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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}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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A. Sturza, M. S. Leisegang, A. Babelova, K. Schroder, S. Benkhoff, A. E. Loot, I. Fleming, R. Schulz, D. M. Muntean, and R. P. Brandes (2013)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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T. Akaike, M. Nishida, and S. Fujii (2013)
J. Biochem. 153, 131-138
   Abstract »    Full Text »    PDF »
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H. S. Chung, S.-B. Wang, V. Venkatraman, C. I. Murray, and J. E. Van Eyk (2013)
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   Abstract »    Full Text »    PDF »
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S. F. Steinberg (2013)
Circ. Res. 112, 393-405
   Abstract »    Full Text »    PDF »
Direct Binding and Regulation of RhoA Protein by Cyclic GMP-dependent Protein Kinase I{alpha}.
M. Kato, R. Blanton, G.-R. Wang, T. J. Judson, Y. Abe, M. Myoishi, R. H. Karas, and M. E. Mendelsohn (2012)
J. Biol. Chem. 287, 41342-41351
   Abstract »    Full Text »    PDF »
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Hypertension 60, 1301-1308
   Abstract »    Full Text »    PDF »
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C. I. Murray and J. E. Van Eyk (2012)
Circ Cardiovasc Genet 5, 591
   Full Text »    PDF »
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Circ. Res. 111, 1091-1106
   Abstract »    Full Text »    PDF »
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W. D. Gao, C. I. Murray, Y. Tian, X. Zhong, J. F. DuMond, X. Shen, B. A. Stanley, D. B. Foster, D. A. Wink, S. B. King, et al. (2012)
Circ. Res. 111, 1002-1011
   Abstract »    Full Text »    PDF »
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O. Rudyk, O. Prysyazhna, J. R. Burgoyne, and P. Eaton (2012)
Circulation 126, 287-295
   Abstract »    Full Text »    PDF »
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A. S. Levy, C. Vigna, and J. W. E. Rush (2012)
J Appl Physiol 113, 246-254
   Abstract »    Full Text »    PDF »
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K. Schroder, M. Zhang, S. Benkhoff, A. Mieth, R. Pliquett, J. Kosowski, C. Kruse, P. Luedike, U. R. Michaelis, N. Weissmann, et al. (2012)
Circ. Res. 110, 1217-1225
   Abstract »    Full Text »    PDF »
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D. X. Zhang, L. Borbouse, D. Gebremedhin, S. A. Mendoza, N. S. Zinkevich, R. Li, and D. D. Gutterman (2012)
Circ. Res. 110, 471-480
   Abstract »    Full Text »    PDF »
Truncated IRAG variants modulate cGMP-mediated inhibition of human colonic smooth muscle cell contraction.
A. v. Werder, M. Mayr, G. Schneider, D. Oesterle, R. M. Fritsch, B. Seidler, J. Schlossmann, F. Hofmann, M. Schemann, H. D. Allescher, et al. (2011)
Am J Physiol Cell Physiol 301, C1445-C1457
   Abstract »    Full Text »    PDF »
Roles for redox mechanisms controlling protein kinase G in pulmonary and coronary artery responses to hypoxia.
B. H. Neo, S. Kandhi, and M. S. Wolin (2011)
Am J Physiol Heart Circ Physiol 301, H2295-H2304
   Abstract »    Full Text »    PDF »
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J. Schlossmann and M. Desch (2011)
Am J Physiol Heart Circ Physiol 301, H672-H682
   Abstract »    Full Text »    PDF »
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I. Tegeder, R. Scheving, I. Wittig, and G. Geisslinger (2011)
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   Abstract »    Full Text »    PDF »
Mechanism of glucose-6-phosphate dehydrogenase-mediated regulation of coronary artery contractility.
H. Ata, D. K. Rawat, T. Lincoln, and S. A. Gupte (2011)
Am J Physiol Heart Circ Physiol 300, H2054-H2063
   Abstract »    Full Text »    PDF »
Role of sulfhydryl-dependent dimerization of soluble guanylyl cyclase in relaxation of porcine coronary artery to nitric oxide.
X. Zheng, L. Ying, J. Liu, D. Dou, Q. He, S. W. S. Leung, R. Y. K. Man, P. M. Vanhoutte, and Y. Gao (2011)
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   Abstract »    Full Text »    PDF »
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Am J Physiol Endocrinol Metab 300, E761-E770
   Abstract »    Full Text »    PDF »
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J. Biol. Chem. 286, 9921-9927
   Abstract »    Full Text »    PDF »
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Y. Liu, A. H. Bubolz, S. Mendoza, D. X. Zhang, and D. D. Gutterman (2011)
Circ. Res. 108, 566-573
   Abstract »    Full Text »    PDF »
cGMP-dependent protein kinase and the regulation of vascular smooth muscle cell gene expression: possible involvement of Elk-1 sumoylation.
C. Choi, H. Sellak, F. M. Brown, and T. M. Lincoln (2010)
Am J Physiol Heart Circ Physiol 299, H1660-H1670
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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T. L. Merry, G. R. Steinberg, G. S. Lynch, and G. K. McConell (2010)
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   Abstract »    Full Text »    PDF »
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 (2010)
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   Abstract »    Full Text »    PDF »
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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)
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   Abstract »    Full Text »    PDF »
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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.
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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M. S. Wolin (2009)
Am J Physiol Heart Circ Physiol 296, H539-H549
   Abstract »    Full Text »    PDF »
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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 »
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B. Kemp-Harper and R. Feil (2008)
Science Signaling 1, pe12
   Abstract »    Full Text »    PDF »
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H. C. Hartzell (2007)
Science 317, 1331-1332
   Abstract »    Full Text »    PDF »

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