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Calcium-calmodulin-dependent kinase II (CaMKII) mediates insulin-stimulated proliferation and glucose uptake

机译:钙钙调蛋白依赖性激酶II(CaMKII)介导胰岛素刺激的增殖和葡萄糖摄取

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Cellular growth and glucose uptake are regulated by multiple signals generated by the insulin receptor. The mechanisms of individual modulation of these signals remain somewhat elusive. We investigated the role of CaMKII in insulin signalling in a rat skeletal muscle cell line, demonstrating that CaMKII modulates the insulin action on DNA synthesis and the negative feedback that down regulates glucose uptake. Insulin stimulation generated partly independent signals leading to the rapid activation of Akt, Erk-1/2 and CaMKII Akt activation was followed by Glut-4 translocation to the plasma membrane and increase of glucose uptake. Then, IRS-1 was phosphorylated at S612, the IRS-1/p85PI3K complex was disrupted, Akt was no more phosphorylated and both Glut-4 translocation and glucose uptake were reduced. Inhibition of CaMKII abrogated the insulin-induced Erk-1/2 activation, DNA synthesis and phosphorylation of IRS-1 at S612. Inhibition of CaMKII also abrogated the down-regulation of insulin-stimulated Akt phosphorylation, Glut-4 membrane translocation and glucose uptake. These results demonstrate that: 1 - CaMKII modulates the insulin-induced Erk-1/2 activation and cell proliferation; 2 - after the initial stimulation of the IRS-1/Akt pathway, CaMKII mediates the down-regulation of stimulated glucose uptake. This represents a novel mechanism in the selective control of insulin signals, and a possible site for pharmacological intervention.
机译:细胞生长和葡萄糖摄取受胰岛素受体产生的多种信号调节。这些信号的单独调制机制仍然难以捉摸。我们调查了CaMKII在大鼠骨骼肌细胞系中胰岛素信号传导中的作用,证明CaMKII调节胰岛素对DNA合成的作用以及下调葡萄糖摄取的负反馈。胰岛素刺激产生部分独立的信号,从而导致Akt,Erk-1 / 2和CaMKII的快速激活。Akt激活后,Glut-4易位至质膜并增加了葡萄糖的摄取。然后,IRS-1在S612处被磷酸化,IRS-1 / p85PI3K复合物被破坏,Akt不再被磷酸化,Glut-4易位和葡萄糖摄取均降低。 CaMKII的抑制废除了胰岛素诱导的Erk-1 / 2活化,DNA合成和SRS处IRS-1的磷酸化。 CaMKII的抑制也消除了胰岛素刺激的Akt磷酸化,Glut-4膜移位和葡萄糖摄取的下调。这些结果证明:1-CaMKII调节胰岛素诱导的Erk-1 / 2活化和细胞增殖; 2-在最初刺激IRS-1 / Akt途径后,CaMKII介导刺激葡萄糖摄取的下调。这代表了选择性控制胰岛素信号的新机制,以及药理干预的可能部位。

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