New transmembrane AMPA receptor regulatory protein isoform, γ-7, differentially regulates AMPA receptors
New transmembrane AMPA receptor regulatory protein isoform, γ-7, differentially regulates AMPA receptors
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DOI：
10.1523/jneurosci.5561-06.2007
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发表时间：
2007-05-02
影响因子：
5.3
通讯作者：
Bredt, David S.
中科院分区：
文献类型：
--
作者：
Kato, Akihiko S.;Zhou, Wei;Bredt, David S.
AMPA型谷氨酸受体（GluRs）介导脑中的大多数兴奋性信号，并且由GluR主要亚基和跨膜AMPA受体调节蛋白（TARP）辅助亚基组成。以前的研究确定了四种哺乳动物的TARP，gamma-2（或stargazin），gamma-3，gamma-4和gamma-8，它们控制AMPA受体的运输，门控和药理学。在这里，我们探讨的同源gamma-5和gamma-7蛋白，这是以前建议不作为TARPs的作用。免疫印迹法显示，γ-5和γ-7在小脑中的高水平，其中γ-7在分子层的浦肯野神经元和颗粒细胞层的肾小球突触中富集。免疫沉淀蛋白质组学显示，小脑γ-7贪婪地和选择性地结合AMPA受体GluR亚基，也结合AMPA受体簇蛋白，突触后密度-95（PSD-95）。此外，γ-7与PSD-95和AMPA受体亚单位一起出现在纯化的突触后密度中。在异源细胞中，γ-7而不是γ-5极大地增强AMPA受体谷氨酸诱发的电流并调节通道门控。在stargazer小鼠的颗粒细胞中，转染gamma-7而不是gamma-5增加了AMPA受体介导的电流。与stargazin相比，gamma-7差异调节AMPA受体谷氨酸亲和力和红藻氨酸功效。这些研究将gamma-7定义为TARP家族的一个新成员，它可以不同地影响小脑神经元中的AMPA受体。
AMPA-type glutamate receptors (GluRs) mediate most excitatory signaling in the brain and are composed of GluR principal subunits and transmembrane AMPA receptor regulatory protein (TARP) auxiliary subunits. Previous studies identified four mammalian TARPs, gamma-2 (or stargazin), gamma-3, gamma-4, and gamma-8, that control AMPA receptor trafficking, gating, and pharmacology. Here, we explore roles for the homologous gamma-5 and gamma-7 proteins, which were previously suggested not to serve as TARPs. Western blotting reveals high levels of gamma-5 and gamma-7 in the cerebellum, where gamma-7 is enriched in Purkinje neurons in the molecular layer and glomerular synapses in the granule cell layer. Immunoprecipitation proteomics shows that cerebellar gamma-7 avidly and selectively binds to AMPA receptor GluR subunits and also binds to the AMPA receptor clustering protein, postsynaptic density-95 (PSD-95). Furthermore, gamma-7 occurs together with PSD-95 and AMPA receptor subunits in purified postsynaptic densities. In heterologous cells, gamma-7 but not gamma-5 greatly enhances AMPA receptor glutamate-evoked currents and modulates channel gating. In granule cells from stargazer mice, transfection of gamma-7 but not gamma-5 increases AMPA receptor-mediated currents. Compared with stargazin, gamma-7 differentially modulates AMPA receptor glutamate affinity and kainate efficacy. These studies define gamma-7 as a new member of the TARP family that can differentially influence AMPA receptors in cerebellar neurons.