Regulation of Metabotropic Glutamate Receptor Signaling

I组mGluR（mGluR 1和mGluR 5）主要是突触后mGluR，与磷脂酶C偶联，释放细胞内Ca 2+，激活多种细胞内信号分子。mGluR 5的PKC磷酸化影响Ca ~（2+）信号传导和受体脱敏已有一段时间，但对mGluR 5的直接磷酸化尚未进行严格的研究。因此，我们正在研究mGluR 5的磷酸化，并确定了几个特定的残基，被蛋白激酶C磷酸化。这些PKC位点位于mGluR 5 C-末端结构域的近端三分之一内。一个磷酸化位点，Ser 839，决定响应mGluR 5激活的细胞内钙振荡的调节。我们已经鉴定的第二个磷酸化位点Ser 901抑制蛋白质钙调素与mGluR 5的结合并降低mGluR 5表面表达。在对突触前受体mGluR 7的平行研究中，我们发现Ser 862的PKC磷酸化抑制钙调素结合，并增加受体表面表达。因此，我们发现一个共同的机制，以快速修改mGluR的表面表达，以响应增加Ca 2+，PKC活性，并在钙调蛋白结合的变化，然而，表面表达的变化取决于受体亚型和可能额外的受体亚型特异性结合蛋白，被破坏的钙调蛋白结合。这些研究精确地定义了PKC对mGluRs的磷酸化，这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。

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.