Department of Pharmacology, School of Medicine, University of California, San Diego, Biomedical Sciences Building, Room 3044A, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
Mini Rev Med Chem. 2012 Aug;12(9):804-11. doi: 10.2174/138955712800959116.
The protease-activated receptors (PARs) are G protein-coupled receptors (GPCRs) that are uniquely activated by proteolysis. PARs mediate hemostasis, thrombosis, inflammation, embryonic development and progression of certain malignant cancers. The family of PARs include four members: PAR1, PAR2, PAR3 and PAR4. PARs harbor a cryptic ligand sequence within their N-terminus that is exposed following proteolytic cleavage. The newly formed PAR Nterminus functions as a tethered ligand that binds intramolecularly to the receptor to trigger transmembrane signaling. This unique mechanism of activation would indicate that regardless of the activating protease, cleavage of PARs would unmask a tethered ligand sequence that would induce a similar active receptor conformation and signaling response. However, this is not the case. Recent studies demonstrate that PARs can be differentially activated by synthetic peptide agonists, proteases or through dimerization, that ultimately result in distinct cellular responses. In some cases, allosteric modulation of PARs involves compartmentalization in caveolae, plasma membrane microdomains enriched in cholesterol. Here, we discuss some mechanisms that lead to allosteric modulation of PAR signaling.
蛋白酶激活受体（PARs）是一种独特的被蛋白水解激活的 G 蛋白偶联受体（GPCRs）。PARs 参与止血、血栓形成、炎症、胚胎发育以及某些恶性肿瘤的进展。PAR 家族包括四个成员：PAR1、PAR2、PAR3 和 PAR4。PARs 的 N 端含有一个隐藏的配体序列，在蛋白水解切割后暴露出来。新形成的 PAR N 端作为一个连接配体，与受体分子内结合，引发跨膜信号转导。这种独特的激活机制表明，无论激活蛋白酶如何，PAR 的切割都会暴露出一个连接的配体序列，从而诱导相似的活性受体构象和信号反应。然而，事实并非如此。最近的研究表明，PAR 可以通过合成肽激动剂、蛋白酶或通过二聚化来进行差异激活，最终导致不同的细胞反应。在某些情况下，PAR 的变构调节涉及到质膜微域中胆固醇富集的 caveolae 的分隔化。在这里，我们讨论了导致 PAR 信号变构调节的一些机制。
