Regulation of thrombin receptor signaling

Abstract

Thrombin, a coagulant protease, is generated at sites of vascular injury and elicits cellular responses critical for haemostasis and thrombosis, as well as inflammation and proliferation. Protease-activated receptors (PARs) are G-protein-coupled receptors that account for the majority of thrombin's effects on cells. PAR1, the prototype for this family, is the predominant mediator of thrombin signaling in most cell types. PAR3 and PAR4 also respond to thrombin and are differentially expressed in various cell types. PARs are uniquely activated by proteolysis, which results in the generation of a tethered ligand that cannot diffuse away, unlike normal reversibly activated G-protein-coupled receptors. Since PARs are irreversibly activated, signaling must be tightly regulated. Desensitization and trafficking of proteolytically activated PARs control the magnitude, duration and spatial aspects of receptor signaling. Thrombin also elicits cell-type-specific response through the activation of distinct PARs and G-protein subtypes. Thus, elucidating the mechanisms that regulate PAR signaling in various cell types is critical for understanding their biological function. Here, I discuss our current understanding of the regulation of thrombin receptor signaling.