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

TY - JOUR

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

AU - Brennan, J P

AU - Bardswell, S C

AU - Burgoyne, Joe

AU - Fuller, W

AU - Schroder, E

AU - Wait, R

AU - Begum, S

AU - Kentish, J C

AU - Eaton, P

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

U2 - 10.1074/jbc.M603952200

DO - 10.1074/jbc.M603952200

M3 - Article

SN - 1083-351X

VL - 281

SP - 21827

EP - 21836

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 31

ER -