Regulation of Glucose Homeostasis by the Kv1.3 Channel

描述（由申请人提供）：电压门控钾（Kv）通道调节细胞膜电位并控制多种细胞过程。Kv1.3是一种Shaker相关的Kv通道，在多种组织中表达，并被认为参与细胞体积调节、凋亡、T细胞活化和肾脏溶质稳态。通道活性以复杂的方式受苏氨酸和丝氨酸磷酸化的调节。5-羟色胺和胰岛素均能下调Kv1.3通道的活性。在胰岛素的情况下，在嗅球中观察到通道抑制，并且通过多个苏氨酸位点的磷酸化介导。为了研究Kv1.3在体内的功能，我们使用通过基因打靶产生的Kv1.3缺陷小鼠（Kv1.3-/-）进行了初步研究。对这些小鼠的检查显示，与对照组同窝出生的小鼠相比，它们的体重更轻，对胰岛素的降糖作用更敏感。此外，在Kv1.3-/-小鼠中观察到的表型被野生型（wt）和糖尿病小鼠中Kv1.3的药理学阻断所概括，表明Kv1.3对胰岛素敏感性的作用与体重无关。此外，在骨骼肌细胞系（L 6）中抑制Kv1.3通道活性显著增加细胞葡萄糖摄取。综上所述，这些数据Kv1.3强烈支持Kv1.3及其信号通路代表调节葡萄糖代谢的稳态机制的新组分的概念。 因此，我们认为，从获得对该过程更详细的生理学理解和发现用于开发糖尿病管理药物的潜在靶点的角度来看，有必要进行进一步的研究。 虽然Kv1.3对体重调节的作用具有重要的生理和临床意义，但目前的建议仅限于研究其在葡萄糖稳态中的作用。 这项工作的主要目的是阐明Kv1.3调节外周葡萄糖代谢和引起胰岛素敏感性增加的细胞和分子机制。 在我们的初步工作的背景下，我们建议测试，如果Kv1.3通过胰岛素依赖性途径调节葡萄糖摄取，并检查介导Kv1.3对葡萄糖代谢的作用的细胞机制。

DESCRIPTION (provided by applicant): Voltage-gated potassium (Kv) channels regulate cell membrane potential and control a variety of cellular processes. Kv1.3, a Shaker-related Kv channel is expressed in several tissues and believed to participate in cell volume regulation, apoptosis, T cell activation, and renal solute homeostasis. Channel activity is regulated, in a complex manner, by threonine and serine phosphorylation. Serotonin and insulin can both down-regulate the activity of the Kv1.3 channel. In the case of insulin, channel inhibition is observed in the olfactory bulb, and is mediated by phosphorylation of multiple threonine sites. To investigate the function of Kv1.3 in vivo, we carried out preliminary studies using Kv1.3 deficient mice (Kv1.3-/-) generated by gene targeting. Examination of these mice revealed that they weigh less and are more sensitive to the glucose-lowering action of insulin than control littermates. Furthermore, the phenotype observed in Kv1.3-/- mice was recapitulated by the pharmacological blockade of Kv1.3 in wild-type (wt) and diabetic mice, suggesting that Kv1.3's action on insulin sensitivity is independent of body weight. Moreover, inhibition of Kv1.3 channel activity in a skeletal muscle cell line (L6) significantly increased cell glucose uptake. Taken together, these data Kv1.3 strongly support the notion that Kv1.3 and its signaling pathway represent a novel component of the homeostatic mechanisms that regulate glucose metabolism. As such, we believe further investigation is warranted, from the standpoint of gaining a more detailed physiological understanding of the process and of uncovering potential targets for the development of drugs useful in the management of diabetes. While the effect of Kv1.3 on the regulation of body weight is of significant physiological and clinical interest, the current proposal is limited to studying its role in glucose homeostasis. The broad aims of the work are to elucidate the cellular and molecular mechanisms by which Kv1.3 modulates peripheral glucose metabolism and cause increased insulin sensitivity. In the context of our preliminary work, we propose to test if Kv1.3 modulate glucose uptake via an insulin-dependent pathway, and to examine the cellular mechanisms that mediate the action of Kv1.3 on glucose metabolism.