Functional specificity of ADP-(P2Y12)-like receptors

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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.