Ossovskaya Valeria S, Bunnett Nigel W
Room C317, UCSF, 513 Parnassus Ave., San Francisco, CA 94143-0660, USA.
Physiol Rev. 2004 Apr;84(2):579-621. doi: 10.1152/physrev.00028.2003.
Proteases acting at the surface of cells generate and destroy receptor agonists and activate and inactivate receptors, thereby making a vitally important contribution to signal transduction. Certain serine proteases that derive from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast cell and neutrophil proteases), and from multiple other sources (e.g., epithelial cells, neurons, bacteria, fungi) can cleave protease-activated receptors (PARs), a family of four G protein-coupled receptors. Cleavage within the extracellular amino terminus exposes a tethered ligand domain, which binds to and activates the receptors to initiate multiple signaling cascades. Despite this irreversible mechanism of activation, signaling by PARs is efficiently terminated by receptor desensitization (receptor phosphorylation and uncoupling from G proteins) and downregulation (receptor degradation by cell-surface and lysosomal proteases). Protease signaling in tissues depends on the generation and release of proteases, availability of cofactors, presence of protease inhibitors, and activation and inactivation of PARs. Many proteases that activate PARs are produced during tissue damage, and PARs make important contributions to tissue responses to injury, including hemostasis, repair, cell survival, inflammation, and pain. Drugs that mimic or interfere with these processes are attractive therapies: selective agonists of PARs may facilitate healing, repair, and protection, whereas protease inhibitors and PAR antagonists can impede exacerbated inflammation and pain. Major future challenges will be to understand the role of proteases and PARs in physiological control mechanisms and human diseases and to develop selective agonists and antagonists that can be used to probe function and treat disease.
作用于细胞表面的蛋白酶可生成并破坏受体激动剂，激活和失活受体，从而对信号转导起到至关重要的作用。某些源自循环系统（如凝血因子）、炎症细胞（如肥大细胞和中性粒细胞蛋白酶）以及多种其他来源（如上皮细胞、神经元、细菌、真菌）的丝氨酸蛋白酶能够切割蛋白酶激活受体（PARs），这是一个由四个G蛋白偶联受体组成的家族。细胞外氨基末端的切割会暴露出一个拴系配体结构域，该结构域与受体结合并激活受体，从而启动多个信号级联反应。尽管存在这种不可逆的激活机制，但PARs的信号传导可通过受体脱敏（受体磷酸化以及与G蛋白解偶联）和下调（通过细胞表面和溶酶体蛋白酶进行受体降解）而有效终止。组织中的蛋白酶信号传导取决于蛋白酶的生成和释放、辅因子的可用性、蛋白酶抑制剂的存在以及PARs的激活和失活。许多激活PARs的蛋白酶是在组织损伤期间产生的，PARs对组织对损伤的反应起着重要作用，包括止血、修复、细胞存活、炎症和疼痛。模拟或干扰这些过程的药物是有吸引力的治疗方法：PARs的选择性激动剂可能促进愈合、修复和保护，而蛋白酶抑制剂和PAR拮抗剂可阻碍炎症和疼痛的加剧。未来的主要挑战将是了解蛋白酶和PARs在生理控制机制和人类疾病中的作用，并开发可用于探究功能和治疗疾病的选择性激动剂和拮抗剂。
