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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Mechanisms of metabotropic glutamate receptor desensitization: role in the patterning of effector enzyme activation.
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Mechanisms of metabotropic glutamate receptor desensitization: role in the patterning of effector enzyme activation.

机译：代谢型谷氨酸受体脱敏的机制：在效应酶激活模式中的作用。

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Metabotropic glutamate receptors (mGluRs) constitute an unique subclass of G protein-coupled receptors (GPCRs). These receptors are activated by the excitatory amino acid glutamate and play an essential role in regulating neural development and plasticity. In the present review, we overview the current understanding regarding the molecular mechanisms involved in the desensitization and endocytosis of Group 1 mGluRs as well as the relative contribution of desensitization to the spatial-temporal patterning of glutamate receptor signaling. Similar to what has been reported previously for prototypic GPCRs, mGluRs desensitization is mediated by second messenger-dependent protein kinases and GPCR kinases (GRKs). However, it remains to be determined whether mGluRs phosphorylation by GRKs and beta-arrestin binding are absolutely required for desensitization. Group 1 mGluRs endocytosis is both agonist-dependent and -independent. Agonist-dependent mGluRs internalization is mediated by a beta-arrestin- and dynamin-dependent clathrin-coated vesicle dependent endocytic pathway. The activation of Group 1 mGluRs also results in oscillatory Gq protein-coupling leading to the cyclical activation of phospholipase Cbeta thereby stimulating oscillations in both inositol 1,4,5-triphosphate formation and Ca(2+) release from intracellular stores. These glutamate receptor-stimulated Ca(2+) oscillations are translated into the synchronous activation of protein kinase C (PKC), which has led to the hypothesis that oscillatory mGluRs signaling involves the repetitive phosphorylation of mGluRs by PKC. However, recent experimental evidence suggests that oscillatory signaling is an intrinsic glutamate receptor property that is independent of feedback receptor phosphorylation by PKC. The challenge in the future will be to determine the structural determinants underlying mGluRs-mediated spatial-temporal signaling as well as to understand how complex signaling patterns can be interpreted by cells in both the developing and adult nervous systems.
机译：代谢型谷氨酸受体（mGluRs）构成G蛋白偶联受体（GPCR）的独特子类。这些受体被兴奋性氨基酸谷氨酸激活，在调节神经发育和可塑性中起重要作用。在本综述中，我们概述了有关第1组mGluRs脱敏和内吞以及脱敏对谷氨酸受体信号的时空模式的相对贡献的分子机制的当前理解。与先前报道的原型GPCR类似，mGluRs脱敏由第二信使依赖性蛋白激酶和GPCR激酶（GRKs）介导。然而，仍然需要确定脱敏性是否绝对需要通过GRKs的mGluRs磷酸化和β-arrestin结合。第1组mGluRs的内吞作用既是激动剂依赖性的，也是非依赖性的。激动剂依赖性mGluRs内在化是由β-arrestin和动力蛋白依赖性网格蛋白涂层的囊泡依赖性内吞途径介导的。组1 mGluRs的激活还导致振荡的Gq蛋白偶联，导致磷脂酶Cbeta的循环激活，从而刺激肌醇1,4,5-三磷酸形成和Ca（2+）从细胞内存储释放的振荡。这些谷氨酸受体刺激的Ca（2+）振荡被转换为蛋白激酶C（PKC）的同步激活，这导致了一个假设，即振荡性mGluRs信号涉及PKC对mGluRs的重复磷酸化作用。但是，最近的实验证据表明，振荡信号是内在的谷氨酸受体特性，与PKC反馈受体的磷酸化无关。未来的挑战将是确定在mGluRs介导的时空信号传导基础上的结构决定因素，以及如何理解发育中和成年神经系统中的细胞如何解释复杂的信号传导模式。

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