Although generally regarded as degradatory enzymes, certain proteases are also signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation, from immune, inflammatory epithelial and cancer cells, as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.

中文翻译：

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健康和疾病中的蛋白酶激活受体

虽然通常被认为是降解酶，但某些蛋白酶也是通过切割蛋白酶激活受体 (PAR) 特异性控制细胞功能的信号分子。四种已知的 PAR 是 G 蛋白偶联受体大家族的成员。这些跨膜受体控制着大部分生理和病理过程，是大部分治疗药物的靶标。信号转导蛋白酶包括来自循环系统、免疫细胞、炎症上皮细胞和癌细胞以及共生菌和致病菌的酶。我们对 PAR 的结构和功能的理解的进展提供了对不同蛋白酶如何激活这些受体以调节大多数组织和器官系统中的生理和病理过程的见解。认识到蛋白酶和 PAR 是疾病的关键介质，再加上对 PAR 的原子级结构及其在亚细胞微域中的信号传导机制的理解取得进展，刺激了拮抗剂的开发，其中一些已进入临床。在此，我们回顾了该受体系统的发现、结构和功能，强调了 PARs 对稳态控制的贡献，并讨论了 PAR 拮抗剂治疗重大疾病的潜力。