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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >M_3-muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1
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M_3-muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1

机译：M_3-毒蕈碱受体通过蛋白激酶D1的受体磷酸化/抑制蛋白激活来促进胰岛素释放

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摘要

The activity of G protein-coupled receptors is regulated via hyper-phosphorylation following agonist stimulation. Despite the universal nature of this regulatory process, the physiological impact of receptor phosphorylation remains poorly' studied. To address this question, we have generated a knock-in mouse strain that expresses a phosphorylation-def icient mutant of the M_3-muscarinic receptor, a prototypical G_(q/11)-coupled receptor. This mutant mouse strain was used here to investigate the role of M_3-muscarinic receptor phosphorylation in the regulation of insulin secretion from pancreatic islets. Importantly, the phosphorylation deficient receptor coupled to G_(q/11)-signaling pathways but was uncoupled from phosphorylation-dependent processes, such as receptor intemaliza-tion and p-arrestin recruitment. The knock-in mice showed impaired glucose tolerance and insulin secretion, indicating that M_3-muscarinic receptors expressed on pancreatic islets regulate glucose homeostasis via receptor phosphorylation-/arrestin-dependent signaling. The mechanism centers on the activation of protein kinase D1, which operates downstream of the recruitment of p-arrestin to the phosphorylated M_3-muscarinic receptor. In conclusion, our findings support the unique concept that M_3-muscarinic receptor-mediated augmentation of sustained insulin release is largely independent of G protein-coupling but involves phosphorylation-/ arrestin-dependent coupling of the receptor to protein kinase D1.
机译：G蛋白偶联受体的活性通过激动剂刺激后的过度磷酸化来调节。尽管这种调节过程具有普遍性，但受体磷酸化的生理影响仍然缺乏研究。为了解决这个问题，我们产生了一种敲入小鼠品系，该品系表达了M_3-毒蕈碱受体（一种典型的G_（q / 11）偶联受体）的磷酸化缺陷型突变体。此突变小鼠品系用于研究M_3-毒蕈碱受体磷酸化在调节胰岛胰岛素分泌中的作用。重要的是，磷酸化缺陷受体耦合到G_（q / 11）信号通路，但与依赖于磷酸化的过程（例如受体个体化和p-arrestin募集）脱钩。敲入的小鼠表现出葡萄糖耐量和胰岛素分泌受损，表明在胰岛上表达的M_3-毒蕈碱受体通过受体磷酸化/ arrestin依赖性信号传导调节葡萄糖稳态。该机制集中在蛋白激酶D1的激活上，该蛋白激酶在p-arrestin募集到磷酸化的M_3-毒蕈碱受体的下游进行。总之，我们的发现支持以下独特概念：M_3-毒蕈碱受体介导的持续胰岛素释放增加在很大程度上与G蛋白偶联无关，但涉及受体与蛋白激酶D1的磷酸化/抑制蛋白偶联。

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    Kok Choi Kong; Adrian J. Butcher; Phillip McWilliams; David Jones; Juergen Wess; Fadi F. Harridan; Tim Werry; Elizabeth M. Rosethorne; Steven J. Charlton; Sarah E. Munson; Hannah A. Cragg; Alison D. Smart; Andrew B. Tobin;

  • 作者单位

    Department of Cell Physiology and Pharmacology University of Leicester, Leicester LE1 9HN, United Kingdom;

    rnDepartment of Cell Physiology and Pharmacology University of Leicester, Leicester LE1 9HN, United Kingdom;

    rnDepartment of Cell Physiology and Pharmacology University of Leicester, Leicester LE1 9HN, United Kingdom;

    rnDepartment of Biomedical Joint Workshop University of Leicester, Leicester LE1 9HN, United Kingdom;

    rnMolecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;

    rnCenter of Excellence in Neuromics of University of Montreal, Sainte-Justine Hospital Research Center, Montreal, QC, Canada H3T 1C5;

    rnNeurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline, Harlow CM19 5AW United Kingdom;

    rnNovartis Institutes for Biomedical Research, Horsham West, Sussex RH125AB United Kingdom;

    rnNovartis Institutes for Biomedical Research, Horsham West, Sussex RH125AB United Kingdom;

    rnDepartment of Geneta Centre for Core Biotechnology Services University of Leicester, Leicester LE1 9HN, United Kingdom;

    rnDepartment of Geneta Centre for Core Biotechnology Services University of Leicester, Leicester LE1 9HN, United Kingdom;

    rnDepartment of Biomedical Services Division, University of Leicester, Leicester LE1 9HN, United Kingdom;

    rnDepartment of Cell Physiology and Pharmacology University of Leicester, Leicester LE1 9HN, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    g-protein coupled receptor; ligand bias;

    机译：g蛋白偶联受体;配体偏差;

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