Protease-activated receptor 4 (PAR-4) (PAR-4)

Protease-activated receptor 4 (PAR-4) is a G protein-coupled receptor (GPCR) that plays a pivotal role in thrombin-induced platelet activation and thrombus stabilization [1, 5]. Unlike its high-affinity counterpart PAR-1, PAR-4 requires higher concentrations of thrombin for activation and mediates a slower, more sustained intracellular calcium flux [1, 11]. This prolonged signaling is essential for the later stages of platelet activation, including the release of dense granules and the exposure of procoagulant phosphatidylserine, which facilitates fibrin formation [2, 9]. PAR-4 is activated through a unique mechanism where thrombin or other proteases, such as cathepsin G, cleave the receptor's N-terminus to expose a tethered ligand that then binds and activates the receptor itself [3, 6]. In the context of cardiovascular disease, PAR-4 is a major driver of pathological arterial thrombosis, making it a high-interest therapeutic target [5, 12]. Antagonists of PAR-4, such as BMS-986120, are being developed to prevent conditions like myocardial infarction and stroke, offering the potential for a wider therapeutic window and lower bleeding risk compared to traditional antiplatelet agents [1, 7].

Other names

F2RL3Coagulation factor II receptor-like 3Thrombin receptor-like 3PAR4Platelet protease-activated receptor 4

Antagonist; Inhibition of thrombin-induced platelet activation; Inhibition of tethered ligand binding