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.
复制标题
DOI：
10.1172/jci22955
复制
发表时间：
2005-02
期刊：
影响因子：
--
通讯作者：
K. Kasai;M. Ohara-Imaizumi;N. Takahashi;Shin Mizutani;Shengli Zhao;T. Kikuta;H. Kasai;S. Nagamatsu-S.-N
中科院分区：
文献类型：
--
作者：
K. Kasai;M. Ohara-Imaizumi;N. Takahashi;Shin Mizutani;Shengli Zhao;T. Kikuta;H. Kasai;S. Nagamatsu-S.-N
单体小GTP酶Rab27a特异性地定位于分泌颗粒和溶酶体相关细胞器。虽然在人类Griscell综合征和灰鼠中，Rab27a基因的自然突变导致部分白化和免疫缺陷，反映了溶酶体相关细胞器的功能障碍，但由于分泌颗粒的缺陷胞吐而导致的表型尚未见报道。为了探索Rab27a在分泌颗粒中的作用，我们分析了灰系小鼠的胰岛素分泌谱。灰白小鼠在葡萄糖负荷后表现出葡萄糖不耐受，外围组织没有胰岛素抵抗的迹象，胰腺也没有胰岛素缺乏的迹象。分离的胰岛胰岛素分泌减少是对高葡萄糖浓度的反应，但不包括其他非生理性促分泌剂，如高K+浓度、Forsklin或佛波酯。葡萄糖刺激后细胞内钙离子浓度和融合孔开放动力学均未发生改变。然而，在葡萄糖刺激期间，预先对接在质膜上的胰岛素颗粒的胞吐作用和对接颗粒的补充显著减少。这些结果为我们了解Rab27a在分泌颗粒的胞吐中的作用提供了第一个遗传学证据，并表明Rab27a/效应系统在胰岛β细胞中介导了胰岛素颗粒的胞吐的葡萄糖特异性信号。
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.