Induced association of mu opioid (MOP) and type 2 cholecystokinin (CCK2) receptors by novel bivalent ligands.
Induced association of mu opioid (MOP) and type 2 cholecystokinin (CCK2) receptors by novel bivalent ligands.
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通过新型二价配体诱导 mu 阿片类药物 (MOP) 和 2 型胆囊收缩素 (CCK2) 受体的结合。
DOI：
10.1021/jm800174p
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发表时间：
2009
影响因子：
7.3
通讯作者：
Portoghese,PhilipS
中科院分区：
文献类型：
--
作者：
Zheng,Yaguo;Akgün,Eyup;Harikumar,KaleeckalG;Hopson,Jessika;Powers,MichaelD;Lunzer,MaryM;Miller,LaurenceJ;Portoghese,PhilipS
μ-阿片样物质（MOP）和2型胆囊收缩素（CCK 2）受体都存在于中枢神经系统的区域，参与疼痛处理的调节。我们对共表达MOP和CCK 2受体的COS细胞进行了生物发光共振能量转移（BRET）研究，以确定受体异源二聚化是否参与了这种调节。这些研究揭示了不存在组成型或单价配体诱导的异源二聚化。因此，MOP和CCK 2受体的异源二聚化不太可能是吗啡和CCK在CNS中的相反作用的原因。然而，如BRET阳性信号所示，当细胞暴露于含有μ-阿片激动剂和CCK 2受体拮抗剂药效团的二价配体时，诱导了缔合，所述药效团通过含有16−22个原子的间隔基连接，但不与较短（9个原子）的间隔基连接。这些研究首次证明，适当设计的二价配体能够诱导G蛋白偶联受体的结合。在小鼠中用这些配体进行的阿片耐受性研究显示与BRET数据无相关性，这一发现与体内MOP和CCK 2受体不存在相关性一致。
Both μ-opioid (MOP) and type 2 cholecystokinin (CCK2) receptors are present in areas of the central nervous system that are involved in modulation of pain processing. We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK2receptors to determine whether receptor heterodimerization is involved in such modulation. These studies revealed the absence of constitutive or monovalent ligand-induced heterodimerization. Heterodimerization of MOP and CCK2receptors therefore is unlikely to be responsible for the opposing effects between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing μ-opioid agonist and CCK2receptor antagonist pharmacophores linked through spacers containing 16−22 atoms but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand is capable of inducing association of G-protein-coupled receptors. The finding that opioid tolerance studies with these ligands in mice showed no correlation with the BRET data is consistent with the absence of association of MOP and CCK2receptors in vivo.