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Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots

机译：单分子成像显示细胞表面热点处的受体-G蛋白相互作用

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摘要

G-protein-coupled receptors mediate the biological effects of many hormones and neurotransmitters and are important pharmacological targets(1). They transmit their signals to the cell interior by interacting with G proteins. However, it is unclear how receptors and G proteins meet, interact and couple. Here we analyse the concerted motion of G-protein-coupled receptors and G proteins on the plasma membrane and provide a quantitative model that reveals the key factors that underlie the high spatiotemporal complexity of their interactions. Using two-colour, single-molecule imaging we visualize interactions between individual receptors and G proteins at the surface of living cells. Under basal conditions, receptors and G proteins form activity-dependent complexes that last for around one second. Agonists specifically regulate the kinetics of receptor-G protein interactions, mainly by increasing their association rate. We find hot spots on the plasma membrane, at least partially defined by the cytoskeleton and clathrin-coated pits, in which receptors and G proteins are confined and preferentially couple. Imaging with the nanobody Nb37 suggests that signalling by G-protein-coupled receptors occurs preferentially at these hot spots. These findings shed new light on the dynamic interactions that control G-protein-coupled receptor signalling.
机译：G蛋白偶联受体介导许多激素和神经递质的生物学作用，并且是重要的药理靶标（1）。它们通过与G蛋白相互作用将信号传递到细胞内部。但是，尚不清楚受体和G蛋白如何相遇，相互作用和偶联。在这里，我们分析了质膜上G蛋白偶联受体和G蛋白的协同运动，并提供了定量模型，揭示了相互作用相互作用时空复杂性高的关键因素。使用双色，单分子成像，我们可以观察活细胞表面单个受体与G蛋白之间的相互作用。在基础条件下，受体和G蛋白形成活性依赖性复合物，持续约一秒钟。激动剂主要通过增加它们的缔合速率来特异性调节受体-G蛋白相互作用的动力学。我们在质膜上发现了热点，至少部分地由细胞骨架和网格蛋白包被的凹坑所限定，在这些凹坑中，受体和G蛋白被限制并且优先耦合。用纳米抗体Nb37成像表明，G蛋白偶联受体发出的信号优先出现在这些热点上。这些发现为控制G蛋白偶联受体信号传导的动态相互作用提供了新的思路。

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  • 来源
    《Nature》 |2017年第7677期|543-547|共5页
  • 作者

    Sungkaworn Titiwat; Jobin Marie-Lise; Burnecki Krzysztof; Weron Aleksander; Lohse Martin J.; Calebiro Davide;

  • 作者单位

    Univ Wurzburg, Inst Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany|Univ Wurzburg, Rudolf Virchow Ctr, Bioimaging Ctr, Versbacher Str 9, D-97078 Wurzburg, Germany;

    Univ Wurzburg, Inst Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany|Univ Wurzburg, Rudolf Virchow Ctr, Bioimaging Ctr, Versbacher Str 9, D-97078 Wurzburg, Germany;

    Wroclaw Univ Sci & Technol, Hugo Steinhaus Ctr, Fac Pure & Appl Math, Wyspianskiego 27, PL-50370 Wroclaw, Poland;

    Wroclaw Univ Sci & Technol, Hugo Steinhaus Ctr, Fac Pure & Appl Math, Wyspianskiego 27, PL-50370 Wroclaw, Poland;

    Univ Wurzburg, Inst Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany|Univ Wurzburg, Rudolf Virchow Ctr, Bioimaging Ctr, Versbacher Str 9, D-97078 Wurzburg, Germany|Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany;

    Univ Wurzburg, Inst Pharmacol & Toxicol, Versbacher Str 9, D-97078 Wurzburg, Germany|Univ Wurzburg, Rudolf Virchow Ctr, Bioimaging Ctr, Versbacher Str 9, D-97078 Wurzburg, Germany|Univ Birmingham, Inst Metab & Syst Res, Birmingham B15 2TT, W Midlands, England|Univ Birmingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham B15 2TT, W Midlands, England|Univ Nottingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham B15 2TT, W Midlands, England;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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