Functional specificity of ADP-(P2Y12)-like receptors

代谢性核苷酸受体(P2YR)属于GPCR超家族。在过去的十年里，已经描述了八种功能性的P2YR亚型。最近，包括对氯吡格雷敏感的ADP受体在内的类P2Y12受体的成员已经去孤儿。P2Y12样受体不仅在血栓细胞中表达，而且在中枢神经系统中也高度丰富。尽管对不同的核苷酸具有高度的选择性，白三烯和PRPP是P2Y12样受体上的额外激动剂；半胱氨酰白三烯受体也可以看到这种激动剂的混杂，其中白三烯和UDP都激活受体。高核苷酸特异性的结构基础，但激动剂的混杂，以及这种不寻常的激动剂结合行为的生理相关性仍不清楚。我们将首先通过对P2Y12样受体中激动剂专一性和混杂决定结构的系统分子分析来解决这一现象，其次，通过产生和表征携带与ADP或白三烯具有受限激动剂结合特性的P2Y12受体的敲入小鼠。我们期望通过这些协调一致的研究，在活体水平上全面描述P2Y12样受体中激动剂混杂的激活机制和生理相关性。

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.