CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice
CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice
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DOI：
10.1038/emboj.2010.120
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发表时间：
2010-07-21
期刊：
影响因子：
11.4
通讯作者：
Dikic, Ivan
中科院分区：
文献类型：
--
作者：
Shimokawa, Noriaki;Haglund, Kaisa;Dikic, Ivan
尽管人们对85 kDa的Cbl-interacting protein（CIN 85）在受体转运和细胞骨架动力学中的作用进行了广泛的研究，但对其在体内的功能知之甚少。在这里，我们报告了一个小鼠缺乏的两个CIN 85异构体在中枢神经系统中表达的研究，暴露的功能CIN 85多巴胺受体内吞。缺乏CIN 85外显子2（CIN 85（Delta ex 2））的小鼠表现出多动表型，其特征在于增加的体力活动和探索行为。有趣的是，CIN 85（Delta ex 2）动物在纹状体中显示出异常高水平的多巴胺和D2多巴胺受体（D2 DR），纹状体是动物行为协调的重要中心。重要的是，CIN 85定位于纹状体神经元的突触后区室，其中它与D2 DR共簇。此外，它与纹状体中的内吞调节因子如发动蛋白和内嗜蛋白相互作用。纹状体CIN 85的缺乏导致纹状体中内嗜蛋白与D2 DR的复合物形成不足，并最终降低纹状体神经元中响应多巴胺刺激的D2 DR内吞作用。这些发现表明了CIN 85在调节多巴胺受体功能中的重要功能，并为CIN 85 Dex 2小鼠的多动行为提供了分子解释。The EMBO Journal（2010）29，2421-2432. doi：10.1038/doj.2010.120; 2010年6月15日在线发布
Despite extensive investigations of Cbl-interacting protein of 85 kDa (CIN85) in receptor trafficking and cytoskeletal dynamics, little is known about its functions in vivo. Here, we report the study of a mouse deficient of the two CIN85 isoforms expressed in the central nervous system, exposing a function of CIN85 in dopamine receptor endocytosis. Mice lacking CIN85 exon 2 (CIN85(Delta ex2)) show hyperactivity phenotypes, characterized by increased physical activity and exploratory behaviour. Interestingly, CIN85(Delta ex2) animals display abnormally high levels of dopamine and D2 dopamine receptors (D2DRs) in the striatum, an important centre for the coordination of animal behaviour. Importantly, CIN85 localizes to the post-synaptic compartment of striatal neurons in which it co-clusters with D2DRs. Moreover, it interacts with endocytic regulators such as dynamin and endophilins in the striatum. Absence of striatal CIN85 causes insufficient complex formation of endophilins with D2DRs in the striatum and ultimately decreased D2DR endocytosis in striatal neurons in response to dopamine stimulation. These findings indicate an important function of CIN85 in the regulation of dopamine receptor functions and provide a molecular explanation for the hyperactive behaviour of CIN85Dex2 mice. The EMBO Journal (2010) 29, 2421-2432. doi:10.1038/emboj.2010.120; Published online 15 June 2010