Interaction of the mu-opioid receptor with GPR177 (Wntless) inhibits Wnt secretion: potential implications for opioid dependence.
Interaction of the mu-opioid receptor with GPR177 (Wntless) inhibits Wnt secretion: potential implications for opioid dependence.
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DOI：
10.1186/1471-2202-11-33
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发表时间：
2010-03-09
期刊：
影响因子：
2.4
通讯作者：
Levenson R
中科院分区：
文献类型：
--
作者：
Jin J;Kittanakom S;Wong V;Reyes BA;Van Bockstaele EJ;Stagljar I;Berrettini W;Levenson R
阿片激动剂药物产生镇痛作用。然而，长期接触阿片类激动剂可能导致阿片类药物依赖。阿片受体激动剂的镇痛和成瘾性主要是通过多阿片受体介导的。阿片受体激动剂似乎改变了与阿片依赖发展有关的关键脑区域的神经元形态。然而，MOR在这些神经元改变发展中的确切作用仍然难以捉摸。我们假设鉴定和表征新的MOR相互作用蛋白（MORIPs）可能有助于阐明涉及阿片类药物依赖发展的潜在机制。在改良的分裂泛素酵母双杂交筛选中，果蝇Wntless/Evi/Sprinter的哺乳动物同源基因GPR177被鉴定为MORIP。GPR177是一种进化保守蛋白，在介导Wnt产生细胞分泌Wnt蛋白中起关键作用。MOR/GPR177相互作用在哺乳动物组织培养细胞的下拉、共免疫沉淀和共定位研究中得到了验证。在啮齿类动物大脑中也观察到这种相互作用，MOR和GPR177在纹状体神经元中紧密地共表达。在细胞水平上，吗啡处理使GPR177的分布从胞浆向细胞表面转移，导致细胞外周MOR/GPR177复合物的形成增强，抑制Wnt蛋白的分泌。众所周知，慢性吗啡治疗可减少树突状树突和海马神经发生，而Wnt蛋白对这些过程至关重要。因此，我们提出吗啡介导的MOR/GPR177相互作用可能导致CNS中Wnt分泌减少，导致树突乔木萎缩和神经发生减少。我们的研究结果表明，GPR177在调节细胞对阿片类药物的反应中具有先前未被认识到的作用。
Opioid agonist drugs produce analgesia. However, long-term exposure to opioid agonists may lead to opioid dependence. The analgesic and addictive properties of opioid agonist drugs are mediated primarily via the mu-opioid receptor (MOR). Opioid agonists appear to alter neuronal morphology in key brain regions implicated in the development of opioid dependence. However, the precise role of the MOR in the development of these neuronal alterations remains elusive. We hypothesize that identifying and characterizing novel MOR interacting proteins (MORIPs) may help to elucidate the underlying mechanisms involved in the development of opioid dependence. GPR177, the mammalian ortholog of Drosophila Wntless/Evi/Sprinter, was identified as a MORIP in a modified split ubiquitin yeast two-hybrid screen. GPR177 is an evolutionarily conserved protein that plays a critical role in mediating Wnt protein secretion from Wnt producing cells. The MOR/GPR177 interaction was validated in pulldown, coimmunoprecipitation, and colocalization studies using mammalian tissue culture cells. The interaction was also observed in rodent brain, where MOR and GPR177 were coexpressed in close spatial proximity within striatal neurons. At the cellular level, morphine treatment caused a shift in the distribution of GPR177 from cytosol to the cell surface, leading to enhanced MOR/GPR177 complex formation at the cell periphery and the inhibition of Wnt protein secretion. It is known that chronic morphine treatment decreases dendritic arborization and hippocampal neurogenesis, and Wnt proteins are essential for these processes. We therefore propose that the morphine-mediated MOR/GPR177 interaction may result in decreased Wnt secretion in the CNS, resulting in atrophy of dendritic arbors and decreased neurogenesis. Our results demonstrate a previously unrecognized role for GPR177 in regulating cellular response to opioid drugs.
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影响因子：
16.2
作者：
Charlton, Joanna J.;Allen, Patrick B.;Zachariou, Venetia
通讯作者：
Zachariou, Venetia
DOI：
10.1073/pnas.120552597
发表时间：
2000-06-20
影响因子：
11.1
作者：
Eisch, AJ;Barrot, M;Nestler, EJ
通讯作者：
Nestler, EJ
影响因子：
3.3
作者：
Arguello AA;Harburg GC;Schonborn JR;Mandyam CD;Yamaguchi M;Eisch AJ
通讯作者：
Eisch AJ
DOI：
10.1007/978-1-59745-540-4_14
发表时间：
2009-01-01
期刊：
YEAST FUNCTIONAL GENOMICS AND PROTEOMICS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Kittanakom, Saranya;Chuk, Matthew;Stagljar, Igor
通讯作者：
Stagljar, Igor
影响因子：
0.9
作者：
Berrettini, W. H.;Alexander, R.;Vogel, W. H.
通讯作者：
Vogel, W. H.