Structural basis of KATP Channel Gating

KATP通道门控的结构基础

• 批准号: 8131340
• 负责人: Show-Ling Shyng
• 金额: $ 30.8万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-06 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131340
• 关键词: ATP-Binding Cassette Transporters; Address; Affect; Affinity; Basic Science; Binding; Cardiac; Cells; Chemicals; Childhood; Complex; Coupling; Data; Development; Diabetes Mellitus; Diagnosis; Diazoxide; Disease; Exhibits; Family; Fostering; Functional disorder; Genetic; Glucose; Goals; Health Sciences; Homeostasis; Human; Hyperinsulinism; Infant; Ion Channel; Kir6.2 channel; Knowledge; Lead; Link; Mediating; Membrane; Metabolic; Metabolism; MgADP; Molecular; Molecular Conformation; Mutagenesis; Mutate; Mutation; Myopathy; N-terminal; Neurologic; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Pancreas; Pathway interactions; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Physiological; Play; Potassium; Probability; Proteins; Publishing; Regulation; Research; Role; Scanning; Screening procedure; Signal Transduction; Signal Transduction Pathway; Structural Models; Structure-Activity Relationship; Sulfonylurea Compounds; Testing; Therapeutic Agents; Work; base; cell type; crosslink; human disease; innovation; insulin secretion; member; neonatal diabetes mellitus; novel; novel therapeutics; response; sulfonylurea receptor

DESCRIPTION (provided by applicant): ATP-sensitive potassium (KATP) channels couple cell metabolism to membrane excitability. They play a vital role in energy homeostasis by eliciting physiological response appropriate to metabolic signals. A member of the inwardly rectifying potassium (Kir) channel family, KATP channels are unique in requiring co-assembly of Kir6.2 with a sulfonylurea receptor (SUR), an ABC transporter, for functional expression. In pancreatic ¿- cells, KATP channels formed by Kir6.2 and SUR1 mediate glucose-stimulated insulin secretion. Mutations in Kir6.2 or SUR1 that reduce channel function cause congenital hyperinsulinism whereas those that increase channel function cause neonatal diabetes. Both Kir6.2 and SUR1 play an integral role in the channel's complex gating regulation. The long-term goal of this project is to understand the structure-function relationship of channel proteins with respect to gating. Work in the previous cycle has identified and elucidated the role of several structural features of the pore-forming subunit Kir6.2 in channel gating. In this renewal application, we will address the mechanisms of functional coupling between SUR1 and Kir6.2. SUR1 increases the open probability (Po) of Kir6.2, hypersensitizes Kir6.2 to the inhibitory effect of ATP and stimulatory effect of membrane phosphoinositides, and confers the effects of MgADP as well as the pharmacological agent sulfonylureas and diazoxide on Kir6.2. Functional coupling between SUR1 and Kir6.2 is thus essential to channel gating; yet significant knowledge gaps remain regarding the mechanisms by which SUR1 exerts its multiple effects on Kir6.2. The goal of this renewal application is to elucidate the mechanisms and structural basis that are responsible for functional coupling between SUR1 and Kir6.2. Based on our preliminary data, we propose a unifying hypothesis to explain how SUR1 imposes its multiple effects on Kir6.2 gating. Specifically, we hypothesize that SUR1 confers the intrinsic Po of KATP channels by stabilizing Kir6.2 in the PIP2-bound open state via molecular interactions between residues in the short cytoplasmic loops of TMD0 in SUR1 and those in the N-terminal domain of Kir6.2; and ATP, MgADP and pharmacological agents modulate channel activity in turn by changing the SUR1-Kir6.2 interface to strengthen or weaken channel-PIP2 interactions. We will interweave forward genetics approach employing disease mutations, guided mutagenesis screening, chemical cross-linking and structural modeling approaches to test the hypothesis. The research is innovative because it presents a novel concept to the field. The research is significant from both the human health and basic science standpoints. It will identify new disease mechanisms to directly facilitate diagnosis and treatment of several rare but devastating infant/childhood diseases and will lead to a better understanding of the structure-function relationship of the channel to foster new ideas on how to modulate channel activity to treat diseases caused by channel dysfunction, including type II diabetes. It will also lead to a better understanding of how a silent ABC transporter regulates an ion channel to advance both the ABC transporter and the ion channel fields. PUBLIC HEALTH RELEVANCE: The ATP-sensitive potassium (KATP) channels play a key role in linking metabolic signals to physiological responses in many cell types. Dysfunction of KATP channels causes human disease including diabetes, hyperinsulinism, cardiac myopathy and neurological deficits. The goal of this project is to understand the molecular basis underlying the ability of the channel to open or close according to metabolic signals to facilitate development of novel therapeutic agents for disease caused by channel dysfunction.

描述（通过应用程序）：ATP敏感的钾（KATP）通道夫妇代谢与膜稳态中的OLE。胰岛素受体（SUR）。 -KIR6.2介导葡萄糖刺激的胰岛素分泌的katp通道会导致先天性高胰岛素。上一个循环中的工作已经确定了孔隙率的几个孔子中的孔子中的含量，并阐明了几种孔子的诱因。对Kir6.2的抑制作用和膜磷酸肌醇的刺激效应，以及MGADP的同盟以及AST Sulfonylureas和二氮氧化物对Kir6.2的差异。 2。通过在kir6.2的N端域中的短细胞质环中稳定在PIP2结合的开放状态下的KIR6.2的固有PO。通过SUR1-KIR6.2界面来增强或削弱通道PIP2相互作用，我们将交织到前向遗传学，疾病突变，引导诱变筛选，化学交叉链接和结构LING的方法来检验该假设。故事的概念。 TOOO。 公共卫生相关性：将代谢信号与细胞类型的生理反应联系起来，对ATP敏感的钾（KATP）通道起着关键作用。要了解开放式开放或饲养的能力，可以根据通道功能障碍引起的新型治疗剂的疾病治疗剂的发展。