The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation
The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation
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DOI：
10.1016/j.cmet.2005.11.003
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发表时间：
2005-12-01
期刊：
影响因子：
29
通讯作者：
Yamagata, K
中科院分区：
文献类型：
--
作者：
Fukui, K;Yang, Q;Yamagata, K
葡萄糖刺激的胰岛素分泌缺陷是2型糖尿病高血糖的主要原因。HNF-1α的突变会导致一种单基因形式的2型糖尿病，即青年成熟型糖尿病(MODY)，其特征是胰岛素分泌受损。在这里，我们报道了最近克隆的未知功能的肾脏特异性基因Colltrin，它是胰腺β细胞中HNF-1α的靶标。在HNF-1α(-/-)小鼠的胰岛中，胶原蛋白的表达减少，而在肥胖高血糖小鼠中表达增加。在大鼠胰岛素瘤INS-1细胞或转基因小鼠的β细胞中过表达Colltrin可促进葡萄糖刺激的胰岛素胞吐，但不影响钙内流。相反，抑制胶原素会减弱胰岛素的分泌。Collectrin通过与SNAP-25结合蛋白Snapin结合到SNAR复合体上，促进了SNAR复合体的形成。因此，胶原素是SNARE复合体功能的调节者，从而控制胰岛素的胞吐。
Defective glucose-stimulated insulin secretion is the main cause of hyperglycemia in type 2 diabetes mellitus. Mutations in HNF-1 alpha cause a monogenic form of type 2 diabetes, maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion. Here we report that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1 alpha in pancreatic beta cells. Expression of collectrin was decreased in the islets of HNF-1 alpha (-/-) mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in rat insulinoma INS-1 cells or in the beta cells of transgenic mice enhanced glucose-stimulated insulin exocytosis, without affecting Ca2+ influx. Conversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP-25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.