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cGMP Signaling in Platelets

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Platelets, Haemostasis and Inflammation

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 5))

Abstract

The cyclic nucleotide cGMP is a key intracellular signaling molecule in mammals. It mediates many effects of nitric oxide (NO) including the regulation of vascular tone and platelet activity. Pharmacological and genetic studies have indicated that the NO-cGMP pathway could be an attractive target for antithrombotic drugs. Here, we summarize the biochemistry and (patho-)physiology of cGMP signaling in platelets. These cells generate and degrade cGMP by the NO-activated soluble guanylate cyclase and several phosphodiesterases (PDE2, PDE3, and PDE5), respectively. An increase of the cGMP concentration activates cGMP-dependent protein kinase type I (cGKI), which phosphorylates several platelet proteins. Among the cGKI substrates are small G-proteins (e.g., Rap1B), regulators of G-protein signaling (e.g., RGS18) and intracellular Ca2+ release (e.g., IRAG), and actin-binding proteins (e.g., VASP). According to the prevalent view, cGKI-dependent substrate phosphorylation limits platelet activation and thrombus formation through the inhibition of intracellular Ca2+ release, integrin activation, cytoskeletal remodeling, and granule secretion. Interestingly, several studies suggest that cGMP also promotes specific aspects of platelet activation. We discuss these seemingly contradictory findings and propose a new model of cGMP-regulated hemostasis that leads to optimal platelet activation in response to vascular injury. This model integrates both platelet stimulation and inhibition by dynamic shear stress-regulated cGMP signals that are generated during different phases of thrombus formation under flow in vivo.

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Acknowledgements

The authors would like to thank Michael Paolillo for reading the manuscript as well as the current and past members of the Feil laboratory for critical discussions. We apologize to all our colleagues, whose work could not be cited due to space limitations. The work in the authors’ laboratory is supported by the Fund for Science and Deutsche Forschungsgemeinschaft (FE 438/2-4, FOR 2060 projects FE 438/5-1 and FE 438/6-1, KFO 274 projects FE 438/7-1 and FE 438/8-2).

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  1. Interfakultäres Institut für Biochemie, University of Tübingen, Hoppe-Seyler-Str. 4, 72076, Tübingen, Germany

    Lai Wen, Susanne Feil & Robert Feil

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  1. Lai Wen
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  2. Susanne Feil
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  3. Robert Feil
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Correspondence to Robert Feil .

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Editors and Affiliations

  1. Cardiology and Angiology I, University-Heart Center Freiburg, Freiburg, Germany

    Andreas Zirlik

  2. Cardiology and Angiology I, University-Heart Center Freiburg, Freiburg, Germany

    Christoph Bode

  3. Department of Cardiology, University Hospital Tübingen, Tübingen, Germany

    Meinrad Gawaz

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Compliance with Ethical Standards

  • Conflict of Interest: Lai Wen, Susanne Feil, and Robert Feil declare that they have no conflict of interest.

  • Ethical Approval: This article does not contain any studies with human participants or animals performed by any of the authors.

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Wen, L., Feil, S., Feil, R. (2017). cGMP Signaling in Platelets. In: Zirlik, A., Bode, C., Gawaz, M. (eds) Platelets, Haemostasis and Inflammation. Cardiac and Vascular Biology, vol 5. Springer, Cham. https://doi.org/10.1007/978-3-319-66224-4_15

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