Molecular Regulation of Metabotropic Glutamate Receptors in Striatal Neurons

项目摘要 代谢型谷氨酸（mGlu）受体2是一种突触前受体，富集在神经元的活动区， 纹状体内的多巴胺能神经末梢，是大脑功能的关键， 精神疾病最近，我们发现钙/钙调素依赖性蛋白激酶II（CaMKII） 直接与mGlu 2受体结合并使mGlu 2受体的苏氨酸残基磷酸化， 细胞内的C-末端尾部。这些发现首次揭示了mGlu 2受体作为一种 CaMKII的直接底物。在这一新发现的鼓舞下，我们提出了这一更新， 应用系统地研究这种以前未被识别的CaMKII-mGlu 2偶联， 探讨CaMK Ⅱ和mGlu 2受体在糖尿病的发病机制和病理学中的作用， 常见的精神疾病我们的假设是CaMKII调节mGlu 2受体， mGlu 2对抑郁样行为的可塑性。使用多学科方法，这一假设 将在以下四个相互支持的目的中进行体外和体内测试。我会瞄准的 在体外表征CaMKII-mGlu 2相互作用的基本蛋白质生物化学。Aim II将 定义CaMKII-mGlu 2相互作用和mGlu 2受体磷酸化的调节， 在体改变纹状体内纹状体神经末梢的Ca ~（2+）信号。Aim III将探索 CaMKII在调节mGlu 2受体运输和亚细胞表达中的功能作用 以及控制各种mGlu 2信号传导事件的功效。目标四将首先监测长期- 纹状体CaMKII-mGlu 2系统对长时间社会性应激反应的持久神经适应 成年大鼠的隔离，一种模拟成年期快感缺乏抑郁的慢性应激范式 动物目的IV将阐明CaMKII-mGlu 2相互作用在分离中的功能作用- 诱发抑郁样行为这里取得的成果将在概念上推进我们目前的 对谷氨酸受体磷酸化依赖性调节机制的理解 突触前位点的信号。他们最终也将为小说的发展做出贡献 通过靶向CaMKII和mGlu 2受体治疗核心 抑郁症的症状

Project Summary Metabotropic glutamate (mGlu) receptor 2 is a presynaptic receptor enriched in active zones of glutamatergic nerve terminals within the striatum and is pivotal for brain functions and some mental illnesses. Recently, we found that Ca2+/calmodulin-dependent protein kinase II (CaMKII) directly binds to mGlu2 receptors and phosphorylates mGlu2 receptors at a threonine residue in the intracellular C-terminal tail. These findings for the first time reveal the mGlu2 receptor as a direct substrate of CaMKII. Encouraged by this novel discovery, we propose this renewal application to systematically study this previously unrecognized CaMKII-mGlu2 coupling and to explore roles of CaMKII and mGlu2 receptors in the pathogenesis and symptomatology of a common mental illness. Our hypothesis is that CaMKII regulates mGlu2 receptors and links mGlu2 plasticity to depression-like behavior. Using multidisciplinary approaches, this hypothesis will be tested both in vitro and in vivo in the following four inter-supportive Aims. Aim I will characterize fundamental protein biochemistry of the CaMKII-mGlu2 interplay in vitro. Aim II will define the regulation of CaMKII-mGlu2 interactions and mGlu2 receptor phosphorylation by changing Ca2+ signals in striatal glutamatergic nerve terminals in vivo. Aim III will explore functional roles of CaMKII in modulating trafficking and subcellular expression of mGlu2 receptors and in controlling the efficacy of various mGlu2 signaling events. Aim IV will first monitor long- lasting neuroadaptations of the striatal CaMKII-mGlu2 system in response to prolonged social isolation in adult rats, a chronic stress paradigm modeling anhedonic depression in adulthood animals. Aim IV will then clarify functional roles of CaMKII-mGlu2 interactions in the isolation- induced depression-like behavior. Results achieved here will conceptually advance our current understanding of a phosphorylation-dependent mechanism in regulating glutamate receptor signaling at presynaptic sites. They will also ultimately contribute to the development of novel pharmacotherapies, by targeting CaMKII and mGlu2 receptors, for the treatment of core symptoms of depression.