Protease-activated receptor 2 (PAR2) (PAR2)

Protease-activated receptor 2 (PAR2) is a member of the G protein-coupled receptor (GPCR) family that is uniquely activated by the proteolytic cleavage of its extracellular N-terminus by serine proteases such as trypsin, mast cell tryptase, and coagulation factors [1, 3]. This cleavage unmasks a "tethered ligand" that binds intramolecularly to the receptor, initiating diverse intracellular signaling pathways including G-protein (Gq/11, Gs, Gi/o, G12/13) and β-arrestin cascades [2, 4]. PAR2 is widely expressed in tissues such as the skin, gastrointestinal tract, lungs, and immune cells, where it acts as a sensor for tissue injury and environmental stress [3, 5]. It plays a pivotal role in the pathogenesis of chronic inflammatory conditions, including asthma, arthritis, and atopic dermatitis, as well as in the transmission of itch and pain sensations [4, 18]. Furthermore, PAR2 is implicated in cancer progression, metabolic disorders like obesity and fatty liver disease, and cardiovascular regulation [11, 19]. Therapeutic development focuses on small-molecule antagonists (e.g., GB88, AZ3451), pepducins, and monoclonal antibodies to modulate its pro-inflammatory and pro-proliferative effects [15, 16]. However, targeting PAR2 presents challenges due to its broad physiological roles and the complexity of its biased signaling pathways [2, 16].

Other names

F2RL1Coagulation factor II receptor-like 1G-protein coupled receptor 11GPR11Thrombin receptor-like 1Proteinase-activated receptor 2PAR-2

PAR2 is activated through the proteolytic cleavage of its N-terminal domain by serine proteases, which reveals a tethered ligand that binds to the receptor's extracellular loops to initiate signaling [1, 5]. Drugs targeting PAR2 primarily act as antagonists that block this activation or as biased modulators that selectively inhibit specific downstream pathways, such as G-protein or β-arrestin signaling [2, 16]. Some experimental agents also include synthetic peptide agonists that mimic the tethered ligand to study receptor function [3, 15].