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Published on: June 21, 2021
Cysteine redox sensor in PKGIa enables oxidant-induced activation.
Joseph R Burgoyne1, Melanie Madhani, Friederike Cuello
1Department of Cardiology, Cardiovascular Division, King's College London, Rayne Institute, St. Thomas' Hospital, London SE1 7EH, UK.
Science (New York, N.Y.)
|August 25, 2007
Summary
Guanylyl cyclase-dependent protein kinase (PKG) acts as a redox sensor. Oxidation activates PKG, enhancing substrate affinity and regulating cell function independently of nitric oxide and cGMP.
Area of Science:
- Biochemistry
- Cell Biology
- Physiology
Background:
- Cellular oxidant levels regulate cell function through biochemical signaling.
- Guanylyl cyclase-dependent protein kinase (PKG) is a key signaling enzyme.
- Nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) are classical activators of PKG.
Purpose of the Study:
- To investigate if PKG can function as a direct redox sensor.
- To elucidate the molecular mechanism of PKG activation by oxidants.
- To explore the physiological relevance of oxidant-mediated PKG activation.
Main Methods:
- Exposure of cells and tissues to hydrogen peroxide.
- Analysis of interprotein disulfide bond formation in PKGIalpha.
- In vitro kinase assays to assess activity and substrate affinity.
- Studies in rat cells and tissues.
Main Results:
- The PKGIalpha isoform forms an interprotein disulfide bond between its subunits upon exposure to hydrogen peroxide.
- This oxidation directly activates PKGIalpha kinase activity.
- Disulfide formation enhances the affinity of PKGIalpha for its substrates.
- Oxidant-induced PKG activation occurs independently of the NO/cGMP pathway.
Conclusions:
- PKG directly senses cellular oxidants, functioning as a redox sensor.
- Oxidation-induced PKG activation provides a cGMP-independent regulatory mechanism.
- This pathway explains oxidant-mediated vasorelaxation and hydrogen peroxide's role as an endothelium-derived hyperpolarizing factor.
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