Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Neurosci. 2012 Jun;15(6):836-44. doi: 10.1038/nn.3103.
Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are G protein–coupled receptors (GPCRs) that are expressed at excitatory synapses in brain and spinal cord. GPCRs are often negatively regulated by specific G protein–coupled receptor kinases and subsequent binding of arrestin-like molecules. Here we demonstrate an alternative mechanism in which group I mGluRs are negatively regulated by proline-directed kinases that phosphorylate the binding site for the adaptor protein Homer, and thereby enhance mGluR–Homer binding to reduce signaling. This mechanism is dependent on a multidomain scaffolding protein, Preso1, that binds mGluR, Homer and proline-directed kinases and that is required for their phosphorylation of mGluR at the Homer binding site. Genetic ablation of Preso1 prevents dynamic phosphorylation of mGluR5, and Preso1(−/−) mice exhibit sustained, mGluR5-dependent inflammatory pain that is linked to enhanced mGluR signaling. Preso1 creates a microdomain for proline-directed kinases with broad substrate specificity to phosphorylate mGluR and to mediate negative regulation.
I 型代谢型谷氨酸受体（mGluRs）包括 mGluR1 和 mGluR5，是在脑和脊髓的兴奋性突触中表达的 G 蛋白偶联受体（GPCR）。GPCR 通常受到特定的 G 蛋白偶联受体激酶的负调控，随后与 arrestin 样分子结合。在这里，我们展示了一种替代机制，其中 I 型 mGluRs 被脯氨酸定向激酶负调控，该激酶磷酸化衔接蛋白 Homer 的结合位点，从而增强 mGluR-Homer 结合，减少信号转导。这种机制依赖于多结构域支架蛋白 Preso1，它结合 mGluR、Homer 和脯氨酸定向激酶，并需要它们在 Homer 结合位点磷酸化 mGluR。Preso1 的基因缺失可防止 mGluR5 的动态磷酸化，而 Preso1（−/−）小鼠则表现出持续的、依赖于 mGluR5 的炎症性疼痛，这与增强的 mGluR 信号转导有关。Preso1 为具有广泛底物特异性的脯氨酸定向激酶创建了一个微区，以磷酸化 mGluR 并介导负调控。
