Hansen Kristina K, Oikonomopoulou Katerina, Baruch Amos, Ramachandran Rithwik, Beck Paul, Diamandis Eleftherios P, Hollenberg Morley D
Proteinases and Inflammation Network, University of Calgary Faculty of Medicine, Calgary T2N 4N1, AB, Canada.
Biol Chem. 2008 Aug;389(8):971-82. doi: 10.1515/BC.2008.120.
Proteinases, such as kallikrein-related peptidases, trypsin and thrombin, can play hormone-like 'messenger roles in vivo. They can regulate cell signaling by cleaving and activating a novel family of G-protein-coupled proteinase-activated receptors (PARs 1-4) by unmasking a tethered receptor-triggering ligand. Short synthetic PAR-derived peptide sequences (PAR-APs) can selectively activate PARs 1, 2 and 4, causing physiological responses in vitro and in vivo. Using the PAR-APs to activate the receptors in vivo, it has been found that PARs, like hormone receptors, can affect the vascular, renal, respiratory, gastrointestinal, musculoskeletal and nervous systems (central and peripheral). PARs trigger responses ranging from vasodilatation to intestinal inflammation, increased cytokine production and increased nociception. These PAR-stimulated responses have been implicated in various disease states, including cancer, atherosclerosis, asthma, arthritis, colitis and Alzheimer's disease. In addition to targeting the PARs, proteinases can also cause hormone-like effects by other signaling mechanisms that may be as important as the activation of PARs. Thus, the PARs themselves, their activating serine proteinases and their signaling pathways can be considered as attractive targets for therapeutic drug development. Further, proteinases can be considered as physiologically relevant 'hormone-like' messengers that can convey signals locally or systemically either via PARs or by other mechanisms.
蛋白酶，如激肽释放酶相关肽酶、胰蛋白酶和凝血酶，在体内可发挥类似激素的“信使作用”。它们可通过切割并激活一类新的G蛋白偶联蛋白酶激活受体（PARs 1 - 4）来调节细胞信号传导，方式是暴露一个拴系的受体触发配体。短的合成PAR衍生肽序列（PAR - APs）可选择性激活PARs 1、2和4，在体外和体内引发生理反应。利用PAR - APs在体内激活这些受体后发现，PARs与激素受体类似，可影响血管、肾脏、呼吸、胃肠、肌肉骨骼和神经系统（中枢和外周）。PARs引发的反应范围从血管舒张到肠道炎症、细胞因子产生增加以及痛觉增强。这些PAR刺激的反应与多种疾病状态有关，包括癌症、动脉粥样硬化、哮喘、关节炎、结肠炎和阿尔茨海默病。除了作用于PARs，蛋白酶还可通过其他可能与激活PARs同样重要的信号传导机制产生类似激素的效应。因此，PARs本身、其激活丝氨酸蛋白酶及其信号通路可被视为治疗药物开发的有吸引力的靶点。此外，蛋白酶可被视为生理上相关的“类激素”信使，它们可通过PARs或其他机制在局部或全身传递信号。
