Cysteine redox sensor in PKGIa enables oxidant-induced activation.
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.
Burgoyne
Joseph R
JR
Department of Cardiology, Cardiovascular Division, King's College London, Rayne Institute, St. Thomas' Hospital, London SE1 7EH, UK.
Madhani
Melanie
M
Cuello
Friederike
F
Charles
Rebecca L
RL
Brennan
Jonathan P
JP
Schröder
Ewald
E
Browning
Darren D
DD
Eaton
Philip
P
D000818:Animals; D001011:Aorta; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D014162:Transfection; D014664:Vasodilation / Q000502:physiology
D004220:Disulfides; D016877:Oxidants; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569718:PRKG1 protein, human; D006152:Cyclic GMP; D003545:Cysteine