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首页> 外文期刊>Nature >X-ray structure of the mammalian GIRK2-βγ G-protein complex
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X-ray structure of the mammalian GIRK2-βγ G-protein complex

机译：哺乳动物GIRK2-βγG蛋白复合物的X射线结构

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摘要

G-protein-gated inward rectifier K~+ (GIRK) channels allow neurotransmitters, through G-protein-coupled receptor stimulation, to control cellular electrical excitability. In cardiac and neuronal cells this control regulates heart rate and neural circuit activity, respectively. Here we present the 3.5 A resolution crystal structure of the mammalian GIRK2 channel in complex with βγ G-protein subunits, the central signalling complex that links G-protein-coupled receptor stimulation to K~+ channel activity. Short-range atomic and long-range electrostatic interactions stabilize four βγ G-protein subunits at the interfaces between four K~+ channel subunits, inducing a pre-open state of the channel. The pre-open state exhibits a conformation that is intermediate between the closed conformation and the open conformation of the constitutively active mutant. The resultant structural picture is compatible with 'membrane delimited' activation of GIRK channels by G proteins and the characteristic burst kinetics of channel gating. The structures also permit a conceptual understanding of how the signalling lipid phosphatidylinositol-4,5-bisphosphate (PIP_2) and intracellular Na~+ ions participate in multi-ligand regulation of GIRK channels. In 1921, Otto Loewi established the existence of chemical synaptic transmission by showing that vagus nerve stimulation slows the heart rate through release of a chemical substance he called vagusstoff. Vagusstoff was later shown to be acetylcholine, the major neurotrans-mitter of the parasympathetic nervous system. Once released from the vagus nerve, acetylcholine binds to the M2 muscarinic receptor, a G-protein-coupled receptor (GPCR) in heart cell membranes, and causes the release of G-protein subunits Gx and Gβγ from the receptor's intracellular surface. The Gβ γ subunits activate GIRK channels, causing them to open. Open GIRK channels drive the membrane voltage towards the resting (Nernst K~+) potential, which slows the rate of membrane depolarization, as depicted (Fig. la). In atrial pacemaker cells of the heart, this directly decreases firing frequency and thus heart rate. Isoforms of the GIRK channel also exist in neurons, which permit G-protein-mediated regulation of neuronal electrical excitability.
机译：G蛋白门控的内向整流K〜+（GIRK）通道允许神经递质通过G蛋白偶联受体的刺激来控制细胞的电兴奋性。在心脏和神经元细胞中，这种控制分别调节心率和神经回路活动。在这里，我们介绍了哺乳动物GIRK2通道的3.5 A分辨率晶体结构，该结构与βγG蛋白亚基复合，这是将G蛋白偶联受体刺激与K〜+通道活性联系起来的中央信号复合体。短程原子和长程静电相互作用在四个K〜+通道亚基之间的界面处稳定了四个βγG蛋白亚基，从而诱导了通道的预开放状态。开放前状态显示的构象介于组成性活性突变体的封闭构象和开放构象之间。最终的结构图与G蛋白对GIRK通道的“膜定界”激活以及通道门控的特征性爆发动力学兼容。这些结构还允许对信号脂质磷脂酰肌醇-4,5-双磷酸酯（PIP_2）和细胞内Na〜+离子如何参与GIRK通道的多配体调控进行概念性理解。 1921年，奥托·洛维（Otto Loewi）通过显示迷走神经刺激通过释放他称为迷走神经阻滞剂的化学物质来减慢心率，从而确立了化学突触传递的存在。后来证实Vagusstoff是乙酰胆碱，副交感神经系统的主要神经递质。一旦从迷走神经中释放出来，乙酰胆碱就会与M2毒蕈碱受体（一种在心脏细胞膜中的G蛋白偶联受体（GPCR））结合，并导致G蛋白亚基Gx和Gβγ从受体的细胞内表面释放。 Gβγ亚基激活GIRK通道，使其打开。如图所示，开放的GIRK通道将膜电压推向静止的（Nernst K +）电势，这减慢了膜的去极化速率。在心脏的心房起搏器细胞中，这会直接降低发动频率，从而降低心率。 GIRK通道的同工型也存在于神经元中，这允许G蛋白介导的神经元电兴奋性调节。

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  • 来源
    《Nature》 |2013年第7453期|190-197|共8页
  • 作者

    Matthew R. Whorton; Roderick MacKinnon;

  • 作者单位

    Laboratory of Molecular Neurobiology and Biophysics ,The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.,Howard Hughes Medical Institute ,The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

    Laboratory of Molecular Neurobiology and Biophysics ,The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.,Howard Hughes Medical Institute ,The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

  • 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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