Protease-activated receptor 2: activation, signalling and function

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.