Résumé
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.