The platelet PARs

Official URL: https://dx.doi.org/10.1007/978-3-319-47462-5_13

The serine protease thrombin is a potent activator of platelets. It binds to two classes of receptors, the GPIb-IX complex and protease-activated receptors (PARs). PARs constitute a family of four G protein-coupled receptors named PARs 1-4 that mediate protease signaling in a wide variety of cells. In this chapter we describe the genomic organization and expression of PARs in platelets from humans and other species. Thrombin is the primary activator of PARs in platelets. We focus on the factors that determine the specificity and rate of cleavage PARs by thrombin, which are the initiating events of thrombin-induced platelet activation. Human platelets express PAR1 and PAR4, which have both overlapping and distinct signaling pathways. These differences have become increasingly important as therapeutics targeting PAR1 and PAR4 are developed. In addition to thrombin-PAR interactions, the activation and downstream signaling of PAR subtypes is influenced by dimerization with one another and other platelet GPCRs. We also discuss the recent identification of genetic variations that impact PAR4 signaling in humans. Finally, we highlight the differences in PAR expression on platelets across species that impact how animal models can be used as preclinical tools.