Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation
Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation
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DOI：
10.1172/jci200522955
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发表时间：
2005-02-01
影响因子：
15.9
通讯作者：
Izumi, T
中科院分区：
文献类型：
--
作者：
Kasai, K;Ohara-Imaizumi, M;Izumi, T
单体的小GTTRab 27 a是专门定位于分泌颗粒和溶酶体相关的细胞器。尽管Rab 27 a基因在人类Griscelli综合征和灰白色小鼠中的自然突变引起部分白化病和免疫缺陷，反映了溶酶体相关细胞器的功能障碍，但由分泌颗粒的缺陷性胞吐作用引起的表型尚未报道。为了探讨Rab 27 a在分泌颗粒中的作用，我们分析了苍白小鼠的胰岛素分泌谱。苍白小鼠在葡萄糖负荷后表现出葡萄糖耐受不良，外周组织没有胰岛素抵抗或胰腺胰岛素缺乏的迹象。来自分离的胰岛的胰岛素分泌特异性地响应于高葡萄糖浓度而降低，但不响应于其它非生理促分泌素如高K+浓度、毛喉素或佛波醇酯。无论是细胞内钙离子浓度，也没有葡萄糖刺激后的融合孔开放的动力学改变。然而，有显着减少胞吐从胰岛素颗粒predocked在质膜上，并在补充停靠颗粒在葡萄糖刺激。这些结果提供了第一个遗传证据，我们的知识Rab 27 a的作用，在分泌颗粒的胞吐，并建议Rab 27 a/效应系统介导的葡萄糖特异性信号的胰岛素颗粒在胰腺β细胞的胞吐。
The monomeric small GTPase Rab27a is specifically localized on both secretory granules and lysosome-related organelles. Although natural mutations of the Rab27a gene in human Griscelli syndrome and in ashen mice cause partial albinism and immunodeficiency reflecting the dysfunction of lysosome-related organelles, phenotypes resulting from the defective exocytosis of secretory granules have not been reported. To explore the roles of Rab27a in secretory granules, we analyzed insulin secretion profiles in ashen mice. Ashen mice showed glucose intolerance after a glucose load without signs of insulin resistance in peripheral tissues or insulin deficiency in the pancreas. insulin secretion from isolated islets was decreased specifically in response to high glucose concentrations but not other nonphysiological secretagogues such as high K+ concentrations, forskolin, or phorbol ester. Neither the intracellular Ca2+ concentration nor the dynamics of fusion pore opening after glucose stimulation were altered. There were, however, marked reductions in the exocytosis from insulin granules predocked on the plasma membrane and in the replenishment of docked granules during glucose stimulation. These results provide the first genetic evidence to our knowledge for the role of Rab27a in the exocytosis of secretory granules and suggest that the Rab27a/effector system mediates glucose-specific signals for the exocytosis of insulin granules in pancreatic beta cells.