NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum.
NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum.
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DOI：
10.1016/j.cub.2016.09.010
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发表时间：
2016-11-21
期刊：
影响因子：
9.2
通讯作者：
Martemyanov, Kirill A.
中科院分区：
文献类型：
--
作者：
Xie, Keqiang;Colgan, Lesley A.;Dao, Maria T.;Muntean, Brian S.;Sutton, Laurie P.;Orlandi, Cesare;Boye, Sanford L.;Boye, Shannon E.;Shih, Chien-Cheng;Li, Yuqing;Xu, Baoji;Smith, Roy G.;Yasuda, Ryohei;Martemyanov, Kirill A.
众所周知，gpcr可以激活ras调控的激酶途径，从而产生神经元功能的持久变化。gpcr转导这些信号的机制及其与脑部疾病的相关性尚不清楚。在这里，我们发现了一个主要的Ras调节因子，神经纤维蛋白1 (NF1)，作为GPCR信号通过纹状体中的Gβγ亚基的直接效应者。我们发现Gβγ与NF1的结合抑制了其灭活Ras的能力。纹状体神经元中NF1的缺失阻止了阿片受体诱导的Ras激活，并消除了其与Akt-mTOR信号通路的偶联。NF1通过作用于直接通路的纹状体中棘神经元，调节阿片诱导的Ras活性变化，从而使小鼠对吗啡的精神运动和奖励作用敏感。这些结果描述了GPCR信号传导到Ras通路的新机制，并确立了NF1在阿片类药物成瘾中的关键作用。
It is well recognized that, GPCRs can activate Ras-regulated kinase pathways to produce lasting changes in neuronal function. Mechanisms by which GPCRs transduce these signals and their relevance to brain disorders are not well understood. Here we identified a major Ras regulator, neurofibromin 1 (NF1), as a direct effector of GPCR signaling via Gβγ subunits in the striatum. We found that binding of Gβγ to NF1 inhibited its ability to inactivate Ras. Deletion of NF1 in striatal neurons prevented the opioid receptor induced activation of Ras and eliminated its coupling to Akt-mTOR signaling pathway. By acting in the striatal medium spiny neurons of the direct pathway, NF1 regulates opioid induced changes in Ras activity thereby sensitizing mice to psychomotor and rewarding effects of morphine. These results delineate a novel mechanism of GPCR signaling to Ras pathways and establish a critical role of NF1 in opioid addiction.
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DOI：
10.1124/jpet.104.066548
发表时间：
2004-08-01
影响因子：
3.5
作者：
Muller, DL;Unterwald, EM
通讯作者：
Unterwald, EM
DOI：
10.1073/pnas.1019012108
发表时间：
2011-09-20
影响因子：
11.1
作者：
Banerjee, Sutapa;Crouse, Nikkilina R.;Gutmann, David H.
通讯作者：
Gutmann, David H.
影响因子：
5.3
作者：
Brown, Jacquelyn A.;Xu, Jinbin;Gutmann, David H.
通讯作者：
Gutmann, David H.
影响因子：
3.8
作者：
Acosta, Maria T.;Kardel, Peter G.;Packer, Roger J.
通讯作者：
Packer, Roger J.
影响因子：
14.5
作者：
Créange, A;Zeller, J;Wolkenstein, P
通讯作者：
Wolkenstein, P