Voltage-gated potassium channel Kv1.3 regulates GLUT4 trafficking to the plasma membrane via a Ca2+-dependent mechanism
Voltage-gated potassium channel Kv1.3 regulates GLUT4 trafficking to the plasma membrane via a Ca2+-dependent mechanism
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DOI：
10.1152/ajpcell.00091.2005
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发表时间：
2006-02-01
影响因子：
5.5
通讯作者：
Desir, GV
中科院分区：
文献类型：
--
作者：
Li, YY;Wang, PL;Desir, GV
Kv1.3是一种电压门控性K+通道，表达于胰岛素敏感组织。我们先前的研究表明，Kv1.3通道活性的基因失活或药物抑制通过增加质膜上GLUT4的量而独立于体重增加外周胰岛素敏感性。在本研究中，我们进一步研究了Kv1.3对GLUT4转运的影响，并测试了它是否通过胰岛素依赖的途径发生。我们发现，抑制Kv1.3能刺激脂肪组织和骨骼肌对葡萄糖的摄取，并且对葡萄糖转运的影响与胰岛素的作用是相加的。此外，尽管摄取的增加是Wortmannin不敏感的，但它完全被丹曲林(Dantrolene)所抑制，丹曲林是细胞内钙释放的阻断剂。在原代培养的白色脂肪细胞中，Psora-4的通道抑制增加了GLUT4到质膜的移位。在这些细胞中，添加Wortmannin不影响GLUT4蛋白转位，但丹曲林显著抑制GLUT4蛋白转位。通道抑制使膜电压去极化，并导致细胞内钙离子浓度持续、丹曲林敏感的振荡。这些结果表明，与抑制Kv1.3通道活动相关的胰岛素敏感性的明显增加是由质膜GLUT4蛋白的增加所介导的，这种增加主要是通过钙依赖的过程发生的。
Kv1.3 is a voltage-gated K+ channel expressed in insulin-sensitive tissues. We previously showed that gene inactivation or pharmacological inhibition of Kv1.3 channel activity increased peripheral insulin sensitivity independently of body weight by augmenting the amount of GLUT4 at the plasma membrane. In the present study, we further examined the effect Kv1.3 on GLUT4 trafficking and tested whether it occurred via an insulin-dependent pathway. We found that Kv1.3 inhibition by margatoxin (MgTX) stimulated glucose uptake in adipose tissue and skeletal muscle and that the effect of MgTX on glucose transport was additive to that of insulin. Furthermore, whereas the increase in uptake was wortmannin insensitive, it was completely inhibited by dantrolene, a blocker of Ca2+ release from intracellular Ca2+ stores. In white adipocytes in primary culture, channel inhibition by Psora-4 increased GLUT4 translocation to the plasma membrane. In these cells, GLUT4 protein translocation was unaffected by the addition of wortmannin but was significantly inhibited by dantrolene. Channel inhibition depolarized the membrane voltage and led to sustained, dantrolene-sensitive oscillations in intracellular Ca2+ concentration. These results indicate that the apparent increase in insulin sensitivity observed in association with inhibition of Kv1.3 channel activity is mediated by an increase in GLUT4 protein at the plasma membrane, which occurs largely through a Ca2+-dependent process.