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Cysteine Redox Sensor in PKGIa Enables Oxidant-Induced Activation

2007; American Association for the Advancement of Science; Volume: 317; Issue: 5843 Linguagem: Inglês

10.1126/science.1144318

1095-9203

Joseph R. Burgoyne, Melanie Madhani, Friederike Cuello, Rebecca L. Charles, Jonathan P. Brennan, Ewald Schröder, Darren D. Browning, Philip Eaton,

Receptor Mechanisms and Signaling

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 Ialpha isoform, PKGIalpha, 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.