Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Originally published in Science Express on 23 August 2007
Science 7 September 2007:
Vol. 317. no. 5843, pp. 1393 - 1397
DOI: 10.1126/science.1144318
Prev | Table of Contents | Next

Reports

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*

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Intrarenal artery superoxide is mainly NADPH oxidase-derived and modulates endothelium-dependent dilation in elderly patients.
T. Schluter, U. Zimmermann, C. Protzel, B. Miehe, K.-J. Klebingat, R. Rettig, and O. Grisk (2009)
Cardiovasc Res
   Abstract »    Full Text »    PDF »
Transnitrosylating Nitric Oxide Species Directly Activate Type I Protein Kinase A, Providing a Novel Adenylate Cyclase-independent Cross-talk to {beta}-Adrenergic-like Signaling.
J. R. Burgoyne and P. Eaton (2009)
J. Biol. Chem. 284, 29260-29268
   Abstract »    Full Text »    PDF »
Endothelial nitric oxide synthase negatively regulates hydrogen peroxide-stimulated AMP-activated protein kinase in endothelial cells.
B. Y. Jin, J. L. Sartoretto, V. N. Gladyshev, and T. Michel (2009)
PNAS 106, 17343-17348
   Abstract »    Full Text »    PDF »
Oxidative Stress Is Linked to ERK1/2-p16 Signaling-mediated Growth Defect in ATM-deficient Astrocytes.
J. Kim and P. K. Y. Wong (2009)
J. Biol. Chem. 284, 14396-14404
   Abstract »    Full Text »    PDF »
Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling.
L. Gao and G. E. Mann (2009)
Cardiovasc Res 82, 9-20
   Abstract »    Full Text »    PDF »
Resolution of Established Cardiac Hypertrophy and Fibrosis and Prevention of Systolic Dysfunction in a Transgenic Rabbit Model of Human Cardiomyopathy Through Thiol-Sensitive Mechanisms.
R. Lombardi, G. Rodriguez, S. N. Chen, C. M. Ripplinger, W. Li, J. Chen, J. T. Willerson, S. Betocchi, S. A. Wickline, I. R. Efimov, et al. (2009)
Circulation 119, 1398-1407
   Abstract »    Full Text »    PDF »
Reactive oxygen species and the control of vascular function.
M. S. Wolin (2009)
Am J Physiol Heart Circ Physiol 296, H539-H549
   Abstract »    Full Text »    PDF »
Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood-brain barrier function.
D. M. Bailey, K. A. Evans, P. E. James, J. McEneny, I. S. Young, L. Fall, M. Gutowski, E. Kewley, J. M. McCord, K. Moller, et al. (2009)
J. Physiol. 587, 73-85
   Abstract »    Full Text »    PDF »
Prolonged treatment of porcine pulmonary artery with nitric oxide decreases cGMP sensitivity and cGMP-dependent protein kinase specific activity.
W. J. Perkins, D. O. Warner, and K. A. Jones (2009)
Am J Physiol Lung Cell Mol Physiol 296, L121-L129
   Abstract »    Full Text »    PDF »
Probing the Interaction between the Coiled Coil Leucine Zipper of cGMP-dependent Protein Kinase I{alpha} and the C Terminus of the Myosin Binding Subunit of the Myosin Light Chain Phosphatase.
A. K. Sharma, G.-P. Zhou, J. Kupferman, H. K. Surks, E. N. Christensen, J. J. Chou, M. E. Mendelsohn, and A. C. Rigby (2008)
J. Biol. Chem. 283, 32860-32869
   Abstract »    Full Text »    PDF »
Formation of Hydrogen Peroxide and Reduction of Peroxynitrite via Dismutation of Superoxide at Reperfusion Enhances Myocardial Blood Flow and Oxygen Consumption in Postischemic Mouse Heart.
Y. Xu, B. Liu, J. L. Zweier, and G. He (2008)
J. Pharmacol. Exp. Ther. 327, 402-410
   Abstract »    Full Text »    PDF »
A Key Role for Redox Signaling in Rapid P2X7 Receptor-Induced IL-1{beta} Processing in Human Monocytes.
J. Hewinson, S. F. Moore, C. Glover, A. G. Watts, and A. B. MacKenzie (2008)
J. Immunol. 180, 8410-8420
   Abstract »    Full Text »    PDF »
Reversal of Cardiac Hypertrophy and Fibrosis From Pressure Overload by Tetrahydrobiopterin: Efficacy of Recoupling Nitric Oxide Synthase as a Therapeutic Strategy.
A. L. Moens, E. Takimoto, C. G. Tocchetti, K. Chakir, D. Bedja, G. Cormaci, E. A. Ketner, M. Majmudar, K. Gabrielson, M. K. Halushka, et al. (2008)
Circulation 117, 2626-2636
   Abstract »    Full Text »    PDF »
Anemia and splenomegaly in cGKI-deficient mice.
M. Foller, S. Feil, K. Ghoreschi, S. Koka, A. Gerling, M. Thunemann, F. Hofmann, B. Schuler, J. Vogel, B. Pichler, et al. (2008)
PNAS 105, 6771-6776
   Abstract »    Full Text »    PDF »
Meeting Report: cGMP Matters.
B. Kemp-Harper and R. Feil (2008)
Science Signaling 1, pe12
   Abstract »    Full Text »    PDF »
S-Glutathionylation: Indicator of Cell Stress and Regulator of the Unfolded Protein Response.
D. M. Townsend (2007)
Mol. Interv. 7, 313-324
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)