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

Brennan, J. P., Bardswell, S. C., Burgoyne, J. R., Fuller, W. , Schröder, E., Wait, R., Begum, S., Kentish, J. C. and 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, 281(31), pp. 21827-21836. (doi:10.1074/jbc.M603952200) (PMID:16754666)

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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 α-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 β-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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fuller, Dr Will
Authors: Brennan, J. P., Bardswell, S. C., Burgoyne, J. R., Fuller, W., Schröder, E., Wait, R., Begum, S., Kentish, J. C., and Eaton, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:05 June 2006

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