Regulation of Glucose Homeostasis by the Kv1.3 Channel

描述(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是一种与Shaker相关的Kv通道，在多种组织中表达，被认为参与了细胞体积调节、细胞凋亡、T细胞激活和肾脏溶质稳态。通道活性由苏氨酸和丝氨酸磷酸化以一种复杂的方式调节。5-羟色胺和胰岛素均可下调Kv1.3通道的活性。在胰岛素的情况下，在嗅球观察到通道抑制，并通过多个苏氨酸位点的磷酸化来调节。为了研究Kv1.3在体内的功能，我们利用基因打靶产生的Kv1.3缺陷小鼠(Kv1.3-/-)进行了初步研究。对这些小鼠的检查表明，它们比对照小鼠体重更轻，对胰岛素的降糖作用更敏感。此外，Kv1.3在野生型(Wt)和糖尿病小鼠中的药理阻断重现了在Kv1.3-/-小鼠中观察到的表型，表明Kv1.3‘S对胰岛素敏感性的作用不依赖体重。此外，抑制骨骼肌细胞系(L6)中Kv1.3通道的活性显著增加了细胞对葡萄糖的摄取。综上所述，这些数据Kv1.3有力地支持了Kv1.3及其信号通路代表着调节葡萄糖代谢的动态平衡机制的一个新的组成部分的观点。因此，我们认为有必要进行进一步的研究，以获得对这一过程的更详细的生理理解，并揭示用于治疗糖尿病的药物开发的潜在靶点。虽然Kv1.3在体重调节中的作用具有重要的生理和临床意义，但目前的提议仅限于研究它在血糖稳态中的作用。这项工作的主要目的是阐明Kv1.3调节外周葡萄糖代谢和导致胰岛素敏感性增加的细胞和分子机制。在我们前期工作的背景下，我们建议测试Kv1.3是否通过胰岛素依赖的途径调节葡萄糖摄取，并研究Kv1.3调节葡萄糖代谢的细胞机制。

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.