Differential Response to Morphine of the Oligomeric State of μ-Opioid in the Presence of δ-Opioid Receptors
Differential Response to Morphine of the Oligomeric State of μ-Opioid in the Presence of δ-Opioid Receptors
复制标题
DOI：
10.1021/bi101701x
复制
发表时间：
2011-04-12
期刊：
影响因子：
2.9
通讯作者：
Scarlate, Suzanne
中科院分区：
文献类型：
--
作者：
Golebiewska, Urszula;Johnston, Jennifer M.;Scarlate, Suzanne
延长吗啡治疗会导致 p-阿片受体 (mu OR) 广泛脱敏，p-阿片受体是 G 蛋白偶联受体，主要介导细胞对吗啡的反应。迄今为止，这一过程背后的分子机制尚不清楚。在这里，我们使用活细胞荧光成像来研究延长吗啡治疗是否会影响两个神经元细胞系中 mu OR 的物理环境或其与 G 蛋白的偶联。我们发现长期吗啡治疗不会改变质膜上增强型黄色荧光蛋白（eYFP）标记的 mu OR 的量，并且仅略微降低其与 G 蛋白亚基的关联。此外，吗啡治疗对 eYFP-mu OR 的扩散系数没有可检测到的影响。然而，在另一个家族成员δ-阿片受体（δ OR）存在的情况下，长时间的吗啡暴露会导致mu OR的扩散速率显着增加。数字和亮度测量表明，mu OR主要以二聚体形式存在，它将与δ OR寡聚成四聚体，并且吗啡促进这些四聚体的解离。为了给这些数据提供合理的结构背景，我们使用同源建模技术来生成 mu OR-delta OR 四聚体的假定配置。总的来说，我们的研究为吗啡敏感性提供了可能的原理。
Prolonged morphine treatment induces extensive desensitization of the p-opioid receptor (mu OR) which is the G-protein-coupled receptor that primarily mediates the cellular response to morphine. To date, the molecular mechanism underlying this process is unknown. Here, we have used live cell fluorescence imaging to investigate whether prolonged morphine treatment affects the physical environment of mu OR, or its coupling with G-proteins, in two neuronal cell lines. We find that chronic morphine treatment does not change the amount of enhanced yellow fluorescence protein (eYFP)-tagged mu OR on the plasma membrane, and only slightly decreases its association with G-protein subunits. Additionally, morphine treatment does not have a detectable effect on the diffusion coefficient of eYFP-mu OR. However, in the presence of another family member, the delta-opioid receptor (delta OR), prolonged morphine exposure results in a significant increase in the diffusion rate of mu OR Number and brightness measurements suggest that mu OR exists primarily as a dimer that will oligomerize with delta OR into tetramers, and morphine promotes the dissociation of these tetramers. To provide a plausible structural context to these data, we used homology modeling techniques to generate putative configurations of mu OR-delta OR tetramers. Overall, our studies provide a possible rationale for morphine sensitivity.