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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Latrophilin 1 and its endogenous ligand Lasso/ teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities
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Latrophilin 1 and its endogenous ligand Lasso/ teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities

机译：Latrophilin 1及其内源性配体Lasso / teneurin-2形成具有信号传导功能的高亲和性突触受体对

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摘要

Latrophilin 1 (LPH1), a neuronal receptor of α-latrotoxin, is implicated in neurotransmitter release and control of presynaptic Ca~(2+). As an "adhesion G-protein-coupled receptor," LPH1 can convert cell surface interactions into intracellular signaling. To examine the physiological functions of LPH1, we used LPH1's extracellular domain to purify its endogenous ligand. A single protein of ~275 kDa was isolated from rat brain and termed Lasso. Peptide sequencing and molecular cloning have shown that Lasso is a splice variant of teneurin-2, a brain-specific orphan cell surface receptor with a function in neuronal pathfinding and synaptogenesis. We show that LPH1 and Lasso interact strongly and specifically. They are always copurified from rat brain extracts. Coculturing cells expressing LPH1 with cells expressing Lasso leads to their mutual attraction and formation of multiple junctions to which both proteins are recruited. Cells expressing LPH1 form chimerical synapses with hippocampal neurons in cocultures; LPH1 and postsynaptic neuronal protein PSD-95 accumulate on opposite sides of these structures. Immunoblotting and immunoelectron microscopy of purified synapses and immunostaining of cultured hippocampal neurons show that LPH1 and Lasso are enriched in synapses; in both systems, LPH1 is presynaptic, whereas Lasso is postsynaptic. A C-terminal fragment of Lasso interacts with LPH1 and induces Ca~(2+) signals in presynaptic boutons of hippocampal neurons and in neuroblastoma cells expressing LPH1. Thus, LPH1 and Lasso can form transsynaptic complexes capable of inducing presynaptic Ca~(2+) signals, which might affect synaptic functions.
机译：Latrophilin 1（LPH1）是α-latrotoxin的神经元受体，与神经递质的释放和突触前Ca〜（2+）的控制有关。 LPH1作为“粘附G蛋白偶联受体”，可以将细胞表面相互作用转化为细胞内信号传导。为了检查LPH1的生理功能，我们使用LPH1的胞外域来纯化其内源配体。从大鼠脑中分离出约275 kDa的单个蛋白质，称为套索。肽测序和分子克隆表明，套索是Teneurin-2的剪接变体，它是一种大脑特异性的孤儿细胞表面受体，在神经元寻路和突触形成中起作用。我们显示LPH1和套索强烈而专门地相互作用。它们总是从大鼠脑提取物中共纯化得到的。将表达LPH1的细胞与表达Lasso的细胞共培养会导致它们的相互吸引，并形成两个蛋白都招募到的多个连接点。在共培养中，表达LPH1的细胞与海马神经元形成嵌合突触。 LPH1和突触后神经元蛋白PSD-95积累在这些结构的相对侧。纯化的突触的免疫印迹和免疫电子显微镜以及培养的海马神经元的免疫染色显示LPH1和Lasso富含突触。在这两个系统中，LPH1是突触前的，而套索是突触后的。 Lasso的C末端片段与LPH1相互作用，并在海马神经元的突触前按钮和表达LPH1的神经母细胞瘤细胞中诱导Ca〜（2+）信号。因此，LPH1和套索可以形成跨突触复合物，能够诱导突触前Ca〜（2+）信号，这可能会影响突触功能。

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    John-Paul Silva; Vera G. Lelianova; Yaroslav S. Ermolyuk; Nickolai Vysokov; Paul G. Hitchen; Otto Berninghausen; M. Atiqur Rahman; Alice Zangrandi; Sara Fidalgo; Alexander G. Tonevitsky; Anne Dell; Kirill E. Volynski; Yuri A. Ushkaryov;

  • 作者单位

    Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom;

    Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom;

    University College London Institute of Neurology,London, WC1N 3BG, United Kingdom;

    Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom;

    Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, United Kingdom;

    Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom;

    Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom;

    Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom;

    Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom;

    Moscow State University, Moscow, 119991, Russia;

    Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, United Kingdom;

    University College London Institute of Neurology,London, WC1N 3BG, United Kingdom;

    Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom;

  • 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);
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