Activated thrombin (factor IIa) cleaves F2R (PAR1), activating it

Thrombin activates proteinase activated receptors (PARs) that signal through heterotrimeric G proteins of the G12/13 and Gq families. In human platelets, PAR1 (F2R) is the predominant thrombin receptor (Vu et al. 1991). Gq is necessary for platelet secretion and aggregation in response to thrombin but is not necessary for thrombin-triggered shape change. G13 appears to contribute to platelet aggregation as well as shape change in response to low concentrations of thrombin but to be unnecessary at higher agonist concentrations; G12 appears to be dispensable for thrombin signaling in platelets.<br><br>The proprotein form of F2R is activated when thrombin cleaves the N-terminal exodomain. This cleavage event unmasks a new N-terminus that serves as a tethered ligand that binds intramolecularly to the body of the receptor to effect transmembrane signaling (Vu et al. 1991). Intermolecular ligation of one PAR molecule by another can occur but, not surprisingly, appears to be less efficient than self-ligation. A synthetic peptide of sequence SFLLRN, the first six amino acids of the new N-terminus generated when thrombin cleaves PAR1, can activate PAR1 independent of protease and receptor cleavage. In addition to providing evidence for the tethered ligand mechanism, such tethered ligand-mimicking peptides have provided a convenient pharmacological tool for probing the effects of PAR activation in cells and tissues.

凝血酶激活蛋白水解酶激活受体（PARs），这些受体通过G12/13和Gq家族的异源三聚体G蛋白进行信号传递。在人类血小板中，PAR1（F2R）是主要的凝血酶受体（Vu等，1991年）。Gq对于血小板在凝血酶作用下的分泌和聚集是必需的，但并不参与凝血酶触发的形态变化。G13似乎在低浓度凝血酶作用下参与血小板聚集和形态变化，但在较高激动剂浓度下则并非必需；G12似乎对于血小板中的凝血酶信号传递并非必需。F2R的前体蛋白在凝血酶切割N端外显域时被激活。这一切割事件揭示了新的N端，该端作为锚定配体与受体的主体部分进行分子内结合，从而实现跨膜信号传递（Vu等，1991年）。一个PAR分子可以通过另一个分子发生分子间交联，但不出所料，这种交联似乎比自交联效率低。序列为SFLLRN的合成肽，它是凝血酶切割PAR1时生成的新N端的头六个氨基酸，可以独立于蛋白酶和受体切割激活PAR1。除了为锚定配体机制提供证据外，这类模拟锚定配体的肽还提供了一种便捷的药理学工具，用于探究PAR激活在细胞和组织中的效应。