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

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 [1, 2]. PAR1 is a high-affinity receptor that initiates rapid, transient signaling at low thrombin concentrations, whereas PAR4 is a low-affinity receptor that provides sustained signaling required for stable thrombus formation and procoagulant activity at higher thrombin levels [3, 9]. These receptors are activated through a unique proteolytic mechanism where thrombin cleaves the N-terminal extracellular domain to expose a tethered ligand that binds and activates the receptor intramolecularly [10, 14]. In clinical practice, the PAR1 antagonist vorapaxar is used for the secondary prevention of thrombotic events, although its use is limited by a significant risk of major bleeding, including intracranial hemorrhage [12, 16]. Current drug development efforts are focused on PAR4 antagonists, such as BMS-986120 and BMS-986141, which may offer a superior safety profile by selectively inhibiting the late-stage stabilization of thrombi while preserving the initial hemostatic response mediated by PAR1 [8, 13]. Beyond thrombosis, these receptors also play roles in inflammation, vascular biology, and cancer progression [11, 17].

Other names

PAR1PAR4Coagulation factor II receptorF2RCoagulation factor II receptor-like 3F2RL3Thrombin receptorThrombin receptor-like 3Protease-activated receptor 1Protease-activated receptor 4

Protease-activated receptor 1 antagonism and protease-activated receptor 4 antagonism