Chapter 192 - cGMP and PKG Signaling in Platelets

Abstract

This chapter focuses on the NO/cGMP/PKG signaling pathways involved in platelet inhibition. Platelets play a key role in normal and pathological hemostasis through their ability rapidly to adhere to activated or injured endothelium and subendothelial matrix proteins and to other activated platelets. A variety of factors, including collagen, fibrinogen, ADP, von Willebrand Factor (vWF), thrombin, thromboxane, and others, promote platelet adhesion and aggregation by utilizing multiple intracellular signal transduction mechanisms. Most of these activating and inhibitory factors bind to specific platelet receptors and stimulate signaling pathways which promote or inhibit platelet adhesion, aggregation, and secretion. The intracellular level of cGMP is controlled primarily by the enzymes involved in synthesis and degradation of cGMP. Two distinct enzyme families are involved in the synthesis of cGMP from GTP: particulate guanylyl cyclases (pGCs), and soluble guanylyl cyclase. Hydrolysis of platelet cGMP is catalyzed by phosphodiesterases (PDEs), a large group of enzymes consisting of at least 11 different families. At present, only three PDEs are definitely established as being expressed in platelets: the cGMP-stimulated PDE2, the cGMP-inhibited PDE3, and cGMP-binding, cGMP-specific PDE5. NO, in addition to its major effect on activation of sGC, can also modulate protein functions by S-nitrosylation of cysteine or nitration of tyrosine residues. Platelet secretion involves release of dense granules, α-granules, and lysosomes, and is a very complex process regulated by multiple intracellular signaling systems. Cytoskeletal protein reorganization, increase of cytosolic Ca2+ concentration, and activation of protein kinase C (PKC) are essential for the regulation of platelet secretion.