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首页> 外文学位 >Novel protein-protein interactions and signaling mechanisms in regulation of the AMPA receptor GluR2 subunit trafficking in cultured hippocampal neurons.
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Novel protein-protein interactions and signaling mechanisms in regulation of the AMPA receptor GluR2 subunit trafficking in cultured hippocampal neurons.

机译：在培养的海马神经元中AMPA受体GluR2亚基运输调节中的新型蛋白质相互作用和信号传导机制。

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摘要

AMPA receptor trafficking into and out of synapses underlies activity-dependent regulation of synaptic strength. Both PICK1 (P&barbelow;rotein I&barbelow;nteracting with C&barbelow;-K&barbelow;inase) and ABP (A&barbelow;MPA receptor B&barbelow;inding P&barbelow;rotein)/GRIP (G&barbelow;lutamate R&barbelow;eceptor I&barbelow;nteracting P&barbelow;rotein) bind to the AMPA receptor GluR2 subunit C-terminus, and are involved in receptor trafficking. Transfer of the receptor from ABP/GRIP to PICK1, facilitated by GluR2 S880 phosphorylation, may initiate receptor trafficking. Here I find novel protein interactions that regulate these steps. The PICK1 BAR (B&barbelow;in/A&barbelow;mphiphysin/R&barbelow;vs) domain interacts intermolecularly with the ABP/GRIP linker II region and intramolecularly with the PICK1 PDZ (P&barbelow;SD95/D&barbelow;lgA/Z&barbelow;O-1) domain. Binding of PKCalpha (P&barbelow;rotein K&barbelow;inase C&barbelow; alpha) or GluR2 to the PICK1 PDZ domain disrupts the intramolecular interaction, and facilitates the PICK1 BAR domain association with ABP/GRIP. Interference with the PICK1-ABP/GRIP interaction impairs 5880 phosphorylation of GluR2 by PKC, and decreases the constitutive surface expression of GluR2, the NMDA-induced endocytosis of G1uR2 and recycling of internalized GluR2. These findings suggest that the PICK1 interaction with ABP/GRIP is a critical step in controlling GluR2 trafficking.; Protein kinases play key roles in receptor trafficking through phosphorylating receptors or factors involved in receptor trafficking. However, a systematic investigation into the role of protein kinases in GluR2 trafficking is scarce. In this study, I demonstrate that activation of CaMKII (Calcium/calmodulin activated kinase II), but not PKC and PKA (P&barbelow;rotein K&barbelow;inase A&barbelow;) is required for GluR2 trafficking to the surface. Calcium release from internal stores mediated by IP-3 receptors and ryanodine receptors is also required for GluR2 trafficking to the surface. These data suggest a key role of CaMKII in GluR2 trafficking.; I also find an interaction between PICK1 and CaMKII that is meditated by the PICK1 BAR domain and the catalytic domain of CaMKII. Interestingly, only active CaMKII interacts with PICK1. As CaMKII plays an important role in GluR2 exocytosis, the PICK1-CaMKII interaction suggests that PICK1 may be involved in targeting active CaMKII to AMPA receptors to regulate receptor trafficking.
机译：AMPA受体进出突触的活动是突触强度依赖活性的调节基础。 PICK1（与C-barinterin相互作用的蛋白）和ABP（与MPA受体B-inteing的蛋白）/ GRIP（与谷氨酸连接的G / barate）和受体I AMPA受体GluR2亚基C末端，并参与受体运输。 GluR2 S880磷酸化促进了受体从ABP / GRIP到PICK1的转移，可能启动受体运输。在这里，我发现了调节这些步骤的新型蛋白质相互作用。 PICK1 BAR（在/ A＆mphiphysin / R＆barvs）域与ABP / GRIP接头II区分子间相互作用，并与PICK1 PDZ（P＆barlow; SD95 / D＆lg; lgA / Z＆O-1）域分子间相互作用。 PKCalpha（蛋白）和GluR2与PICK1 PDZ域的结合会破坏分子内相互作用，并促进PICK1 BAR域与ABP / GRIP的缔合。干扰PICK1-ABP / GRIP相互作用会破坏PKC的5880磷酸化GluR2，并降低GluR2的组成型表面表达，NMDA诱导的G1uR2内吞作用和内在化GluR2的回收利用。这些发现表明，PICK1与ABP / GRIP的相互作用是控制GluR2转运的关键步骤。蛋白激酶通过磷酸化受体或参与受体运输的因子在受体运输中起关键作用。但是，缺乏对蛋白激酶在GluR2转运中的作用的系统研究。在这项研究中，我证明了激活CaMKII（钙/钙调蛋白激活的激酶II），而不是PKC和PKA（激活酶A，激活）对于GluR2转运到表面是必需的。 GluR2转运到地表也需要从IP-3受体和ryanodine受体介导的内部储存中释放钙。这些数据表明CaMKII在GluR2运输中起关键作用。我还发现PICK1和CaMKII之间的相互作用被PICK1 BAR结构域和CaMKII的催化结构域所冥想。有趣的是，只有活跃的CaMKII与PICK1相互作用。由于CaMKII在GluR2胞吐作用中起重要作用，因此PICK1-CaMKII相互作用表明PICK1可能参与将活性CaMKII靶向AMPA受体以调节受体运输。

著录项

  • 作者

    Lu, Wei.;

  • 作者单位

    New York University.;

  • 授予单位 New York University.;
  • 学科 Biology Molecular.; Biology Neuroscience.; Biology Cell.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 214 p.
  • 总页数 214
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;神经科学;细胞生物学;
  • 关键词

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