首页> 美国卫生研究院文献>The Journal of Neuroscience >D2 Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways
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D2 Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways

机译:D2多巴胺受体通过RGS9 DEP域共定位G蛋白信号9-2(RGS9-2)的调节剂而RGS9敲除小鼠发展与多巴胺途径相关的运动障碍

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摘要

Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of Gα GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D2-like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D2-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D2DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D2DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D2DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D2DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease.
机译:G蛋白信号转导9-2(RGS9-2)的调节剂是GαGTPase加速蛋白的RGS家族的成员,在纹状体中特别表达,纹状体参与了抗精神病药引起的迟发性运动障碍和左旋多巴引起的运动障碍。我们报告RGS9基因敲除小鼠发展异常的不自主运动时,抑制多巴胺能传递,然后激活D2样多巴胺受体(DRs)。与其他啮齿动物模型相比,这些异常运动更类似于药物引起的运动障碍。这些小鼠的纹状体神经元的记录表明,D2样DR的激活异常抑制了谷氨酸引起的电流。我们显示RGS9-2,通过其DEP域(对于Disheveled,EGL-10,Pleckstrin同源性),在哺乳动物细胞中共表达时与D2DRs共定位。共表达D2DR或m2毒蕈碱受体和G蛋白门控的内向整流钾通道的卵母细胞的记录显示,RGS9-2通过其DEP结构域优先加速D2DR信号的终止。因此,RGS9-2的改变可能是导致D2DR导致与精神病和帕金森氏病相关的副作用的途径中的关键因素。

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