Further stimulators of JAK2 include osmotic cell shrinkage, and the kinase activates the cell volume regulatory Na(+)/H(+) exchanger. The kinase may thus participate in cell volume regulation. Cell shrinkage is known to inhibit K(+) channels. Volume-regulatory K(+) channels include the voltage-gated K(+) channel KCNQ4. The present study explored the effect of JAK2 on KCNQ4 channel activity. KCNQ4 was expressed in Xenopus oocytes with or without wild-type JAK2, constitutively active (V617F)JAK2 or inactive (K882E)JAK2; and cell membrane conductance was determined by dual-electrode voltage clamp. Expression of KCNQ4 was followed by the appearance of voltage-gated K(+) conductance. Coexpression of JAK2 or of (V617F)JAK2, but not of (K882E)JAK2, resulted in a significant decrease in conductance. Treatment of KCNQ4 and JAK2 coexpressing oocytes with the JAK2 inhibitor AG490 (40 μM) was followed by an increase in conductance. Treatment of KCNQ4 expressing oocytes with brefeldin A (5 μM) was followed by a decrease in conductance, which was similar in oocytes expressing KCNQ4 together with JAK2 as in oocytes expressing KCNQ4 alone. Thus, JAK2 apparently does not accelerate channel protein retrieval from the cell membrane. In conclusion, JAK2 downregulates KCNQ4 activity and thus counteracts K(+) exit, an effect which may contribute to cell volume regulation.
authors.affiliation: Department of Physiology I, University of Tübingen, Tübingen, Germany.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Hosseinzadeh
authors.forename: Mentor
authors.initials: M
authors.lastname: Sopjani
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Pakladok
authors.forename: Shefalee K
authors.initials: SK
authors.lastname: Bhavsar
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D014981:Xenopus
chemical_list: D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D004921:Erythropoietin; D020126:Brefeldin A; D053614:Janus Kinase 2
references.citation: Neurobiol Aging. 2011 Nov;32(11):2109.e15-28
references.pmid: 21782286
references.citation: Contrib Nephrol. 2006;152:142-160
references.pmid: 17065810
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Jul;297(1):G107-15
references.pmid: 19389803
references.citation: Biochim Biophys Acta. 2004 Jan 28;1660(1-2):1-6
references.pmid: 14757214
references.citation: Leukemia. 2011 Feb;25(2):218-25
references.pmid: 21079613
references.citation: Leukemia. 2010 Jun;24(6):1128-38
references.pmid: 20428194
references.citation: Circulation. 2011 Aug 2;124(5):602-11
references.pmid: 21747056
references.citation: FEBS Lett. 1992 Jul 27;307(1):93-6
references.pmid: 1639200
references.citation: Cell Physiol Biochem. 2010;25(6):723-32
references.pmid: 20511718
references.citation: Nat Rev Clin Oncol. 2009 Nov;6(11):627-37
references.pmid: 19806146
references.citation: Biochem Biophys Res Commun. 2011 Oct 28;414(3):456-61
references.pmid: 21964291
references.citation: Cell Physiol Biochem. 2010;26(4-5):641-6
references.pmid: 21063101
references.citation: Genet Test Mol Biomarkers. 2011 Apr;15(4):263-5
references.pmid: 21198321
references.citation: Cell Physiol Biochem. 2010;26(4-5):503-12
references.pmid: 21063088
references.citation: Curr Opin Otolaryngol Head Neck Surg. 2008 Oct;16(5):441-4
references.pmid: 18797286
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 Oct;301(4):R1169-76
references.pmid: 21813872
references.citation: Biochem Biophys Res Commun. 2011 May 6;408(2):208-13
references.pmid: 21406183
references.citation: J Biol Chem. 1998 Sep 4;273(36):22962-8
references.pmid: 9722518
references.citation: J Assoc Genet Technol. 2010;36(3):107-9
references.pmid: 20978341
references.citation: J Biol Chem. 2003 May 9;278(19):16908-15
references.pmid: 12626508
references.citation: Curr Med Chem. 2010;17(36):4551-8
references.pmid: 21062251
references.citation: Blood Rev. 2011 Mar;25(2):53-63
references.pmid: 21095048
references.citation: Mol Cell Biol. 1997 May;17(5):2497-501
references.pmid: 9111318
references.citation: PLoS One. 2011;6(7):e21792
references.pmid: 21750731
references.citation: Expert Rev Hematol. 2010 Jun;3(3):323-37
references.pmid: 21082983
references.citation: Proc Natl Acad Sci U S A. 2012 May 29;109(22):8552-7
references.pmid: 22538811
references.citation: J Pharmacol Exp Ther. 2009 Mar;328(3):951-62
references.pmid: 19098162
references.citation: Cell Physiol Biochem. 2005;16(4-6):255-62
references.pmid: 16301825
references.citation: J Pharmacol Exp Ther. 2009 Apr;329(1):368-76
references.pmid: 19151245
references.citation: IUBMB Life. 2010 Jul;62(7):509-18
references.pmid: 20540154
references.citation: J Physiol. 2009 May 15;587(Pt 10):2225-31
references.pmid: 19289549
references.citation: Biochem Biophys Res Commun. 2012 Mar 30;420(1):172-7
references.pmid: 22405821
references.citation: Physiol Rev. 1998 Jan;78(1):247-306
references.pmid: 9457175
references.citation: J Membr Biol. 2012 Mar;245(3):157-63
references.pmid: 22407360
references.citation: Hypertension. 2011 Sep;58(3):497-504
references.pmid: 21730298
references.citation: Pflugers Arch. 2004 Jun;448(3):325-34
references.pmid: 15057559
references.citation: Cell Physiol Biochem. 2011;27(5):443-52
references.pmid: 21691061
references.citation: Cell Physiol Biochem. 2011;28(2):251-8
references.pmid: 21865732
references.citation: Cell Physiol Biochem. 2012;29(5-6):737-42
references.pmid: 22613974
references.citation: Nat Neurosci. 2011 Nov 20;15(1):138-45
references.pmid: 22101641
references.citation: J Membr Biol. 1997 Feb 1;155(3):229-37
references.pmid: 9050446
references.citation: Cell Physiol Biochem. 2006;18(1-3):57-66
references.pmid: 16914890
references.citation: Am J Physiol Endocrinol Metab. 2009 Dec;297(6):E1247-59
references.pmid: 19724019
references.citation: EMBO J. 1997 Nov 3;16(21):6325-36
references.pmid: 9351815
references.citation: Nat Rev Endocrinol. 2010 Sep;6(9):515-25
references.pmid: 20664532
references.citation: Cell Physiol Biochem. 2011;28(4):693-702
references.pmid: 22178881
references.citation: Ann Intern Med. 2010 Mar 2;152(5):300-6
references.pmid: 20194236