Dhami Gurpreet K, Ferguson Stephen S G
Cell Biology Research Group, Robarts Research Institute, London, Ontario, Canada N6A 5K8.
Pharmacol Ther. 2006 Jul;111(1):260-71. doi: 10.1016/j.pharmthera.2005.01.008. Epub 2006 Mar 6.
Metabotropic glutamate receptors (mGluRs) comprise a unique family of G protein-coupled receptors (GPCR) that can be classified into 3 groups based on G protein coupling specificity and sequence similarity. Group I mGluRs (mGluR1 and mGluR5) are coupled to the heterotrimeric G protein Galpha(q/11) and trigger the release of calcium from intracellular stores. In the present review, we discuss the molecular mechanisms involved in the desensitization and endocytosis of group I mGluRs. Group I mGluRs desensitize in response to both second-messenger-dependent protein kinases and G protein-coupled receptor kinases (GRK). However, GRK2-mediated mGluR1 desensitization appears to be both phosphorylation- and beta-arrestin-independent. In addition to GRK-mediated uncoupling of mGluRs from heterotrimeric G proteins, the huntingtin-interacting protein, optineurin, also contributes to mGluR1 and mGluR5 desensitization. The G protein-uncoupling activity of optineurin appears to be facilitated by the presence of polyglutamine-expanded mutant huntingtin but not wild-type huntingtin. Group I mGluRs also undergo both agonist-dependent and -independent endocytosis in both heterologous cell expression systems and primary neuronal cultures. The present review overviews the current understanding of the contribution of second messenger-dependent protein kinases, beta-arrestins and a novel Ral/phospholipase D2 (PLD2)-mediated endocytic pathway to the regulation of Group I mGluR endocytosis. Overall, the regulation of Group I mGluR desensitization and endocytosis appears to be mediated by the same molecular intermediates as have been described for more typical GPCR such as the beta(2)-adrenergic receptor. However, there appears to be subtle, but important, differences in the mechanisms by which these intermediates are employed to regulate Group I mGluR desensitization and endocytosis.
代谢型谷氨酸受体（mGluRs）构成了一类独特的G蛋白偶联受体（GPCR）家族，根据G蛋白偶联特异性和序列相似性可分为3组。I组mGluRs（mGluR1和mGluR5）与异源三聚体G蛋白Gα(q/11)偶联，并触发细胞内钙库释放钙。在本综述中，我们讨论了I组mGluRs脱敏和内吞作用所涉及的分子机制。I组mGluRs对第二信使依赖性蛋白激酶和G蛋白偶联受体激酶（GRK）的反应都会发生脱敏。然而，GRK2介导的mGluR1脱敏似乎与磷酸化和β-抑制蛋白无关。除了GRK介导的mGluRs与异源三聚体G蛋白解偶联外，亨廷顿相互作用蛋白视黄醛结合蛋白也有助于mGluR1和mGluR5的脱敏。视黄醛结合蛋白的G蛋白解偶联活性似乎因多聚谷氨酰胺扩展突变型亨廷顿蛋白的存在而增强，而野生型亨廷顿蛋白则无此作用。在异源细胞表达系统和原代神经元培养物中，I组mGluRs还会发生激动剂依赖性和非依赖性内吞作用。本综述概述了目前对第二信使依赖性依赖性蛋白激酶、β-抑制蛋白以及一种新的Ral/磷脂酶D2（PLD2）介导的内吞途径在调节I组mGluR内吞作用中所起作用的理解。总体而言，I组mGluR脱敏和内吞作用的调节似乎是由与更典型的GPCR（如β(2)-肾上腺素能受体）中所描述的相同分子中间体介导的。然而，这些中间体用于调节I组mGluR脱敏和内吞作用的机制似乎存在细微但重要的差异。
