Preso1 dynamically regulates group I metabotropic glutamate receptors.
Preso1 dynamically regulates group I metabotropic glutamate receptors.
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I组代谢型谷氨酸受体（mGluRs），包括mGluR 1和mGluR 5，是在脑和脊髓中的兴奋性突触处表达的G蛋白偶联受体（GPCR）。GPCR通常受特异性G蛋白偶联受体激酶和随后的抑制蛋白样分子结合的负调控。在这里，我们证明了一种替代机制，其中I组mGluRs由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结合以减少信号传导。该机制依赖于多结构域支架蛋白Preso 1，其结合mGluR、Homer和脯氨酸导向激酶，并且是它们在Homer结合位点磷酸化mGluR所需的。Preso 1的基因切除可防止mGluR 5的动态磷酸化，Preso 1 −/−小鼠表现出持续的mGluR 5依赖性炎症疼痛，这与增强的mGluR信号有关。Preso 1为脯氨酸导向激酶创建了一个微结构域，具有广泛的底物特异性，可磷酸化mGluR并介导负调控。
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.
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