Melanophilin Accelerates Insulin Granule Fusion without Predocking to the Plasma Membrane

  • Hao Wang
    Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
  • Kouichi Mizuno
    Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
  • Noriko Takahashi
    Department of Physiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
  • Eri Kobayashi
    Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
  • Jun Shirakawa
    Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan
  • Yasuo Terauchi
    Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan
  • Haruo Kasai
    Laboratory of Structural Physiology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
  • Katsuhide Okunishi
    Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
  • Tetsuro Izumi
    Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan

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説明

<jats:p>Direct observation of fluorescence-labeled secretory granule exocytosis in living pancreatic β-cells has revealed heterogeneous prefusion behaviors: some granules dwell beneath the plasma membrane before fusion, while others fuse immediately once they are recruited to the plasma membrane. Although the former mode seems to follow sequential docking-priming-fusion steps as found in synaptic vesicle exocytosis, the latter mode, which is unique to secretory granule exocytosis, has not been explored well. Here, we show that melanophilin, one of the effectors of the monomeric guanosine-5′-triphosphatase Rab27 on the granule membrane, is involved in such an accelerated mode of exocytosis. Melanophilin-mutated leaden mouse and melanophilin-downregulated human pancreatic β-cells both exhibit impaired glucose-stimulated insulin secretion, with a specific reduction in fusion events that bypass stable docking to the plasma membrane. Upon stimulus-induced [Ca2+]i rise, melanophilin mediates this type of fusion by dissociating granules from myosin-Va and actin in the actin cortex and by associating them with a fusion-competent, open form of syntaxin-4 on the plasma membrane. These findings provide the hitherto unknown mechanism to support sustainable exocytosis by which granules are recruited from the cell interior and fuse promptly without stable predocking to the plasma membrane.</jats:p>

収録刊行物

  • Diabetes

    Diabetes 69 (12), 2655-2666, 2020-11-29

    American Diabetes Association

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