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Science 317 (5843): 1393-1397

Copyright © 2007 by the American Association for the Advancement of Science

Cysteine Redox Sensor in PKGIa 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 Eaton1*

Abstract: Changes in the concentration of oxidants in cells can regulate biochemical signaling mechanisms that control cell function. We have found that guanosine 3',5'-monophosphate (cGMP)–dependent protein kinase (PKG) functions directly as a redox sensor. The I{alpha} isoform, PKGI{alpha}, formed an interprotein disulfide linking its two subunits in cells exposed to exogenous hydrogen peroxide. This oxidation directly activated the kinase in vitro, and in rat cells and tissues. The affinity of the kinase for substrates it phosphorylates was enhanced by disulfide formation. This oxidation-induced activation represents an alternate mechanism for regulation along with the classical activation involving nitric oxide and cGMP. This mechanism underlies cGMP-independent vasorelaxation in response to oxidants in the cardiovascular system and provides a molecular explantion for how hydrogen peroxide can operate as an endothelium-derived hyperpolarizing factor.

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. E-mail: philip.eaton{at}kcl.ac.uk


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