Grant Andrew, Amadesi Silvia, Bunnett Nigel W.
University of California, San Francisco
Proteolytic enzymes comprise approximately 2 percent of the human genome [1]. Given their abundance, it is not surprising that proteases have diverse biological functions, ranging from the degradation of proteins in lysosomes to the control of physiological processes such as the coagulation cascade. However, a subset of serine proteases (possessing serine residues within their catalytic sites), which may be soluble in the extracellular fluid or tethered to the plasma membrane, are signaling molecules that can specifically regulate cells by cleaving protease-activated receptors (PARs), a family of four G-protein-coupled receptors (GPCRs). These serine proteases include members of the coagulation cascade (e.g., thrombin, factor VIIa, and factor Xa), proteases from inflammatory cells (e.g., mast cell tryptase, neutrophil cathepsin G), and proteases from epithelial tissues and neurons (e.g., trypsins). They are often generated or released during injury and inflammation, and they cleave PARs on multiple cell types, including platelets, endothelial and epithelial cells, myocytes, fibroblasts, and cells of the nervous system. Activated PARs regulate many essential physiological processes, such as hemostasis, inflammation, pain, and healing. These proteases and their receptors have been implicated in human disease and are potentially important targets for therapy. Proteases and PARs participate in regulating most organ systems and are the subject of several comprehensive reviews [2, 3]. Within the central and peripheral nervous systems, proteases and PARs can control neuronal and astrocyte survival, proliferation and morphology, release of neurotransmitters, and the function and activity of ion channels, topics that have also been comprehensively reviewed [4, 5]. This chapter specifically concerns the ability of PARs to regulate TRPV channels of sensory neurons and thereby affect neurogenic inflammation and pain transmission [6, 7].
蛋白水解酶约占人类基因组的2%[1]。鉴于其丰富性，蛋白酶具有多种生物学功能也就不足为奇了，从溶酶体中蛋白质的降解到诸如凝血级联反应等生理过程的控制。然而，一部分丝氨酸蛋白酶（在其催化位点内含有丝氨酸残基），它们可能可溶于细胞外液或与质膜相连，是通过裂解蛋白酶激活受体（PARs）来特异性调节细胞的信号分子，PARs是一个由四个G蛋白偶联受体（GPCRs）组成的家族。这些丝氨酸蛋白酶包括凝血级联反应的成员（如凝血酶、因子VIIa和因子Xa）、炎症细胞的蛋白酶（如肥大细胞组织蛋白酶、中性粒细胞组织蛋白酶G）以及上皮组织和神经元的蛋白酶（如胰蛋白酶）。它们通常在损伤和炎症过程中产生或释放，并在多种细胞类型上裂解PARs，包括血小板、内皮细胞和上皮细胞、心肌细胞、成纤维细胞以及神经系统的细胞。激活的PARs调节许多重要的生理过程，如止血、炎症、疼痛和愈合。这些蛋白酶及其受体与人类疾病有关，并且可能是重要的治疗靶点。蛋白酶和PARs参与调节大多数器官系统，并且是几篇综述的主题[2,3]。在中枢和外周神经系统中，蛋白酶和PARs可以控制神经元和星形胶质细胞的存活、增殖和形态、神经递质的释放以及离子通道的功能和活性，这些主题也已经有了全面的综述[4,5]。本章特别关注PARs调节感觉神经元的TRPV通道从而影响神经源性炎症和疼痛传递的能力[6,7]。
