Inhibition of Pancreatic β-Cell Ca2+/Calmodulin-dependent Protein Kinase II Reduces Glucose-stimulated Calcium Influx and Insulin Secretion, Impairing Glucose Tolerance
Inhibition of Pancreatic β-Cell Ca2+/Calmodulin-dependent Protein Kinase II Reduces Glucose-stimulated Calcium Influx and Insulin Secretion, Impairing Glucose Tolerance
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DOI：
10.1074/jbc.m114.562587
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发表时间：
2014-05-02
影响因子：
4.8
通讯作者：
Jacobson, David A.
中科院分区：
文献类型：
--
作者：
Dadi, Prasanna K.;Vierra, Nicholas C.;Jacobson, David A.
背景：葡萄糖激活细胞中的CaMKII，其如何影响葡萄糖稳态尚未确定。结果：抑制小鼠细胞中的CaMKII通过减少Ca2+进入和胰岛素分泌引起葡萄糖耐受不良。结论：CaMKII是一种-细胞Ca2+传感器，可以放大分泌诱导的Ca2+进入和胰岛素分泌，以维持葡萄糖稳态。意义：这提供了-细胞CaMKII在生理和胰岛素抵抗状态下调节葡萄糖稳态的第一个证据。葡萄糖刺激胰岛素分泌（GSIS）从胰腺细胞是由Ca2+通过电压依赖性Ca2+通道进入引起的。CaMKII是许多组织中Ca2+信号的关键介质和反馈调节器，但其在细胞中的作用知之甚少，特别是在体内。在这里，我们报告了在-细胞中条件抑制CaMKII的小鼠由于GSIS降低而表现出显著的糖耐量受损。此外，-细胞CaMKII抑制显著加剧了暴露于高脂肪饮食后的葡萄糖耐受不良。抑制-细胞CaMKII对胰岛GSIS的损害不伴有糖代谢或K-ATP和电压门控钾通道活性的改变。然而，在CaMKII抑制的胰岛细胞以及CaMKII肽抑制剂处理的原代野生型细胞中，葡萄糖刺激的Ca2+通过电压依赖性Ca2+通道进入减少。基底细胞胞浆Ca2+和内质网Ca2+储存水平也因CaMKII抑制而降低。此外，CaMKII抑制抑制葡萄糖刺激的动作电位放电频率。这些结果表明，CaMKII是一种Ca2+传感器，在生理和病理条件下作为-细胞Ca2+信号的前馈刺激因子，增强GSIS的关键作用。
Background: Glucose activates CaMKII in -cells, how this influences glucose homeostasis has not been determined. Results: Inhibiting CaMKII in mouse -cells causes glucose intolerance by reducing Ca2+ entry and insulin secretion. Conclusion: CaMKII is a -cell Ca2+ sensor that amplifies secretagogue-induced Ca2+ entry and insulin secretion to maintain glucose homeostasis. Significance: This provides the first evidence that -cell CaMKII modulates glucose homeostasis under physiological and insulin resistant states.Glucose-stimulated insulin secretion (GSIS) from pancreatic -cells is caused by Ca2+ entry via voltage-dependent Ca2+ channels. CaMKII is a key mediator and feedback regulator of Ca2+ signaling in many tissues, but its role in -cells is poorly understood, especially in vivo. Here, we report that mice with conditional inhibition of CaMKII in -cells show significantly impaired glucose tolerance due to decreased GSIS. Moreover, -cell CaMKII inhibition dramatically exacerbates glucose intolerance following exposure to a high fat diet. The impairment of islet GSIS by -cell CaMKII inhibition is not accompanied by changes in either glucose metabolism or the activities of K-ATP and voltage-gated potassium channels. However, glucose-stimulated Ca2+ entry via voltage-dependent Ca2+ channels is reduced in islet -cells with CaMKII inhibition, as well as in primary wild-type -cells treated with a peptide inhibitor of CaMKII. The levels of basal -cell cytoplasmic Ca2+ and of endoplasmic reticulum Ca2+ stores are also decreased by CaMKII inhibition. In addition, CaMKII inhibition suppresses glucose-stimulated action potential firing frequency. These results reveal that CaMKII is a Ca2+ sensor with a key role as a feed-forward stimulator of -cell Ca2+ signals that enhance GSIS under physiological and pathological conditions.