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
Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
Max Planck Florida Institute for Neuroscience, 1 Max Planck Way, Jupiter, FL 33458, USA.
Curr Biol. 2016 Nov 21;26(22):2992-3003. doi: 10.1016/j.cub.2016.09.010. Epub 2016 Oct 20.
It is well recognized that G-protein-coupled receptors (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 identify a major Ras regulator, neurofibromin 1 (NF1), as a direct effector of GPCR signaling via Gβγ subunits in the striatum. We find that binding of Gβγ to NF1 inhibits its ability to inactivate Ras. Deletion of NF1 in striatal neurons prevents the opioid-receptor-induced activation of Ras and eliminates 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.
众所周知，G蛋白偶联受体（GPCRs）可激活Ras调节的激酶途径，从而在神经元功能上产生持久变化。GPCRs转导这些信号的机制及其与脑部疾病的相关性尚不清楚。在此，我们确定一种主要的Ras调节因子神经纤维瘤蛋白1（NF1）是纹状体中通过Gβγ亚基介导的GPCR信号传导的直接效应器。我们发现Gβγ与NF1的结合会抑制其使Ras失活的能力。纹状体神经元中NF1的缺失可阻止阿片受体诱导的Ras激活，并消除其与Akt-mTOR信号通路的偶联。通过作用于直接通路的纹状体中等棘状神经元，NF1调节阿片类药物诱导的Ras活性变化，从而使小鼠对吗啡的精神运动和奖赏效应敏感。这些结果阐明了GPCR信号传导至Ras途径的新机制，并确立了NF1在阿片类药物成瘾中的关键作用。
