Differential Regulation of Kainate Receptor Trafficking by Phosphorylation of Distinct Sites on GluR6
Differential Regulation of Kainate Receptor Trafficking by Phosphorylation of Distinct Sites on GluR6
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DOI：
10.1074/jbc.m109.081141
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发表时间：
2010-01-22
影响因子：
4.8
通讯作者：
Roche, Katherine W.
中科院分区：
文献类型：
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作者：
Nasu-Nishimura, Yukiko;Jaffe, Howard;Roche, Katherine W.
红藻氨酸受体在脑中广泛表达，并且存在于突触前和突触后位点，在那里它们在突触可塑性和网络活动的调节中发挥突出作用。在单个神经元内，不同亚基组成的红藻氨酸受体靶向于它们发挥不同功能作用的各个位置。尽管这种复杂的靶向，相对知之甚少的分子机制调节红藻氨酸受体亚基贩运。在这里，我们调查的作用，磷酸化的GluR6红藻氨酸受体亚基的贩运。我们确定了GluR6 C末端的两个特定残基，Ser（846）和Ser（868），它们被蛋白激酶C（PKC）磷酸化并显著调节GluR6表面表达。通过使用GluR6含有磷酸化和nonphosphorylatable突变的这些网站表达在异源细胞或缺乏内源性GluR6的神经元，我们表明，丝氨酸（846）或丝氨酸（868）的磷酸化调节受体贩运通过生物合成途径。此外，Ser（846）磷酸化动态调节GluR6在质膜上的内吞作用。因此，我们的研究结果表明，磷酸化的PKC位点上的GluR6调节GluR6的表面表达在不同的细胞内运输途径，提供潜在的分子机制PKC依赖性调节突触红藻氨酸受体的功能，在各种形式的突触可塑性。
Kainate receptors are widely expressed in the brain, and are present at pre- and postsynaptic sites where they play a prominent role in synaptic plasticity and the regulation of network activity. Within individual neurons, kainate receptors of different subunit compositions are targeted to various locations where they serve distinct functional roles. Despite this complex targeting, relatively little is known about the molecular mechanisms regulating kainate receptor subunit trafficking. Here we investigate the role of phosphorylation in the trafficking of the GluR6 kainate receptor subunit. We identify two specific residues on the GluR6 C terminus, Ser(846) and Ser(868), which are phosphorylated by protein kinase C(PKC) and dramatically regulate GluR6 surface expression. By using GluR6 containing phosphomimetic and nonphosphorylatable mutations for these sites expressed in heterologous cells or in neurons lacking endogenous GluR6, we show that phosphorylation of Ser(846) or Ser(868) regulates receptor trafficking through the biosynthetic pathway. Additionally, Ser(846) phosphorylation dynamically regulates endocytosis of GluR6 at the plasma membrane. Our findings thus demonstrate that phosphorylation of PKC sites on GluR6 regulates surface expression of GluR6 at distinct intracellular trafficking pathways, providing potential molecular mechanisms for the PKC-dependent regulation of synaptic kainate receptor function observed during various forms of synaptic plasticity.