Effects of the Ras homolog Rhes on Akt/protein kinase B and glycogen synthase kinase 3 phosphorylation in striatum.
Effects of the Ras homolog Rhes on Akt/protein kinase B and glycogen synthase kinase 3 phosphorylation in striatum.
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DOI：
10.1016/j.neuroscience.2012.12.062
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发表时间：
2013-04-16
期刊：
影响因子：
3.3
通讯作者：
Spano, D.
中科院分区：
文献类型：
--
作者：
Harrison, L. M.;Muller, S. H.;Spano, D.
G蛋白偶联受体不仅可以通过异源三聚体G蛋白进行信号传递，还可以通过其他途径进行信号传递。因此，纹状体中的多巴胺D2受体通过g - αi/o以及促进含有β-arrestin2、蛋白磷酸酶2A和Akt的多蛋白复合物的形成来传递信号，从而使Akt去磷酸化。另一方面，锂会破坏这种复合物，从而增加Akt的磷酸化。Rhes是一种纹状体富集的GTP结合蛋白，已被证明可通过异源三聚体G蛋白抑制多巴胺受体介导的行为和信号传导。因此，我们的目的是测试Rhes是否同样影响纹状体中Akt/GSK3通路的信号传导。与Rhes +/+小鼠相比，Rhes−/−小鼠的Akt和GSK3β磷酸化基本增加，锂处理未进一步增强。此外，它们对D1/D2激动剂阿波啡有反应，Akt和GSK3磷酸化增加。共免疫沉淀实验表明，阿波啡处理在rhes+/+和rhes - / -小鼠中均可将蛋白磷酸酶2A-C募集到Akt。在rhes - / -小鼠中，锂离子没有破坏它们的相互作用，因为它们之间几乎没有基础相互作用。Rhes与β-阻滞蛋白共免疫沉淀，表明它是多蛋白复合物的组成部分。因此，Rhes是纹状体多蛋白复合物对Akt去磷酸化所必需的，如果Rhes缺失，则会导致锂处理的表型。
G protein-coupled receptors signal not only through heterotrimeric G proteins, but also through alternate pathways. Thus, dopamine D2 receptors in striatum signal through Gαi/o and also by promoting formation of a multi-protein complex containing β-arrestin2, protein phosphatase 2A, and Akt in order to dephosphorylate Akt. Lithium, on the other hand, disrupts this complex to increase Akt phosphorylation. Rhes is a striatally-enriched GTP binding protein that has been shown to inhibit dopamine receptor-mediated behavior and signaling through heterotrimeric G proteins. Therefore, our objective was to test whether Rhes similarly affects signaling through the Akt/GSK3 pathway in striatum. Rhes−/− mice showed basally increased Akt and GSK3β phosphorylation relative to rhes+/+ mice that was not further enhanced by lithium treatment. Furthermore, they responded to the D1/D2 agonist apomorphine with increased Akt and GSK3 phosphorylation. Co-immunoprecipitation experiments revealed that apomorphine treatment recruits protein phosphatase 2A-C to Akt in both rhes+/+ and rhes−/− mice. Lithium did not disrupt their interaction in rhes−/− mice as there was little basal interaction. Rhes co-immunoprecipitated with β-arrestins, suggesting that it is integral to the multi-protein complex. Thus, Rhes is necessary for Akt dephosphorylation by the striatal multi-protein complex, and in its absence, a lithium-treated phenotype results.
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影响因子：
11.4
作者：
CADE, JFJ
通讯作者：
CADE, JFJ
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