Protease-activated receptor 2: activation, signalling and function

Abstract

PARs (protease-activated receptors) are a family of four G-protein-coupled receptors for proteases from the circulation, inflammatory cells and epithelial tissues. This report focuses on PAR2, which plays an important role in inflammation and pain. Pancreatic (trypsin I and II) and extrapancreatic (trypsin IV) trypsins, mast cell tryptase and coagulation factors VIIa and Xa cleave and activate PAR2. Proteases cleave PAR2 to expose a tethered ligand that binds to the cleaved receptor. Despite this irreversible activation, PAR2 signalling is attenuated by β-arrestin-mediated desensitization and endocytosis, and by lysosomal targeting and degradation, which requires ubiquitination of PAR2. β-Arrestins also act as scaffolds for the assembly of multi-protein signalling complexes that determine the location and function of activated mitogen-activated protein kinases. Observations of PAR2-deficient mice support a role for PAR2 in inflammation, and many of the effects of PAR2 activators promote inflammation. Inflammation is mediated in part by activation of PAR2 in the peripheral nervous system, which results in neurogenic inflammation and hyperalgesia.