New Roles of Syntaxin-1A in Insulin Granule Exocytosis and Replenishment
New Roles of Syntaxin-1A in Insulin Granule Exocytosis and Replenishment
复制标题
DOI：
10.1074/jbc.m116.769885
复制
发表时间：
2017-02-10
影响因子：
4.8
通讯作者：
Gaisano, Herbert Y.
中科院分区：
文献类型：
--
作者：
Liang, Tao;Qin, Tairan;Gaisano, Herbert Y.
在2型糖尿病（T2 D）中，严重降低的胰岛突触融合蛋白-1A（Syn-1A）水平导致胰岛素分泌不足。我们产生了β细胞特异性Syn-1A-KO（Syn-1A-beta KO）小鼠，以模拟T2 D中的β细胞Syn-1A缺陷。葡萄糖耐量试验表明，Syn-1A-β KO小鼠表现出血糖升高，对应于降低的血液胰岛素水平。Syn-1A-β KO胰岛的灌流表现出第一和第二时相葡萄糖刺激的胰岛素分泌（GSIS）受损，这是由于易释放池和颗粒池再填充减少所致。为了明确地确定由Syn-1A缺失引起的β细胞胞吐缺陷，EM和全内反射荧光显微镜显示Syn-1A-KO β细胞在静止时停靠在质膜（PM）上的分泌颗粒（SG）的数量严重减少，并且在葡萄糖刺激后减少SG向PM的募集，后者指示维持第二阶段GSIS所需的可释放池的补充中的缺陷。而减少predocked SG融合占减少第一阶段GSIS，选择性减少胞吐的短码头（但不是无码头）的新人SG占减少第二阶段GSIS。这些Syn-1A对新SG的作用部分由Syn-1A与新SG VAMP 8的相互作用介导。
In type-2 diabetes (T2D), severely reduced islet syntaxin-1A (Syn-1A) levels contribute to insulin secretory deficiency. We generated beta-cell-specific Syn-1A-KO (Syn-1A-beta KO) mice to mimic beta-cell Syn-1A deficiency in T2D. Glucose tolerance tests showed that Syn-1A-beta KO mice exhibited blood glucose elevation corresponding to reduced blood insulin levels. Perifusion of Syn-1A-beta KO islets showed impaired first-and second-phase glucose-stimulated insulin secretion (GSIS) resulting from reduction in readily releasable pool and granule pool refilling. To unequivocally determine the beta-cell exocytotic defects caused by Syn-1A deletion, EM and total internal reflection fluorescence microscopy showed that Syn-1A-KO beta-cells had a severe reduction in the number of secretory granules (SGs) docked onto the plasma membrane (PM) at rest and reduced SG recruitment to the PM after glucose stimulation, the latter indicating defects in replenishment of releasable pools required to sustain second-phase GSIS. Whereas reduced predocked SG fusion accounted for reduced first-phase GSIS, selective reduction of exocytosis of short-dock (but not no-dock) newcomer SGs accounted for the reduced second-phase GSIS. These Syn-1A actions on newcomer SGs were partly mediated by Syn-1A interactions with newcomer SG VAMP8.