Multiple actions of spinophilin regulate mu opioid receptor function
Multiple actions of spinophilin regulate mu opioid receptor function
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DOI：
10.1016/j.neuron.2008.02.006
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发表时间：
2008-04-24
期刊：
影响因子：
16.2
通讯作者：
Zachariou, Venetia
中科院分区：
文献类型：
--
作者：
Charlton, Joanna J.;Allen, Patrick B.;Zachariou, Venetia
亲刺蛋白是一种富含树突棘的支架蛋白，它通过蛋白质不同结构域介导的多种功能来调节突触传递。在这里，我们证明了亲棘素是阿片类药物作用的关键调节剂。SPIN基因敲除导致对吗啡止痛作用的敏感性降低，并早期形成耐受性，但对身体的依赖程度更高，对药物的有益作用更敏感。在细胞水平上，亲棘素与纹状体内的阿片受体(MOR)结合，调节MOR信号和内吞作用。阿片激动剂如芬太尼和吗啡激活MOR促进了这些事件，这些事件反馈抑制MOR的反应。我们的发现支持了亲刺蛋白在调节MOR功能中的强大生理作用，并为阿片成瘾的治疗提供了一个潜在的新靶点。
Spinophilin, a dendritic spine-enriched scaffold protein, modulates synaptic transmission via multiple functions mediated by distinct domains of the protein. Here, we show that spinophilin is a key modulator of opiate action. Knockout of the spinophilin gene causes reduced sensitivity to the analgesic effects of morphine and early development of tolerance but a higher degree of physical dependence and increased sensitivity to the rewarding actions of the drug. At the cellular level, spinophilin associates with the mu opioid receptor (MOR) in striatum and modulates MOR signaling and endocytosis. Activation of MOR by opiate agonists such as fentanyl and morphine promotes these events, which feedback to suppress MOR responsiveness. Our findings support a potent physiological role of spinophilin in regulating MOR function and provide a potential new target for the treatment of opiate addiction.