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α26 expression sets presynaptic calcium channel abundance and release probability

机译：α26表达设定突触前钙通道的丰度和释放概率

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摘要

Synaptic neurotransmitter release is driven by Ca~(2+) influx through active zone voltage-gated calcium channels (VGCCs). Control of active zone VGCC abundance and function remains poorly understood. Here we show that a trafficking step probably sets synaptic VGCC levels in rats, because overexpression of the pore-forming αl_ A VGCC subunit fails to change synaptic VGCC abundance or function. α2δs are a family of glycosylphosphatidylinositol (GPI)-anchored VGCC-associated subunit s that, in addition to being the target of the potent neuropathic analgesics gabapentin and pregabalin (α2δ-1 and α2δ-2), were also identified in a forward genetic screen for pain genes (α2δ-3). We show that these proteins confer powerful modulation of presynaptic function through two distinct molecular mechanisms. First, α2δ subunits set synaptic VGCC abundance, as predicted from their chaperone-like function when expressed in non-neuronal cells. Second, α2δs configure synaptic VGCCs to drive exocytosis through an extracellular metal ion-dependent adhesion site (MIDAS), a conserved set of amino acids within the predicted von Willebrand A domain of α2δ . Expression of α2δ with an intact MIDAS motif leads to an 80% increase in release probability, while simultaneously protecting exocytosis from blockade by an intracellular Ca~(2+) chelator. Α2δs harbouring MIDAS site mutations still drive synaptic accumulation of VGCCs; however, they no longer change release probability or sensitivity to intracellular Ca~(2+) chelators. Our data reveal dual functionality of these clinically important VGCC sub-units, allowing synapses to make more efficient use of Ca~(2+) entry to drive neurotransmitter release.
机译：突触神经递质的释放是由Ca〜（2+）通过活动区电压门控钙通道（VGCC）流入驱动的。对活动区VGCC丰度和功能的控制仍然知之甚少。在这里，我们显示出运输步骤可能在大鼠中设定了突触VGCC水平，因为成孔αlVGCC亚基的过表达不能改变突触VGCC的丰度或功能。 α2δ是糖基磷脂酰肌醇（GPI）锚定的VGCC相关亚基家族，除了作为强效神经性镇痛药加巴喷丁和普瑞巴林（α2δ-1和α2δ-2）的靶标外，还在正向遗传筛选中鉴定出用于疼痛基因（α2δ-3）。我们显示这些蛋白质通过两个不同的分子机制赋予突触前功能的强大调节。首先，如在非神经元细胞中表达时，从其伴侣状功能预测，α2δ亚基可设置突触VGCC丰度。其次，α2δs配置突触VGCCs通过胞外金属离子依赖性粘附位点（MIDAS）驱动胞吐作用，MIDAS是α2δ的预测von Willebrand A结构域中的保守氨基酸。具有完整MIDAS基序的α2δ的表达导致释放概率增加80％，同时保护胞吐作用不受细胞内Ca〜（2+）螯合剂的阻滞。携带MIDAS位点突变的A2δ仍然驱动VGCC的突触积累。但是，它们不再改变对细胞内Ca〜（2+）螯合剂的释放概率或敏感性。我们的数据揭示了这些临床上重要的VGCC亚基的双重功能，使突触能够更有效地利用Ca〜（2+）进入来驱动神经递质的释放。

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  • 来源
    《Nature》 |2012年第7401期|p.122-125|共4页
  • 作者

    Michael B. Hoppa; Beatrice Lana; Wojciech Margas; Annette C. Dolphin; Timothy A. Ryan;

  • 作者单位

    Department of Biochemistry, Weill Cornell Medical College, New York, New York 10023, USA;

    Department of Neuroscience, Physiology and Pharmacology, Laboratory of Cellular and Molecular Neuroscience, University College London, London WC1E6BT, UK.;

    Department of Neuroscience, Physiology and Pharmacology, Laboratory of Cellular and Molecular Neuroscience, University College London, London WC1E6BT, UK.;

    Department of Neuroscience, Physiology and Pharmacology, Laboratory of Cellular and Molecular Neuroscience, University College London, London WC1E6BT, UK.;

    Department of Biochemistry, Weill Cornell Medical College, New York, New York 10023, 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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