Oxidant-induced activation of type I protein kinase A is mediated by RI subunit interprotein disulfide bond formation

Jonathan P. Brennan, Sonya C. Bardswell, Joseph R. Burgoyne, William Fuller, Ewald Schroder, Robin Wait, Shajna Begum, Jonathan C. Kentish, Philip Eaton

    Research output: Contribution to journalArticle

    149 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)21827-21836
    Number of pages10
    JournalJournal of Biological Chemistry
    Volume281
    Issue number31
    DOIs
    Publication statusPublished - 4 Aug 2006

    Cite this

    Brennan, Jonathan P. ; Bardswell, Sonya C. ; Burgoyne, Joseph R. ; Fuller, William ; Schroder, Ewald ; Wait, Robin ; Begum, Shajna ; Kentish, Jonathan C. ; Eaton, Philip. / Oxidant-induced activation of type I protein kinase A is mediated by RI subunit interprotein disulfide bond formation. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 31. pp. 21827-21836.
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    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.",
    author = "Brennan, {Jonathan P.} and Bardswell, {Sonya C.} and Burgoyne, {Joseph R.} and William Fuller and Ewald Schroder and Robin Wait and Shajna Begum and Kentish, {Jonathan C.} and Philip Eaton",
    year = "2006",
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    language = "English",
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    Brennan, JP, Bardswell, SC, Burgoyne, JR, Fuller, W, Schroder, E, Wait, R, Begum, S, Kentish, JC & Eaton, P 2006, 'Oxidant-induced activation of type I protein kinase A is mediated by RI subunit interprotein disulfide bond formation', Journal of Biological Chemistry, vol. 281, no. 31, pp. 21827-21836. https://doi.org/10.1074/jbc.M603952200

    Oxidant-induced activation of type I protein kinase A is mediated by RI subunit interprotein disulfide bond formation. / Brennan, Jonathan P.; Bardswell, Sonya C.; Burgoyne, Joseph R.; Fuller, William; Schroder, Ewald; Wait, Robin; Begum, Shajna; Kentish, Jonathan C.; Eaton, Philip.

    In: Journal of Biological Chemistry, Vol. 281, No. 31, 04.08.2006, p. 21827-21836.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Oxidant-induced activation of type I protein kinase A is mediated by RI subunit interprotein disulfide bond formation

    AU - Brennan, Jonathan P.

    AU - Bardswell, Sonya C.

    AU - Burgoyne, Joseph R.

    AU - Fuller, William

    AU - Schroder, Ewald

    AU - Wait, Robin

    AU - Begum, Shajna

    AU - Kentish, Jonathan C.

    AU - Eaton, Philip

    PY - 2006/8/4

    Y1 - 2006/8/4

    N2 - 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.

    AB - 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.

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