title: Oxidant-induced activation of type I protein kinase A is mediated by RI subunit interprotein disulfide bond formation.
abstract: Here we demonstrate that type I protein kinase A is redoxactive, forming an interprotein disulfide bond between its two regulatory RI subunits in response to cellular hydrogen peroxide. This oxidative disulfide formation causes a subcellular translocation and activation of the kinase, resulting in phosphorylation of established substrate proteins. The translocation is mediated at least in part by the oxidized form of the kinase having an enhanced affinity for alpha-myosin heavy chain, which serves as a protein kinase A (PKA) anchor protein and localizes the PKA to its myofilament substrates troponin I and myosin binding protein C. The functional consequence of these events in cardiac myocytes is that hydrogen peroxide increases contractility independently of beta-adrenergic stimulation and elevations of cAMP. The oxidant-induced phosphorylation of substrate proteins and increased contractility is blocked by the kinase inhibitor H89, indicating that these events involve PKA activation. In essence, type I PKA contains protein thiols that operate as redox sensors, and their oxidation by hydrogen peroxide directly activates the kinase.
authors.affiliation: Department of Cardiology, The Rayne Institute, St. Thomas' Hospital, London, SE1 7EH.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Brennan
authors.affiliation: Cardiovascular Division, King's College London, The Rayne Institute, St. Thomas' Hospital, London, SE1 7EH.
authors.forename: Sonya C
authors.initials: SC
authors.lastname: Bardswell
authors.affiliation: Department of Cardiology, The Rayne Institute, St. Thomas' Hospital, London, SE1 7EH.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Burgoyne
authors.affiliation: Cardiovascular Division, King's College London, The Rayne Institute, St. Thomas' Hospital, London, SE1 7EH.
authors.forename: William
authors.initials: W
authors.lastname: Fuller
authors.affiliation: Department of Cardiology, The Rayne Institute, St. Thomas' Hospital, London, SE1 7EH.
authors.forename: Ewald
authors.initials: E
authors.lastname: Schröder
authors.affiliation: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1, Aspenlea Rd., Hammersmith, London, W6 8LH United Kingdom.
authors.forename: Robin
authors.initials: R
authors.lastname: Wait
authors.affiliation: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1, Aspenlea Rd., Hammersmith, London, W6 8LH United Kingdom.
authors.forename: Shajna
authors.initials: S
authors.lastname: Begum
authors.affiliation: Cardiovascular Division, King's College London, The Rayne Institute, St. Thomas' Hospital, London, SE1 7EH.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Kentish
authors.affiliation: Department of Cardiology, The Rayne Institute, St. Thomas' Hospital, London, SE1 7EH. Electronic address: philip.eaton@kcl.ac.uk.
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004220:Disulfides; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D021122:Protein Subunits; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D024723:Ventricular Myosins
chemical_list: D004220:Disulfides; D016877:Oxidants; D021122:Protein Subunits; D006861:Hydrogen Peroxide; D017868:Cyclic AMP-Dependent Protein Kinases; D024723:Ventricular Myosins