title: Novel roles of cAMP/cGMP-dependent signaling in platelets.
abstract: Endothelial prostacyclin and nitric oxide potently inhibit platelet functions. Prostacyclin and nitric oxide actions are mediated by platelet adenylyl and guanylyl cyclases, which synthesize cyclic AMP (cAMP) and cyclic GMP (cGMP), respectively. Cyclic nucleotides stimulate cAMP-dependent protein kinase (protein kinase A [PKA]I and PKAII) and cGMP-dependent protein kinase (protein kinase G [PKG]I) to phosphorylate a broad panel of substrate proteins. Substrate phosphorylation results in the inactivation of small G-proteins of the Ras and Rho families, inhibition of the release of Ca(2+) from intracellular stores, and modulation of actin cytoskeleton dynamics. Thus, PKA/PKG substrates translate prostacyclin and nitric oxide signals into a block of platelet adhesion, granule release, and aggregation. cAMP and cGMP are degraded by phosphodiesterases, which might restrict signaling to specific subcellular compartments. An emerging principle of cyclic nucleotide signaling in platelets is the high degree of interconnection between activating and cAMP/cGMP-dependent inhibitory signaling pathways at all levels, including cAMP/cGMP synthesis and breakdown, and PKA/PKG-mediated substrate phosphorylation. Furthermore, defects in cAMP/cGMP pathways might contribute to platelet hyperreactivity in cardiovascular disease. This article focuses on recent insights into the regulation of the cAMP/cGMP signaling network and on new targets of PKA and PKG in platelets.
authors.affiliation: UCD Conway Institute, UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland. albert.smolenski@ucd.ie
authors.forename: A
authors.initials: A
authors.lastname: Smolenski
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000097:blood*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood*; D006152:Cyclic GMP / Q000097:blood*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000097:blood*; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D010975:Platelet Aggregation Inhibitors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP