Subunit-Specific Regulation Of Glutamate Receptors

受体及其亚型在单个细胞内和整个大脑中的独特分布需要高度选择性的细胞内靶向机制。我的实验室研究谷氨酸受体运输和本地化的生物化学和分子技术相结合的调节。我们正在研究NMDA受体亚基的差异运输，特别是集中在受体磷酸化。我们发现，NR 2B亚基，而不是NR 2A，是专门磷酸化酪蛋白激酶2（CK 2）的一个关键残基在NR 2B的C-末端结构域。出生后第二周，NR 2B的CK 2磷酸化增加，在亚基转换（NR 2B到NR 2A）中很重要，这在发育期间和对活动的反应中发生在许多皮质区域。这些数据支持独特的贡献，个别NMDA受体亚基的NMDA受体的贩运和本地化。我们还在研究PSD-95蛋白家族对NR 2A和NR 2B的特异性调节。我们的研究结果支持SAP 102在调节含NR 2B的NMDA受体中的独特作用。我们还研究了介导NMDA受体胞吐的突触后机制，并确定SNAP-23是调节谷氨酸受体表面表达的关键蛋白。除了NMDA受体，我们的特点是贩运红藻氨酸受体通过分泌途径途中质膜。我们已经确定了红藻氨酸受体内的两个不同的磷酸化位点，调节细胞内运输和表面表达。

The unique distribution of receptors and their subtypes within a single cell and throughout the brain requires highly selective intracellular targeting mechanisms. My laboratory studies the regulation of glutamate receptor trafficking and localization using a combination of biochemical and molecular techniques. We are investigating the differential trafficking of NMDA receptor subunits, specifically focusing on receptor phosphorylation. We find that the NR2B subunit, and not NR2A, is specifically phosphorylated by casein kinase 2 (CK2) on a critical residue in the NR2B C-terminal domain. CK2 phosphorylation of NR2B increases in the second postnatal week and is important in the subunit switch (NR2B to NR2A), which takes place in many cortical regions during development and in response to activity. These data support unique contributions of the individual NMDA receptor subunits to NMDA receptor trafficking and localization. We are also studying the specific regulation of NR2A and NR2B by the PSD-95 family of proteins. Our results support a unique role for SAP102 in regulating NR2B-containing NMDA receptors. We have also examined the postsynaptic machinery that mediates NMDA receptor exocytosis and identified SNAP-23 as a critical protein regulating glutamate receptor surface expression. In addition to NMDA receptors, we have characterized the trafficking of kainate receptors through the secretory pathway en route to the plasma membrane. We have identified two distinct phosphorylation sites within kainate receptors that regulate intracellular transport and surface expression.