Regulation of Glucose Homeostasis by the Kv1.3 Channel

Kv1.3 通道对血糖稳态的调节

• 批准号: 7391194
• 负责人: Gary V. Desir
• 金额: $ 23.99万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391194
• 关键词: Adipocytes; Adipose tissue; Apoptosis; Biology; Body Weight; Cell Line; Cell Volumes; Cell membrane; Cell physiology; Cells; Clinical; Complex; Data; Diabetic mouse; Gene Deletion; Gene Targeting; Glucose; Homeostasis; In Vitro; Insulin; Insulin Signaling Pathway; Investigation; Kidney; Liver; Mediating; Membrane Potentials; Molecular; Mus; Muscle Contraction; Muscle Fibers; Pathway interactions; Pattern; Peripheral; Phenotype; Phosphorylation; Physiological; Potassium; Process; Regulation; Role; Serine/Threonine Phosphorylation; Serotonin; Signal Pathway; Site; Skeletal Muscle; T-Cell Activation; Testing; Threonine; Tissues; Work; blood glucose regulation; diabetes management; drug development; glucose disposal; glucose metabolism; glucose uptake; immunocytochemistry; in vivo; insulin sensitivity; interest; novel; olfactory bulb; solute; voltage

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.

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 是一种与 Shaker 相关的 Kv 通道，在多种组织中表达，据信参与细胞体积调节、细胞凋亡、T 细胞激活和肾溶质稳态。通道活性通过苏氨酸和丝氨酸磷酸化以复杂的方式调节。血清素和胰岛素均可下调 Kv1.3 通道的活性。就胰岛素而言，在嗅球中观察到通道抑制，并且是由多个苏氨酸位点的磷酸化介导的。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。对这些小鼠的检查表明，与对照同窝小鼠相比，它们的体重更轻，并且对胰岛素的降血糖作用更敏感。此外，在野生型 (wt) 和糖尿病小鼠中通过药理阻断 Kv1.3 重现了在 Kv1.3-/- 小鼠中观察到的表型，表明 Kv1.3 对胰岛素敏感性的作用与体重无关。此外，抑制骨骼肌细胞系 (L6) 中的 Kv1.3 通道活性可显着增加细胞葡萄糖摄取。总而言之，这些数据 Kv1.3 强烈支持这样的观点：Kv1.3 及其信号通路代表了调节葡萄糖代谢的稳态机制的一个新组成部分。 因此，我们认为，从更详细地了解这一过程的生理学角度以及发现用于治疗糖尿病的药物开发的潜在目标的角度来看，有必要进行进一步的研究。 虽然 Kv1.3 对体重调节的影响具有重要的生理和临床意义，但目前的提议仅限于研究其在葡萄糖稳态中的作用。 这项工作的主要目标是阐明 Kv1.3 调节外周葡萄糖代谢并导致胰岛素敏感性增加的细胞和分子机制。 在我们的初步工作中，我们建议测试 Kv1.3 是否通过胰岛素依赖性途径调节葡萄糖摄取，并检查介导 Kv1.3 对葡萄糖代谢作用的细胞机制。