Potassium Channels as Macromolecular Complexes

作为大分子复合物的钾通道

基本信息

批准号：
8741656
负责人：
William A Coetzee
金额：
$ 28.96万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-27 至 2015-09-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8741656
关键词：
Affect Aldehyde-Lyases Biochemistry Biological Assay Blood flow Cardiac Cardiac Myocytes Cardiovascular Diseases Co-Immunoprecipitations Complement Complex Coronary Data Depressed mood Dilatation - action Disease Dominant-Negative Mutation Electrophysiology (science)Endothelium Energy Metabolism Enzyme Interaction Enzymes Event Exercise Functional disorder Genetic Glycolysis Health Heart Hypertrophy Hypoxia Impairment Individual Ion Channel Ischemia Knowledge Link Macromolecular Complexes Membrane Metabolic Modality Molecular Molecular Biology Muscle Cells Myocardial Myocardial Ischemia Myocardium Nucleotides Pathway interactions Physiological Physiological Processes Potassium Potassium Channel Proteins Proteomics Pyruvate Kinase Regulation Research Role Smooth Muscle Specificity Stimulus Stress Techniques Testing Tissues Transgenic Mice Triose-Phosphate Isomerase Ventricular biological adaptation to stress cell type glucose metabolism insight insulin secretion interest mouse model mutant novel prevent promoter protective effect protein complex reactive hyperemia research study response tool

项目摘要

DESCRIPTION (provided by applicant): ATP-sensitive potassium [KATP] channels in the heart muscle and coronary myocytes couple cellular metabolic status to membrane excitability, thereby contributing to the regulation of tissue responses to physiological and pathophysiological stimuli. In the heart muscle, opening of KATP channels participate in the stress response and protect against ischemic episodes. In the coronary vasculature, K(ATP/NDP) channels contribute to the regulation of basal flow as well as responses to metabolic impairment (hypoxic dilatation and ischemic reactive hyperemia). We found glycolytic enzymes to associate with KATP channel subunits, We hypothesize that glycolytic enzymes are integral components of the KATP channel macromolecular complex and that glycolytic enzymes regulate KATP channel activity under physiological and pathophysiological conditions, both in the cardiac myocyte as well as in the coronary smooth muscle and endothelium. In a first Specific Aim, we will investigate the hypothesis that enzymes of the glycolytic complex are associated with the KATP channel. Using co-immunoprecipitation assays we will investigate the specificity of interaction of glycolytic enzymes with individual KATP channel subunits (Kir6.1, Kir6.2, SUR1, SUR2A and SUR2B). Co-immunoprecipitation assays of native proteins will be performed to investigate interactions under physiologically relevant conditions. Protein interactions will also be investigated using advanced proteomic approaches (ICAT & ITRAQ), which has the potential to uncover additional novel KATP channel interacting proteins. In a second Aim, we will examine the hypothesis that physical interaction of glycolytic enzymes with KATP channel subunits is required and that channel modulation occurs because of altered nucleotide levels in the microenvironment of the channel complex. This will be accomplished using mutant KATP channel subunits (lacking interaction with glycolytic enzymes or altered nucleotide sensitivity). In a final Aim, we will investigate the interaction of glycolysis and KATP channels in the context of ischemic protection in cardiac myocytes and the coronary vasculature. To this end, we will utilize our genetic mouse models that express dominant-negative K(ATP) channel subunits specifically in the cardiac myocyte, smooth muscle or endothelium. Our findings may have important implications for understanding the role of KATP channels in the heart and coronary vasculature under physiological and non-pathophysiological conditions.

描述（由申请人提供）：心肌和冠状动脉肌细胞中的ATP敏感钾[KATP]通道夫妇对膜兴奋性的细胞代谢状态，从而有助于调节组织对生理和病理生理生理学刺激的组织反应。在心脏肌肉中，开放KATP通道参与压力反应并预防缺血性发作。在冠状动脉脉管系统中，K（ATP/NDP）通道有助于基础流量的调节以及对代谢损伤的反应（低氧扩张和缺血性反应性充血性血症）。我们发现糖酵解酶与KATP通道亚基相关，我们假设糖酵解酶是KATP通道大分子复合物的积分成分，并且糖酵解酶调节KATP通道在生理和病理学条件下调节KATP通道在心理和肌肉群中的均及其均在coronary and Coronary中，均在生理和病理学条件下。在第一个特定目的中，我们将研究糖酵解复合物的酶与KATP通道有关的假设。使用共免疫沉淀测定法，我们将研究糖酵解酶与单个KATP通道亚基的相互作用的特异性（Kir6.1，Kir6.2，Sur1，Sur1，Sur2a和Sur2a）。将对天然蛋白质的共免疫沉淀测定法进行研究在生理相关条件下的相互作用。还将使用先进的蛋白质组学方法（ICAT和ITRAQ）研究蛋白质相互作用，该方法有可能发现其他新型的KATP通道相互作用蛋白。在第二个目标中，我们将研究以下假设：糖酵解酶与KATP通道亚基的物理相互作用是由于通道复合物的微环境中核苷酸水平改变而发生的。这将使用突变的KATP通道亚基（缺乏与糖酵解酶相互作用或改变核苷酸敏感性的相互作用）来实现。在最终目标中，我们将在心肌细胞和冠状动脉脉管系统的缺血性保护下研究糖酵解和KATP通道的相互作用。为此，我们将利用我们在心肌细胞，平滑肌或内皮中表达显性阴性K（ATP）通道亚基的遗传小鼠模型。我们的发现可能对理解KATP通道在生理和非病态生理条件下的心脏和冠状动脉脉管系统中的作用具有重要意义。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Measuring and evaluating the role of ATP-sensitive K+ channels in cardiac muscle.

测量和评估 ATP 敏感 K 通道在心肌中的作用。

DOI：
10.1016/j.yjmcc.2011.12.012
发表时间：
2012
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Kefaloyianni,Eirini;Bao,Li;Rindler,MichaelJ;Hong,Miyoun;Patel,Tejaskumar;Taskin,Eylem;Coetzee,WilliamA
通讯作者：
Coetzee,WilliamA

Multiplicity of effectors of the cardioprotective agent, diazoxide.