Activated thrombin (factor IIa) cleaves PAR3,4, activating them

Thrombin signaling is mediated at least in part by a small family of G protein-coupled Proteinase Activated Receptors (PARs). Human platelet activation by thrombin is mediated predominantly by PAR1; PAR4-induced platelet responses are less pronounced. PAR2 is not present in human platelets. PARs 1, 3 and 4 are activated when thrombin cleaves an 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. 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.

凝血酶信号传导至少部分由一小族G蛋白偶联蛋白酶激活受体（PARs）介导。人类血小板在凝血酶作用下主要通过与PAR1相互作用而被激活；由PAR4诱导的血小板反应则相对不显著。人类血小板中不存在PAR2。当凝血酶切割PAR1的N端外结构域时，PARs 1、3和4被激活。这一切割事件暴露出一个新的N端，该端作为连接配体，与受体的主体部分内分子结合，从而实现跨膜信号传导。一个PAR分子通过另一个PAR分子进行分子间交联是可能的，但不出所料，其效率似乎低于自交联。一种合成的序列为SFLLRN的肽段，即凝血酶切割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。除了为连接配体机制提供证据之外，此类模拟连接配体的肽段还提供了一种便捷的药理学工具，用于研究PAR激活在细胞和组织中的效应。