title: Role of kinases and G-proteins in the hyposmotic stimulation of cardiac IKs.
abstract: Exposure of cardiac myocytes to hyposmotic solution stimulates slowly-activating delayed-rectifying K(+) current (I(Ks)) via unknown mechanisms. In the present study, I(Ks) was measured in guinea-pig ventricular myocytes that were pretreated with modulators of cell signaling processes, and then exposed to hyposmotic solution. Pretreatment with compounds that (i) inhibit serine/threonine kinase activity (10-100 microM H89; 200 microM H8; 50 microM H7; 1 microM bisindolylmaleimide I; 10 microM LY294002; 50 microM PD98059), (ii) stimulate serine/threonine kinase activity (1-5 microM forskolin; 0.1 microM phorbol-12-myristate-13-acetate; 10 microM acetylcholine; 0.1 microM angiotensin II; 20 microM ATP), (iii) suppress G-protein activation (10 mM GDPbetaS), or (iv) disrupt the cytoskeleton (10 microM cytochalasin D), had little effect on the stimulation of I(Ks) by hyposmotic solution. In marked contrast, pretreatment with tyrosine kinase inhibitor tyrphostin A25 (20 microM) strongly attenuated both the hyposmotic stimulation of I(Ks) in myocytes and the hyposmotic stimulation of current in BHK cells co-expressing Ks channel subunits KCNQ1 and KCNE1. Since attenuation of hyposmotic stimulation was not observed in myocytes and cells pretreated with inactive tyrphostin A1, we conclude that TK has an important role in the response of cardiac Ks channels to hyposmotic solution.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
authors.forename: Sergey
authors.initials: S
authors.lastname: Missan
authors.forename: Paul
authors.initials: P
authors.lastname: Linsdell
authors.forename: Terence F
authors.initials: TF
authors.lastname: McDonald
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D051657:KCNQ1 Potassium Channel / Q000187:drug effects / Q000502:physiology; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D009997:Osmotic Pressure; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D002839:Chromans; D007211:Indoles; D007546:Isoquinolines; D051657:KCNQ1 Potassium Channel; D008301:Maleimides; D015221:Potassium Channels; D013449:Sulfonamides; D020032:Tyrphostins; C079836:tyrphostin 25; D005576:Colforsin; D015638:Cytochalasin D; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013755:Tetradecanoylphorbol Acetate; C060641:tyrphostin A23