Protease-activated receptor 1 and Protease-activated receptor 4 (PAR1 and PAR4)

Protease-activated receptor 1 (PAR1) and Protease-activated receptor 4 (PAR4) are the two primary G protein-coupled receptors (GPCRs) on human platelets that mediate the effects of thrombin, the most potent physiological activator of platelets (1.2.1, 1.3.2). Thrombin activates these receptors through a unique proteolytic mechanism, cleaving the N-terminal extracellular domain to expose a tethered ligand that then binds to the receptor's own active site (1.2.1, 1.2.3). PAR1 is a high-affinity receptor that initiates rapid, transient platelet activation at low thrombin concentrations, while PAR4 has a lower affinity and mediates the sustained signaling necessary for stable thrombus formation (1.2.1, 1.4.4). This dual-receptor system is a critical therapeutic target for antiplatelet therapy in cardiovascular diseases such as myocardial infarction and stroke (1.2.2, 1.5.1). While the PAR1 antagonist vorapaxar is clinically approved, its use is limited by a significant risk of major bleeding and intracranial hemorrhage (1.1.2, 1.5.1). In contrast, selective PAR4 antagonists like BMS-986120 and BMS-986141 have been investigated as potentially safer alternatives, as they may inhibit pathological thrombosis while preserving the initial PAR1-mediated hemostatic response (1.1.1, 1.4.3).

Other names

Thrombin receptorCoagulation factor II receptorF2RCoagulation factor II receptor-like 3F2RL3Proteinase-activated receptor 1Proteinase-activated receptor 4

Antagonism of protease-activated receptors to inhibit thrombin-induced platelet activation.