Functional specificity of ADP-(P2Y12)-like receptors

代谢型核苷酸受体（P2 YR）属于GPCR超家族。在过去的十年中，八个功能性P2 YR亚型已被表征。最近，P2 Y12样受体组的成员，包括氯吡格雷敏感的ADP受体，已被去活化。P2 Y12样受体不仅在血小板中表达，而且在CNS中也高度丰富。虽然对不同的核苷酸具有高度选择性，但白三烯和PRPP是P2 Y12样受体的额外激动剂;对于半胱氨酰白三烯受体也观察到激动剂混杂性，其中白三烯和UDP都激活受体。高核苷酸特异性但激动剂混杂的结构基础和这种不寻常的激动剂结合行为的生理相关性仍然未知。我们将解决这一现象，首先通过系统的分子分析的激动剂特异性和滥交决定结构的P2 Y12样受体，第二，通过产生和表征的敲入小鼠携带P2 Y12受体与限制激动剂结合特性的ADP或白三烯。我们期望从这些协调一致的研究的激活机制和激动剂混杂在P2 Y12样受体在体内水平的生理相关性的全面表征。

Metabotropic nucleotide receptors (P2YR) belong to the superfamily of GPCR. Over the past decade eight functional P2YR subtypes have been characterized. Most recently, members of the P2Y12-like receptor group, which includes the clopidogrel-sensitive ADP receptor, have been deorphanized. P2Y12-like receptors are not only expressed at thrombocytes but are also highly abundant in the CNS. Although highly selective towards distinct nucleotides, leukotrienes and PRPP are additional agonists on P2Y12-like receptors; an agonist promiscuity that has also be seen for cysteinylleukotriene receptors where both, leukotrienes and UDP, activate the receptors. The structural basis of the high nucleotide specificity but agonist promiscuity and the physiological relevance of this unusual agonist binding behaviour are still unknown. We will address this phenomenon first by a systematic molecular analysis of agonist specificity and of promiscuity-determining structures in P2Y12-like receptors, and second, by generation and characterization of knock-in mice carrying a P2Y12 receptor with restricted agonist binding properties for either ADP or leukotrienes. We expect from these concerted studies the comprehensive characterization of the activation mechanisms and of the physiological relevance of agonist promiscuity in P2Y12-like receptors at the in vivo level.