Regulation of Glut 1 Function

Glut 1 功能的调节

• 批准号: 6771818
• 负责人: FARAMARZ ISMAIL-BEIGI
• 金额: $ 24.86万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6771818
• 关键词: binding proteins; cell membrane; electron microscopy; fatty acylation; genetically modified animals; glucose transporter; immunoprecipitation; laboratory mouse; membrane proteins; oxidative phosphorylation; palmitates; posttranslational modifications; protein binding; protein kinase; protein localization; protein protein interaction; protein structure function; protein transport; tissue /cell culture

DESCRIPTION (provided by applicant): Glut1 glucose transporter is an integral plasma membrane protein that is expressed in many cells and tissues. We have found that the acute (1-2 h) stimulation of Glut 1-mediated glucose transport is controlled by "activation "' of Glut1 transporters pre-existing in the plasma membrane. We have also found that a fraction of cell Glut 1 is bound by stomatin resulting in inhibition of Glut1 function. More recently we have made the novel observation that a significant fraction of Glut1, and virtually all of stomatin, reside in the cholesterol- and sphingolipid-rich detergent-resistant membranes (DRMs), and that a fraction of Glut l (but not stomatin) moves out of the DRMs upon stimulation of glucose transport in response to inhibition of oxidative phosphorylation. Based on our results we propose that Glut 1 localized in the plasma membrane exists in two-states, namely inactive and active. This proposal will be tested by the following Specific Aims: 1) Test the hypothesis that association of stomatin and Glutl leads to inhibition of Glut1 function, 2) Test the hypothesis that Glutl dissociates from stomatin during its activation in response to inhibition of oxidative phosphorylation and following stimulation of AMP-activated protein kinase (AMPK), 3) Test the hypothesis that Glut l present in plasma membrane DRMs are palmitoylated and the movement of Glutl out of this micro-domain reflects its de-palmitoylation, and 4) Identify Glutl-binding proteins under basal and stimulated conditions. An understanding of the molecular events leading to control of Glut l function should provide new insights into potentially novel physiological and pharmacological regulators of this important transporter.

描述（由申请人提供）：Glut 1葡萄糖转运蛋白是一种在许多细胞和组织中表达的整合质膜蛋白。我们发现Glut 1介导的葡萄糖转运的急性（1-2小时）刺激是由预先存在于质膜中的Glut 1转运蛋白的“激活”控制的。我们还发现，细胞Glut 1的一部分是由气孔蛋白导致Glut 1功能的抑制绑定。最近，我们已经进行了新的观察，即显著部分的Glut 1和几乎所有的气孔蛋白存在于富含胆固醇和鞘脂的耐洗涤剂膜（DRM）中，并且在响应于氧化磷酸化的抑制而刺激葡萄糖转运时，一部分Glut 1（但不是气孔蛋白）移出DRM。基于我们的研究结果，我们建议，Glut 1定位在质膜上存在两种状态，即无活性和活性。这一建议将通过以下具体目标进行检验：2）检验Glutl在响应氧化磷酸化抑制的活化过程中和在AMP活化蛋白激酶（AMPK）刺激后从气孔蛋白解离的假设，3）检验存在于质膜DRM中的Glutl被棕榈酰化并且Glutl移出该微结构域反映其去棕榈酰化的假设，以及4）鉴定基础和刺激条件下的Glutl结合蛋白。 对导致控制Glutl功能的分子事件的理解应该为这种重要转运蛋白的潜在的新型生理和药理调节剂提供新的见解。