Molecular Regulation of Metabotropic Glutamate Receptors in Striatal Neurons

项目摘要 代谢性谷氨酸(MGlu)受体2是一种突触前受体，富含 纹状体内的谷氨酸能神经末梢，对大脑功能和一些 精神疾病。最近，我们发现钙/钙调蛋白依赖的蛋白激酶II(CaMKII) 直接与mGlu2受体结合，并在苏氨酸残基上磷酸化mGlu2受体 细胞内的C末端尾巴。这些发现首次揭示了mGlu2受体是一种 CaMKII的直接底物。受到这一新发现的鼓舞，我们建议更新 应用于系统研究这种以前未知的CaMKII-mGlu2偶联，并对 探讨CaMKII和mGlu2受体在阿尔茨海默病发病机制和症状学中的作用 常见的精神疾病。我们的假设是CaMKII调节mGlu2受体和连接 MGlu2对抑郁样行为的可塑性。使用多学科方法，这一假说 将在以下四个相互支持的目标中进行体外和体内测试。我会瞄准的 体外鉴定CaMKII-mGlu2相互作用的基本蛋白质生物化学。AIM II将 明确CaMKII-mGlu2相互作用和mGlu2受体磷酸化的调节 体内纹状体谷氨酸能神经末梢钙信号的变化。AIM III将探索 CaMKII在调节mGlu2受体转运和亚细胞表达中的作用 以及控制各种mGlu2信号事件的有效性。AIM IV将首先监测Long- 纹状体CaMKII-mGlu2系统对长时间社会适应的持久神经适应 成年大鼠的隔离，一种模拟成年后非享乐性抑郁的慢性应激范式 动物。然后，AIM IV将阐明CaMKII-mGlu2相互作用在分离- 诱发抑郁样行为。在这里取得的成果将在概念上推进我们目前的 对谷氨酸受体调节中磷酸化依赖机制的认识 突触前部位的信号。他们最终也将为小说的发展做出贡献。 以CaMKII和mGlu2受体为靶点的药物治疗CORE 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.