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Submitted on April 26, 2007
Accepted on July 16, 2007
Cysteine Redox Sensor in PKGI Enables Oxidant-Induced Activation
Joseph R. Burgoyne 1, Melanie Madhani 1, Friederike Cuello 2, Rebecca L. Charles 1, Jonathan P. Brennan 1, Ewald Schröder 1, Darren D. Browning 3, Philip Eaton 1*
1 Department of Cardiology, Cardiovascular Division, King’s College London, The Rayne Institute, St. Thomas’ Hospital, London SE1 7EH, UK. 2 Cardiovascular Division, King’s College London, The Rayne Institute, St. Thomas’ Hospital, London SE1 7EH, UK. 3 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
* To whom correspondence should be addressed.
Philip Eaton , E-mail: philip.eaton{at}kcl.ac.uk
Changes in the concentration of oxidants in cells can regulatebiochemical signaling mechanisms that control cell function.We have found that guanosine 3',5'-monophosphate (cGMP)–dependentprotein kinase (PKG) functions directly as a redox sensor. TheI isoform, PKGI, formed an interprotein disulfide linking itstwo subunits in cells exposed to exogenous hydrogen peroxide.This oxidation directly activated the kinase in vitro, and inrat cells and tissues. The affinity of the kinase for substratesit phosphorylates was enhanced by disulfide formation. Thisoxidation-induced activation represents an alternate mechanismfor regulation along with the classical activation involvingnitric oxide and cGMP. This mechanism underlies cGMP-independentvasorelaxation in response to oxidants in the cardiovascularsystem and provides a molecular explanation for how hydrogenperoxide can operate as an endothelium-derived hyperpolarizingfactor.
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Enables Oxidant-Induced Activation
isoform, PKGI
