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（由适用提供）：2型糖尿病是美国最普遍的糖尿病形式。导致2型糖尿病发展的主要因素是周围组织，原发性骨骼肌和脂肪组织的胰岛素抵抗。 胰岛素介导的胰岛素响应性葡萄糖转运蛋白（GLUT4）到质膜的转运和融合对于适当的葡萄糖稳态至关重要。这就是细胞因子和过程调节GLUT4运输的鉴定和表征对于理解胰岛素敏感性受损的分子机制至关重要。胰岛素信号传导通过控制肌动蛋白细胞骨架来部分控制GLUT4蔬菜的束缚，对接和融合。虽然GLUT4囊泡运输需要肌动蛋白的重组，但对于控制这些过程所需的细胞骨架重排的因素知之甚少。该建议的广泛目的是了解控制胰岛素刺激的GLUT4囊泡运输过程中细胞骨架动态重组的机制。肌动蛋白基蛋白的肌球蛋白家族，特别是肌球蛋白II（MyOII），已显示可调节肌动蛋白细丝的重组，以促进各种细胞类型的囊泡traplickig。肌球蛋白II已被证明在“结构”角色中发挥作用，以帮助肌动蛋白细胞骨架的重组以及在“运动”角色中重组以收缩肌动蛋白丝。我们的研究表明，在胰岛素刺激后，在质膜上激活了肌醇同工型，并与Glut4和丝状肌动蛋白（F-肌动蛋白（F-肌动蛋白）共定位，以促进GLUT4介导的葡萄糖摄取。此外，我们表明抑制肌电肌活性会损害质膜上glut4的适当插入。由于肌动蛋白是在质膜上绑定GLUT4蔬菜的组成部分以及囊泡融合事件，因此我们假设Myoiia构成了与质子膜连接和融合所需的肌动蛋白重组。这是该提案的具体目的是识别和表征肌动蛋白刺激的GLUT4囊泡在脂肪细胞中调节肌动蛋白细胞骨架的机制。