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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The interaction of nucleoside diphosphate kinase B with Gβγ dimers controls heterotrimeric G protein function
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The interaction of nucleoside diphosphate kinase B with Gβγ dimers controls heterotrimeric G protein function

机译：核苷二磷酸激酶B与Gβγ二聚体的相互作用控制异三聚体G蛋白的功能

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摘要

Heterotrimeric G proteins in physiological and pathological processes have been extensively studied so far. However, little is known about mechanisms regulating the cellular content and compartmentalization of G proteins. Here, we show that the association of nucleoside diphosphate kinase B (NDPK B) with the G protein βγ dimer (Gβγ) is required for G protein function in vivo. In zebrafish embryos, morpholino-mediated knockdown of ze-brafish NDPK B, but not NDPK A, results in a severe decrease in cardiac contractility. The depletion of NDPK B is associated with a drastic reduction in Gβ_(1γ2) dimer expression. Moreover, the protein levels of the adenylyl cyclase (AC)-regulating Gα_s and Gα_i subunits as well as the caveolae scaffold proteins caveolin-1 and -3 are strongly reduced. In addition, the knockdown of the zebrafish Gβ_1 orthologs, Gβ_1 and Gβ_(1like), causes a cardiac phenotype very similar to that of NDPK B morphants. The loss of Gβ_1/Gβ_(1like) is associated with a down-regulation in caveolins, AC-regulating Gα-subunits, and most important, NDPK B. A comparison of embryonic fibro-blasts from wild-type and NDPK A/B knockout mice demonstrate a similar reduction of G protein, caveolin-1 and basal cAMP content in mammalian cells that can be rescued by re-expression of human NDPK B. Thus, our results suggest a role for the interaction of NDPK B with Gβγ dimers and caveolins in regulating membranous G protein content and maintaining normal G protein function in vivo.
机译：迄今为止，已经广泛地研究了生理和病理过程中的异三聚体G蛋白。然而，关于调节G蛋白的细胞含量和区室化的机制知之甚少。在这里，我们显示核苷二磷酸激酶B（NDPK B）与G蛋白βγ二聚体（Gβγ）的关联是体内G蛋白功能所必需的。在斑马鱼的胚胎中，吗啉代介导的斑马鱼NDPK B（而不是NDPK A）的敲低导致心脏收缩力的严重降低。 NDPK B的消耗与Gβ_（1γ2）二聚体表达的急剧减少有关。此外，调节腺苷酸环化酶（AC）的Gα_s和Gα_i亚基以及小窝支架蛋白caveolin-1和-3的蛋白质水平大大降低。此外，斑马鱼Gβ_1直系同源物Gβ_1和Gβ_（1like）的敲除导致心脏表型与NDPK B突变体非常相似。 Gβ_1/Gβ_（1like）的丧失与小窝蛋白的下调，AC调节的Gα亚基以及最重要的NDPK B相关。来自野生型和NDPK A / B敲除的胚胎成纤维细胞的比较小鼠表现出哺乳动物细胞中G蛋白，caveolin-1和基础cAMP含量的类似降低，可以通过人类NDPK B的重新表达来挽救。因此，我们的研究结果提示了NDPK B与Gβγ二聚体和caveolins相互作用的作用在体内调节膜G蛋白含量并维持正常G蛋白功能。

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    Hans-Joerg Hippe; Nadine M. Wolf; Issam Abu-Taha; Rebecca Mehringer; Steffen Just; Susanne Lutz; Feraydoon Niroomand; Edith H. Postel; Hugo A. Katus; Wolfgang Rottbauer; Thomas Wieland;

  • 作者单位

    Department of Internal Medicine III, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany;

    Department of Internal Medicine III, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Maybachstrasse 14, D-68169 Mannheim, Germany;

    Department of Internal Medicine III, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Maybachstrasse 14, D-68169 Mannheim, Germany;

    Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Maybachstrasse 14, D-68169 Mannheim, Germany;

    Department of Internal Medicine III, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany;

    Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Maybachstrasse 14, D-68169 Mannheim, Germany;

    Department of Internal Medicine III, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany;

    Robert Wood Johnson Medical School, New Brunswick, NJ 08903-0019;

    Department of Internal Medicine III, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany;

    Department of Internal Medicine III, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany;

    Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Maybachstrasse 14, D-68169 Mannheim, Germany;

  • 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

    cAMP; cardiac contractility; G proteins; NDPK; zebrafish;

    机译：营;心脏收缩力G蛋白;NDPK;斑马鱼;

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