Mechanism of Myosin Action in Glucose Uptake

肌球蛋白在葡萄糖摄取中的作用机制

• 批准号: 9099316
• 负责人: YASHOMATI M PATEL
• 金额: $ 43.65万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-08 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099316
• 关键词: Actins; Address; Adipocytes; Adipose tissue; Affect; African American; Automobile Driving; Biological Assay; Cell membrane; Cell physiology; Complex; Contracts; Cytoskeletal Modeling; Cytoskeleton; Development; Diabetes Mellitus; Disease; Docking; Elderly; Event; F-Actin; Family; GLUT 4 protein; GLUT4 gene; Hispanics; Incidence; Insulin; Insulin Resistance; Mediating; Microfilaments; Molecular; Motor; Muscle; Myosin ATPase; Myosin Type II; Native Americans; Non-Insulin-Dependent Diabetes Mellitus; Peripheral; Pharmacologic Substance; Play; Population; Prevalence; Process; Protein Isoforms; Proteins; Public Health; Research; Role; Site; Skeletal Muscle; Testing; Tissues; United States; Vesicle; base; blood glucose regulation; cell cortex; cell type; crosslink; design; effective therapy; glucose uptake; insight; insulin sensitivity; insulin signaling; prevent; public health relevance; trafficking; trend; type 2 diabetes in children

 DESCRIPTION (provided by applicant): Type 2 diabetes is the most prevalent form of diabetes in the United States. The major contributing factor to the development of type 2 diabetes is insulin resistance of peripheral tissues, primarily skeletal muscle and adipose tissue. Insulin-mediated translocation and fusion of insulin-responsive glucose transporter (GLUT4)-containing vesicles to the plasma membrane is critical for proper glucose homeostasis. Thus, the identification and characterization of cellular factors and processes regulating GLUT4 trafficking are critical to understanding the molecular mechanisms underlying impaired insulin sensitivity. Insulin signaling coordinates the tethering, docking and fusion of GLUT4 vesicles in part by regulating the actin cytoskeletal. While actin reorganization is required for GLUT4 vesicle trafficking, little is known about the factors regulating the cytoskeletal rearrangements required for these processes. The broad aim of this proposal is to gain insight on the mechanisms regulating the dynamic reorganization of the cytoskeleton during insulin-stimulated GLUT4 vesicle trafficking. The myosin family of actin- based motor proteins, specifically myosin II (MyoII) has been shown to regulate actin filament reorganization to facilitate vesicle traffickig in various cell types. Myosin II has been shown to function in a "structural" role to aid in the reorganization of the actin cytoskeleton as well as in a "motor" role to contract actin filaments. Our studies show that the MyoIIA isoform is activated and colocalizes with GLUT4 and filamentous actin (F-actin) at the plasma membrane upon insulin stimulation to facilitate GLUT4-mediated glucose uptake. Furthermore, we show that inhibition of MyoII activity impairs the proper insertion of GLUT4 at the plasma membrane. Since actin is an integral component tethering GLUT4 vesicles at the plasma membrane as well as vesicle fusion events, we hypothesize that MyoIIA facilitates the actin reorganization required for GLUT4 vesicle tethering and fusion with the plasma membrane. Thus, the specific aims of this proposal are to identify and characterize the mechanisms by which MyoIIA regulates the actin cytoskeleton during insulin-stimulated GLUT4 vesicle trafficking in adipocytes.

 描述（由申请人提供）：2 型糖尿病是美国最常见的糖尿病形式，导致 2 型糖尿病发生的主要因素是外周组织（主要是骨骼肌和脂肪组织）的胰岛素抵抗。 胰岛素介导的含有胰岛素响应性葡萄糖转运蛋白 (GLUT4) 的囊泡与膜质的易位和融合对于正确的葡萄糖稳态至关重要，因此，调节 GLUT4 运输的细胞因子和过程的识别和表征对于理解分子机制至关重要。胰岛素敏感性受损的原因是胰岛素信号传导部分通过调节肌动蛋白来协调 GLUT4 囊泡的束缚、对接和融合。虽然 GLUT4 囊泡运输需要肌动蛋白重组，但对于调节这些过程所需的细胞骨架重排的因素知之甚少，该提案的主要目的是深入了解胰岛素过程中细胞骨架动态重组的调节机制。刺激 GLUT4 囊泡运输。基于肌动蛋白的运动蛋白的肌球蛋白家族，特别是肌球蛋白 II (MyoII) 已被证明可以调节肌动蛋白丝重组。肌球蛋白 II 已被证明具有帮助肌动蛋白细胞骨架重组的“结构”作用以及收缩肌动蛋白丝的“运动”作用。在胰岛素刺激下，亚型被激活并与 GLUT4 和丝状肌动蛋白 (F-肌动蛋白) 共定位于质膜，以促进 GLUT4 介导的葡萄糖摄取。此外，我们发现抑制 MyoII 活性会损害 GLUT4 在质膜上的正确插入，因为肌动蛋白是在质膜上束缚 GLUT4 囊泡以及囊泡融合事件的重要组成部分，因此我们认为 MyoIIA 促进了肌动蛋白重组所需的功能。 GLUT4 囊泡与质膜的束缚和融合因此，本提案的具体目的是确定和表征其机制。 MyoIIA 在脂肪细胞中胰岛素刺激的 GLUT4 囊泡运输过程中调节肌动蛋白细胞骨架。