Protease-Activated Receptor 4: A Critical Participator in Inflammatory Response
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Protease-Activated Receptor 4: A Critical Participator in Inflammatory Response Qiang Fu,1 Jing Cheng,2 Yebo Gao,3 Yonglei Zhang,1 Xiaobing Chen,1 and Jianguo Xie1,4
Abstract—Protease-activated receptors (PARs) are G protein-coupled receptors of which four members PAR1, PAR2, PAR3, and PAR4 have been identified, characterized by a typical mechanism of activation involving various related proteases. The amino-terminal sequence of PARs is cleaved by a broad array of proteases, leading to specific proteolytic cleavage which forms endogenous tethered ligands to induce agonist-biased PAR activation. The biological effect of PARs activated by coagulation proteases to regulate hemostasis and thrombosis plays an enormous role in the cardiovascular system, while PAR4 can also be activated by trypsin, cathepsin G, the activated factor X of the coagulation cascade, and trypsin IV. Irrespective of its role in thrombin-induced platelet aggregation, PAR4 activation is believed to be involved in inflammatory lesions, as show by investigations that have unmasked the effects of PAR4 on neutrophil recruitment, the regulation of edema, and plasma extravasation. This review summarizes the roles of PAR4 in coagulation and other extracellular protease pathways, which activate PAR4 to participate in normal regulation and disease. KEY WORDS: protease-activated receptor 4; inflammation; mechanisms; coagulation.
INTRODUCTION The protease-activated receptors (PARs) belong to a developing family of four transmembrane G proteincoupled receptors (GCPR) activated by a unique mode, underlined by the proteolytic cleavage of their extracellular N-terminal domain. After the interaction with various proteases, this cleavage site releases a new N-terminal domain that acts as a tethered ligand to induce an intracellular signal by linking the receptor itself to its second extracellular loop [1–5]. Four members of the PARs family, PAR1, PAR3, and PAR4, have been cloned [3, 6, 7] as thrombin receptors, since they have been shown to be responsible for thrombin-induced platelet activation. PAR1, 3, and 4 were Qiang Fu and Jing Cheng are co-first authors; they contributed equally to the work. 1
Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, China 2 Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, China 3 Guang’anmen Hospital, China Academy of Chinese Medical Science, Beijing, 100053, China 4 To whom correspondence should be addressed at Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, China. E-mail: [email protected]
initially recognized as receptors for the coagulation protease and are involved in thrombin signaling, mainly as a heterodimer [8–11]. In addition, PAR1 activation is induced by other coagulation proteases [12, 13], matrix metalloproteinase 1 [14], and microbial proteases [15]. PAR2 is activated by a series of extracellular proteases including coagulation factors, trypsin, tryptase, tissue kallikreins, and transmembr
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