Lipid Modulation of Potassium Channels

钾通道的脂质调节

• 批准号: 8811568
• 负责人: Linda M Boland
• 金额: $ 28.38万
• 依托单位: UNIVERSITY OF RICHMOND
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811568
• 关键词: Address; Affinity; Anesthesia procedures; Animal Model; Arachidonic Acids; Binding; Binding Sites; Biomedical Research; Brain; C-terminal; Cardiac; Cardiovascular system; Cell membrane; Cells; Cellular Membrane; Characteristics; Charge; Chickens; Communication; Computer Simulation; Consensus; Consumption; Cyclic AMP-Dependent Protein Kinases; Data; Diet; Disease; Electrodes; Electrophysiology (science); Environment; Enzymes; Epilepsy; Epitopes; Event; Excision; Fatty Acids; Fatty acid glycerol esters; Fishes; Genome; Goals; Grant; Head; Health; Heart; Homology Modeling; Hormones; Human; Inositol; Ion Channel; Ischemia; Lipids; Location; Mass Spectrum Analysis; Measures; Mediating; Membrane; Membrane Potentials; Memory Disorders; Mental disorders; Mentors; Modeling; Molecular; Molecular Models; Muscarinic M1 Receptor; Mutagenesis; Mutation; Myocardial Infarction; Myocardium; Nature; Neurodegenerative Disorders; Neurons; Pain; Pattern; Periodicity; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phospholipid Interaction; Phospholipids; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Polyunsaturated Fatty Acids; Porifera; Potassium Channel; Principal Investigator; Protein Kinase; Protein Kinase C; Proteins; Regulation; Relative (related person); Research; Role; Side; Signal Transduction; Site; Sodium Chloride; Specificity; Stroke; Structure; Structure-Activity Relationship; Students; Surface; Testing; Time; Tissues; Universities; Work; base; citrate carrier; comparative; design; direct application; experience; extracellular; inhibitor/antagonist; inorganic phosphate; interest; molecular dynamics; molecular modeling; mutant; prevent; programs; public health relevance; research study; simulation; transcriptomics; undergraduate research; undergraduate student; voltage; voltage clamp; wortmannin

DESCRIPTION (provided by applicant): Our project focuses on how potassium ion channels are modified by the actions of lipids including polyphosphoinositides and polyunsaturated fatty acids. These two classes of lipids are structural components of the cellular membrane and also act as lipid signals following certain forms of cellular communication. The fatty acids are present in oily fish, and their consumption is promoted as part of a healthy heart diet. This research has important health implications for how lipid signals impact the proper rhythmicity of heart muscle, neuronal firing patterns, memory disorders, pain and anesthesia, epilepsy, and ischemic damage during stroke and heart attack. To better understand the molecular basis for how these lipids regulate the electrical activity of cells, we will study two channels known as Kir and K2P. We use channels cloned from sponges, a valuable animal model organism, because they give us a way to understand human ion channels by comparative analysis. We will determine how the Kir channel from sponge is regulated by different polyphosphoinositides and compare this to the effects of these lipids on vertebrate ion channels. We found that the Kir channels can be modified by activating enzymes that add phosphate groups to proteins; we will determine how this phosphorylation event may interact with the regulation of the channel by lipid signals. We made a computer model of the sponge Kir channel, at the atomic level, based on atomic structural data for vertebrate Kir channels. We use this model to help predict how the lipids interact with the channel, how phosphorylation may interact with the lipids, and what specific parts of the channel may be important in determining the type of lipid that can interact with the channel. We also plan to measure the lipids in sponge cells and to investigate information in the sponge genome to predict which of the different types of these lipids may exist in the native environment of the channels. For a second type of channel known as K2P, we found that opening of the sponge channel requires the fatty acid, arachidonic acid. Previous work on fatty acid effects in vertebrate channels has implicated a certain region of the K2P channel. We will examine the role of this region for the sponge K2P channel activation by fatty acids using molecular approaches and electrophysiology. Overall, this project will help us better understand the structure-function relationships of lipid signals and ion channels. The principal investigator s an experienced ion channel biologist who has successfully mentored 40 undergraduate research students in almost 10 years at the University of Richmond. In addition to the research goals, this project provides undergraduates with meaningful research experiences and they contribute to biomedically important research, which is the main goal of the AREA grant program.

描述(申请人提供)：我们的项目集中在钾离子通道如何被包括多磷肌醇和多不饱和脂肪酸在内的脂类的作用所修饰。这两类脂质是细胞膜的结构成分，也是某些形式的细胞通讯后的脂质信号。脂肪酸是存在的 在油性鱼类中，它们的摄入量被作为健康心脏饮食的一部分进行推广。这项研究对于脂质信号如何影响中风和心脏病发作期间心肌的适当节律性、神经元放电模式、记忆障碍、疼痛和麻醉、癫痫以及缺血性损害具有重要的健康意义。为了更好地了解这些脂类如何调节细胞电活动的分子基础，我们将研究两个被称为KIR和K2P的通道。我们使用从海绵克隆的通道，海绵是一种有价值的动物模式生物，因为它们给了我们一种通过比较分析来理解人类离子通道的方法。我们将确定海绵KIR通道是如何被不同的聚磷脂酰肌醇调节的，并将其与这些脂类对脊椎动物离子通道的影响进行比较。我们发现，KIR通道可以通过激活将磷酸基团添加到蛋白质中的酶来修饰；我们将确定这种磷酸化事件可能如何与脂信号对通道的调节相互作用。我们根据脊椎动物KIR通道的原子结构数据，在原子水平上建立了海绵KIR通道的计算机模型。我们使用这个模型来帮助预测脂类如何与通道相互作用，磷酸化可能如何与脂类相互作用，以及通道的哪些特定部分在确定可以与通道相互作用的脂质类型方面可能是重要的。我们还计划测量海绵细胞中的脂类，并调查海绵基因组中的信息，以预测这些不同类型的脂类中哪些可能存在于通道的自然环境中。对于第二种被称为K2P的通道，我们发现海绵通道的打开需要脂肪酸，花生四烯酸。先前关于脂肪酸在脊椎动物通道中的作用的工作已经涉及到K2P通道的某个区域。我们将使用分子方法和电生理学研究该区域在脂肪酸激活海绵K2P通道中的作用。总体而言，该项目将帮助我们更好地了解脂质信号和离子通道的结构-功能关系。首席研究员S是一位经验丰富的离子通道生物学家，他在里士满大学近10年的时间里成功地指导了40名本科生。除了研究目标之外，这个项目还为本科生提供了有意义的研究经验，他们对生物医学的重要研究做出了贡献，这也是地区资助计划的主要目标。

项目成果

Membrane Proteins Mediating Reception and Transduction in Chemosensory Neurons in Mosquitoes.

• DOI: 10.3389/fphys.2018.01309
• 发表时间: 2018
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Sparks JT;Botsko G;Swale DR;Boland LM;Patel SS;Dickens JC
• 通讯作者: Dickens JC

Expression of a poriferan potassium channel: insights into the evolution of ion channels in metazoans.

孔洞钾通道的表达：深入了解后生动物离子通道的进化。

• DOI: 10.1242/jeb.026971
• 发表时间: 2009
• 期刊: The Journal of experimental biology
• 作者: Tompkins-Macdonald,GabrielleJ;Gallin,WarrenJ;Sakarya,Onur;Degnan,Bernard;Leys,SallyP;Boland,LindaM
• 通讯作者: Boland,LindaM