Extracellularly regulated kinases 1/2 (p44/42 mitogen-activated protein kinases) phosphorylate synapsin I and regulate insulin secretion in the MIN6 β-cell line and islets of Langerhans
Extracellularly regulated kinases 1/2 (p44/42 mitogen-activated protein kinases) phosphorylate synapsin I and regulate insulin secretion in the MIN6 β-cell line and islets of Langerhans
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DOI：
10.1210/en.2004-0841
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发表时间：
2005-02-01
期刊：
影响因子：
4.8
通讯作者：
Dalle, S
中科院分区：
文献类型：
--
作者：
Longuet, C;Broca, C;Dalle, S
p44/p42 MAPK (ERK1/2) 级联调节 β 细胞核事件，从而调节细胞分化和基因转录，但其对细胞质中发生的过程（例如胞吐机制的激活）的影响仍不清楚。使用 MIN6 β 细胞系和分离的大鼠胰岛，我们研究了葡萄糖是否通过激活 ERK1/2 级联，诱导与突触蛋白 I 等胰岛素颗粒的胞吐作用有关的细胞质蛋白的磷酸化。我们观察到，由葡萄糖诱导的大部分 ERK1/2 活性保留在细胞质中，并与突触蛋白 I 发生物理相互作用，从而允许底物磷酸化。因此，我们重新审视了 ERK1/2 对胰岛素分泌的潜在需求。使用 MEK1/2、MAPK 激酶抑制剂 PD98059 或使用小干扰 RNA 介导的 ERK1 和 ERK2 表达沉默来阻断 ERK1/2 的激活，可部分抑制葡萄糖诱导的胰岛素释放，表明 ERK1/2 途径也参与胰岛素分泌的调节。此外，利用胰岛灌注模型，我们发现ERK1/2活性参与葡萄糖诱导的胰岛素释放的第一阶段和第二阶段。总而言之，我们的结果证明了β细胞中ERK1/2对细胞质蛋白（包括突触蛋白I）的葡萄糖依赖性作用的新方面，并参与了整个葡萄糖诱导的胰岛素分泌。
The p44/p42 MAPKs (ERK1/2) cascade regulates beta-cell nuclear events, which modulates cell differentiation and gene transcription, whereas its implication in processes occurring in the cytoplasm, such as activation of the exocytotic machinery, is still unclear. Using the MIN6 beta-cell line and isolated rat islets of Langerhans, we investigated whether glucose, by activating the ERK1/2 cascade, induces phosphorylation of cytoplasmic proteins implicated in exocytosis of insulin granules such as synapsin I. We observed that the majority of ERK1/2 activity induced by glucose remains in the cytoplasm and physically interacts with synapsin I, allowing phosphorylation of the substrate. Therefore, we reexamined the potential requirement of ERK1/2 for insulin secretion. Blocking activation of ERK1/2 using MEK1/2, the MAPK kinase inhibitor PD98059 or using small interfering RNA-mediated silencing of ERK1 and ERK2 expressions resulted in partial inhibition of glucose-induced insulin release, indicating that ERK1/2 pathway participates also in the regulation of insulin secretion. Moreover, using the pancreatic islet perifusion model, we found that the ERK1/2 activity participates in the first and second phases of insulin release induced by glucose. Taken together, our results demonstrate new aspects of the glucose-dependent actions of ERK1/2 in beta-cells exerted on cytoplasmic proteins, including synapsin I, and participating in the overall glucose-induced insulin secretion.