Cottrell G S, Amadesi S, Schmidlin F, Bunnett N
Departments of Surgery and Physiology, University of California-San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, U.S.A.
Biochem Soc Trans. 2003 Dec;31(Pt 6):1191-7. doi: 10.1042/bst0311191.
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 PAR(2), 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 PAR(2). Proteases cleave PAR(2) to expose a tethered ligand that binds to the cleaved receptor. Despite this irreversible activation, PAR(2) signalling is attenuated by beta-arrestin-mediated desensitization and endocytosis, and by lysosomal targeting and degradation, which requires ubiquitination of PAR(2). beta-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 PAR(2)-deficient mice support a role for PAR(2) in inflammation, and many of the effects of PAR(2) activators promote inflammation. Inflammation is mediated in part by activation of PAR(2) in the peripheral nervous system, which results in neurogenic inflammation and hyperalgesia.
蛋白酶激活受体（PARs）是一类由四种G蛋白偶联受体组成的家族，可被循环系统、炎症细胞和上皮组织中的蛋白酶激活。本报告重点关注PAR(2)，它在炎症和疼痛中起重要作用。胰腺（胰蛋白酶I和II）和胰腺外（胰蛋白酶IV）的胰蛋白酶、肥大细胞组织蛋白酶以及凝血因子VIIa和Xa可切割并激活PAR(2)。蛋白酶切割PAR(2)以暴露与切割后的受体结合的拴系配体。尽管这种激活是不可逆的，但PAR(2)信号传导可通过β-抑制蛋白介导的脱敏和内吞作用，以及通过溶酶体靶向和降解而减弱，这需要PAR(2)的泛素化。β-抑制蛋白还作为多蛋白信号复合物组装的支架，这些复合物决定了活化的丝裂原活化蛋白激酶的位置和功能。对PAR(2)缺陷小鼠的观察支持PAR(2)在炎症中的作用，并且PAR(2)激活剂的许多作用会促进炎症。炎症部分是由外周神经系统中PAR(2)的激活介导的，这会导致神经源性炎症和痛觉过敏。
