Protease-activated receptor 1 and 4 (PAR1/4)

Protease-activated receptors 1 (PAR1) and 4 (PAR4) are G protein-coupled receptors (GPCRs) that serve as the primary mediators of thrombin-induced platelet activation in humans [PMID: 11163203]. Thrombin activates these receptors through a unique proteolytic mechanism, cleaving the N-terminal extracellular domain to expose a tethered ligand that binds intramolecularly to initiate signaling [PMID: 24782063]. PAR1 is a high-affinity thrombin receptor that triggers rapid, transient platelet activation, whereas PAR4 has a lower affinity and mediates a more sustained response [PMID: 15155819]. Beyond platelets, these receptors are expressed on endothelial cells and vascular smooth muscle cells, where they regulate vascular tone, permeability, and inflammatory responses [PMID: 21835014]. In clinical practice, PAR1 is targeted by the antagonist vorapaxar to reduce the risk of recurrent myocardial infarction and peripheral arterial disease [PMID: 22417203]. PAR4 is currently being explored as a therapeutic target with the goal of providing potent antithrombotic effects with a potentially lower risk of bleeding compared to PAR1 inhibition [PMID: 28818833].

Other names

Thrombin receptorCoagulation factor II receptorF2RF2RL3Protease-activated receptor 1Protease-activated receptor 4

PAR1 and PAR4 antagonists inhibit thrombin-mediated signaling by blocking the interaction between the receptor and its proteolytically unmasked N-terminal tethered ligand, thereby preventing G-protein-mediated platelet activation and vascular responses [PMID: 24782063, PMID: 30104241].