Cdk5-dependent regulation of glucose-stimulated insulin secretion
Cdk5-dependent regulation of glucose-stimulated insulin secretion
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DOI：
10.1038/nm1299
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发表时间：
2005-10-01
期刊：
影响因子：
82.9
通讯作者：
Tomizawa, K
中科院分区：
文献类型：
--
作者：
Wei, FY;Nagashima, K;Tomizawa, K
糖尿病患者严格的血糖控制对于预防或延缓其并发症是必不可少的。目前降血糖的治疗方法主要针对胰岛β细胞的K+-ATP敏感钾通道，以增加胰岛素的分泌。这些目前的治疗方法往往与低血糖的副作用有关。在这里，我们发现抑制细胞周期蛋白依赖性激酶5(CDK5)的活性可以促进在高糖而不是低糖刺激的MIN6细胞和胰岛中胰岛素的分泌。在缺乏CDK5激活剂p35的胰岛β细胞中，证实了CDK5在调节胰岛素分泌中的作用。P35基因敲除的小鼠也表现出对葡萄糖挑战的胰岛素分泌增加。抑制CDK5使高糖刺激下β细胞全细胞内向钙通道电流增加，跨L型电压依赖性钙通道的钙内流增加，但对无糖刺激时的钙内流无影响。CDK5对L-VDCC的抑制作用归因于其在Ser783位的α(1C)亚基II-III环的磷酸化，阻止了与SNAR蛋白的结合，从而导致了L-VDCC活性的降低。这些结果表明，CDK5/p35可能是调节葡萄糖刺激的胰岛素分泌的药物靶点。
Tight glycemic control in individuals with diabetes mellitus is essential to prevent or delay its complications(1). Present treatments to reduce hyperglycemia mainly target the ATP-sensitive K+ (K-ATP) channel of pancreatic beta cells to increase insulin secretion. These current approaches are often associated with the side effect of hypoglycemia. Here we show that inhibition of the activity of cyclin-dependent kinase 5 (Cdk5) enhanced insulin secretion under conditions of stimulation by high glucose but not low glucose in MIN6 cells and pancreatic islets. The role of Cdk5 in regulation of insulin secretion was confirmed in pancreatic beta cells deficient in p35, an activator of Cdk5. p35-knockout mice also showed enhanced insulin secretion in response to a glucose challenge. Cdk5 kinase inhibition enhanced the inward whole-cell Ca2+ channel current and increased Ca2+ influx across the L-type voltage-dependent Ca2+ channel ( L-VDCC) upon stimulation with high glucose in beta cells, but had no effect on Ca2+ influx without glucose stimulation. The inhibitory regulation by Cdk5 on the L-VDCC was attributed to the phosphorylation of loop II-III of the alpha(1C) subunit of L-VDCC at Ser783, which prevented the binding to SNARE proteins and subsequently resulted in a decrease of the activity of L-VDCC. These results suggest that Cdk5/p35 may be a drug target for the regulation of glucose-stimulated insulin secretion.