Regulation of Metabotropic Glutamate Receptor Signaling

代谢型谷氨酸受体信号传导的调节

• 批准号: 7735324
• 负责人: Katherine Roche
• 金额: $ 85.02万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7735324
• 关键词: Affect; Binding; Binding Proteins; Brain; C-terminal; Calcium Oscillations; Calmodulin; Calmodulin-Binding Proteins; Development; Endocytosis; G-Protein-Coupled Receptors; Glutamate Receptor; Goals; Metabotropic Glutamate Receptors; Molecular; Phospholipase C; Phosphorylation; Phosphorylation Site; Presynaptic Receptors; Protein Kinase C; Receptor Signaling; Regulation; Signal Transduction; Signaling Molecule; Site; Surface; Synapses; Synaptic plasticity; Time; beta-2 Adrenergic Receptors; desensitization; member; metabotropic glutamate receptor 7; neurotransmission; postsynaptic; receptor; receptor coupling; response; trafficking

The group I mGluRs (mGluR1 and mGluR5) are predominantly postsynaptic mGluRs that are coupled to phospholipase C, release of intracellular Ca2+, and activation of a variety of intracellular signaling molecules. PKC phosphorylation of mGluR5 has been known to affect Ca2+ signaling and receptor desensitization for some time, but rigorous studies on the direct phosphorylation of mGluR5 havent been conducted. Therefore, we are investigating the phosphorylation of mGluR5 and have identified several specific residues that are phosphorylated by protein kinase C. These PKC sites are located within the proximal one-third of the mGluR5 C-terminal domain. One phosphorylation site, Ser839, determines the regulation of intracellular calcium oscillations in response to mGluR5 activation. A second phosphorylation site that we have identified, Ser901, inhibits the binding of the protein calmodulin to mGluR5 and decreases mGluR5 surface expression. In parallel studies on the presynaptic receptor, mGluR7, we find that PKC phosphorylation of Ser862 inhibits calmodulin binding, and increases receptor surface expression. Therefore, we find a common mechanism to rapidly modify mGluR surface expression in response to increases in Ca2+, PKC activity, and changes in calmodulin binding; however, the changes in surface expression depend on receptor subtype and likely additional receptor subtype-specific binding proteins that are disrupted by calmodulin binding. These studies precisely defining the phosphorylation of mGluRs by PKC will allow us to study the functional consequences of glutamate receptor phosphorylation and the regulation of intracellular signaling and receptor trafficking.

I组mGluRs （mGluR1和mGluR5）主要是突触后mGluRs，它们与磷脂酶C偶联，释放细胞内Ca2+，并激活多种细胞内信号分子。PKC磷酸化mGluR5影响Ca2+信号和受体脱敏已经有一段时间了，但对mGluR5直接磷酸化的严格研究还没有进行。因此，我们正在研究mGluR5的磷酸化，并确定了几个被蛋白激酶c磷酸化的特定残基。这些PKC位点位于mGluR5 c末端结构域的近三分之一。一个磷酸化位点Ser839决定了响应于mGluR5激活的细胞内钙振荡的调节。我们发现的第二个磷酸化位点Ser901抑制钙调蛋白与mGluR5的结合并降低mGluR5表面的表达。在对突触前受体mGluR7的平行研究中，我们发现PKC磷酸化Ser862抑制钙调蛋白结合，增加受体表面表达。因此，我们发现了一种共同的机制，可以快速改变mGluR表面表达，以响应Ca2+、PKC活性的增加和钙调素结合的变化；然而，表面表达的变化取决于受体亚型和可能被钙调素结合破坏的其他受体亚型特异性结合蛋白。这些研究精确地定义了PKC对mGluRs的磷酸化，将使我们能够研究谷氨酸受体磷酸化的功能后果以及细胞内信号传导和受体运输的调节。