Functional specificity of ADP-(P2Y12)-like receptors

ADP-(P2Y12) 样受体的功能特异性

• 批准号: 32952146
• 负责人: Dr. Angela Schulz
• 金额: --
• 依托单位: Rudolf-Schönheimer-Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/32952146?language=en
• 关键词: Functional; specificity; ADP; P2Y12; like

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.

代谢性核苷酸受体（P2YR）属于GPCR的超家族。在过去的十年中，已经表征了八个功能性P2YR亚型。最近，包括氯吡格雷敏感的ADP受体在内的P2Y12样受体组的成员已被脱氧化。 P2Y12样受体不仅在血小板上表达，而且在中枢神经系统中也很丰富。尽管对不同的核苷酸的选择性高度选择性，但白细胞和PRPP是P2Y12样受体上的其他激动剂。在白细胞和UDP都激活受体的半胱氨酸丁丁三烯受体中，也可以看到一种激动剂的滥交。高核苷酸特异性，但激动剂的滥交以及这种异常激动性结合行为的生理相关性的结构基础仍然未知。我们将首先通过对P2Y12样受体的激动剂特异性和滥交结构的系统分子分析来解决这一现象，其次，通过对ADP或Leukotrienes的受限激动剂结合特性的P2Y12受体的产生和表征。从这些协同研究中，我们期望激活机制的全面表征以及在体内p2Y12样受体中激动剂滥交的生理相关性。

项目成果

Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

• DOI: 10.1124/mol.112.082198
• 发表时间: 2013-01-01
• 期刊: MOLECULAR PHARMACOLOGY
• 影响因子: 3.6
• 作者: Schmidt, Philipp;Ritscher, Lars;Schoeneberg, Torsten
• 通讯作者: Schoeneberg, Torsten