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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A chemical-genetic approach to study G protein regulation of β cell function in vivo
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A chemical-genetic approach to study G protein regulation of β cell function in vivo

机译：化学遗传方法研究G蛋白在体内对β细胞功能的调节

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摘要

Impaired functioning of pancreatic β cells is a key hallmark of type 2 diabetes. β cell function is modulated by the actions of different classes of heterotrimeric G proteins. The functional consequences of activating specific β cell G protein signaling pathways in vivo are not well understood at present primarily due to the fact that β cell G protein-coupled receptors (GPCRs) are also expressed by many other tissues. To circumvent these difficulties, we developed a chemical-genetic approach that allows for the conditional and selective activation of specific β cell G proteins in intact animals. Specifically, we created two lines of transgenic mice each of which expressed a specific designer GPCR in β cells only. Importantly, the two designer receptors differed in their G protein-coupling properties (G_(q/11) versus G_s). They were unable to bind endogenous ligand(s), but could be efficiently activated by an otherwise pharmacologically inert compound (clozapine-N-oxide), leading to the conditional activation of either β ceil G_(q/11) or G_s G proteins. Here we report the findings that conditional and selective activation of β cell G_(q/11) signaling in vivo leads to striking increases in both first- and second-phase insulin release, greatly improved glucose tolerance in obese, insulin-resistant mice, and elevated β cell mass, associated with pathway-specific alterations in islet gene expression levels. Selective stimulation of β cell G_s triggered qualitatively similar in vivo metabolic effects. Thus, this developed chemical-genetic strategy represents a powerful approach to study G protein regulation of β cell function in vivo.
机译：胰腺β细胞功能受损是2型糖尿病的关键标志。 β细胞功能受不同类别的异源三聚体G蛋白的作用调节。目前，由于在许多其他组织中也表达了β细胞G蛋白偶联受体（GPCR）这一事实，目前尚未很好地理解体内激活特定β细胞G蛋白信号通路的功能后果。为了避免这些困难，我们开发了一种化学遗传方法，可以在完整的动物中有条件地选择性激活特定的β细胞G蛋白。具体来说，我们创建了两条转基因小鼠品系，每只仅在β细胞中表达特定的GPCR设计者。重要的是，两个设计受体的G蛋白偶联特性不同（G_（q / 11）与G_s）。它们不能结合内源性配体，但是可以被其他药理惰性的化合物（氯氮平-N-氧化物）有效地激活，从而导致β细胞G_（q / 11）或G_s G蛋白的条件激活。在这里，我们报告了以下发现：在体内条件性和选择性激活β细胞G_（q / 11）信号导致第一阶段和第二阶段胰岛素释放显着增加，大大改善了肥胖，胰岛素抵抗小鼠的葡萄糖耐量β细胞量增加，与胰岛基因表达水平的通路特异性改变有关。 β细胞G_s的选择性刺激在质量上触发了相似的体内代谢作用。因此，这种发达的化学遗传策略代表了研究体内β细胞功能的G蛋白调节的有力方法。

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  • 作者

    Jean-Marc Guettier; Dinesh Gautam; Marco Scarselli; Inigo Ruiz de Azua; Jian Hua Li; Erica Rosemond; Xiaochao Ma; Frank J. Gonzalez; Blaine N. Armbruster; Huiyan Lu; Bryan L Roth; Juergen Wess;

  • 作者单位

    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, MD 20892;

    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, MD 20892;

    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, MD 20892 Ecole Polytechnique Federale de Lausanne, Laboratory of Nanoscale Biology, Lausanne, Switzerland;

    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, MD 20892;

    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, MD 20892;

    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, MD 20892;

    Laboratory of Metabolism, National Cancer Institute, MD 20892 Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160;

    Laboratory of Metabolism, National Cancer Institute, MD 20892;

    Department of Pharmacology and Division of Medicinal Chemistry and Natural Products, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514 Millipore Drug Discovery Division, Millipore Corporation, St. Charles, MO 63304;

    Mouse Transgenic Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;

    Department of Pharmacology and Division of Medicinal Chemistry and Natural Products, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514;

    Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, MD 20892;

  • 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
  • 中图分类
  • 关键词

    beta cells; G protein-coupled receptors; transgenic mice; type 2 diabetes;

    机译：β细胞;G蛋白偶联受体;转基因小鼠2型糖尿病;

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