Cardiac KATP Channels in Health and Disease

健康和疾病中的心脏 KATP 通道

• 批准号: 6858695
• 负责人: ANDRE TERZIC
• 金额: $ 33.19万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858695
• 关键词: adenosinetriphosphatase; bioenergetics; disease /disorder model; electrophysiology; enzyme activity; enzyme mechanism; enzyme structure; functional /structural genomics; gene mutation; genetically modified animals; glycolysis; high throughput technology; human genetic material tag; idiopathic dilated cardiomyopathy; ischemic preconditioning; laboratory mouse; membrane activity; myocardium; myocardium disorder; nucleotides; potassium channel; protein sequence; protein structure function; proteomics; stress; voltage /patch clamp

DESCRIPTION (provided by applicant): Cardiac ATP-sensitive K+ (KATP) channels, formed by the pore-forming Kir6.2 and regulatory SUR2A subunits, are characterized by nucleotide-dependent regulation that allows the channel complex to adjust membrane excitability in response to changes in the cellular energetic state. However, it is unknown how cardiac KATP channels translate nucleotide signals into pore gating, what is the full impact of channel activity on cardiac homeostasis, and ultimately whether channel defects contribute to heart disease. In the previous funding period of this proposal we identified an ATPase activity intrinsic to the SUR2A subunit, demonstrated that deficient KATP channel function reduces cardiac tolerance to adrenergic challenge, and discovered KATP channel mutations in initial screening of patients with heart failure. Based on these findings, we here put forward the novel concept that cardiac KATP channels operate as a bi-functional channel/enzyme molecular combination serving a vital role under diverse stressors. Aim #1 will define the molecular mechanisms governing the SUR2A catalysis-based nucleotide gating of the Kir6.2 pore. Aim #2 will establish the impact of KATP channels on prevention of maladaptive structural remodeling, and preservation of energetic and electrical stability in the physiologically and pathologically stressed myocardium. Aim #3 will determine the spectrum of cardiac KATP channel mutations in patients with idiopathic dilated cardiomyopathy, and define the consequences of these mutations on the KATP channel/enzyme phenotype, metabolic sensing and cell adaptation to stress. To this end, we will employ murine knockout and disease models, along with genomic specimens from an existing cohort of patients with cardiomyopathy. The complementary technologies of enzymology, electrophysiology, physiological genomics, high-throughput DNA screening and functional proteomic analysis will be applied to study the cardiac KATP channel at the organism, organ, cellular and molecular levels. Thus, this proposal will provide an integrated understanding of cardiac KATP channels in metabolic signal decoding, stress adaptation, and their impact for clinical medicine.

描述（由申请人提供）：心脏 ATP 敏感 K+ (KATP) 通道由成孔 Kir6.2 和调节性 SUR2A 亚基形成，其特点是核苷酸依赖性调节，允许通道复合物根据细胞能量状态的变化调整膜兴奋性。然而，尚不清楚心脏 KATP 通道如何将核苷酸信号转化为孔门控、通道活动对心脏稳态的全面影响是什么，以及最终通道缺陷是否会导致心脏病。在本提案的前一个资助期间，我们鉴定了 SUR2A 亚基固有的 ATP 酶活性，证明 KATP 通道功能缺陷会降低心脏对肾上腺素能挑战的耐受性，并在心力衰竭患者的初始筛查中发现 KATP 通道突变。基于这些发现，我们在此提出了一个新概念：心脏 KATP 通道作为双功能通道/酶分子组合在不同的应激源下发挥着至关重要的作用。目标#1 将定义控制 Kir6.2 孔基于 SUR2A 催化的核苷酸门控的分子机制。目标 #2 将确定 KATP 通道对预防适应不良的结构重塑以及保持生理和病理应激心肌中的能量和电稳定性的影响。目标 #3 将确定特发性扩张型心肌病患者心脏 KATP 通道突变谱，并确定这些突变对 KATP 通道/酶表型、代谢传感和细胞应激适应的影响。为此，我们将采用小鼠基因敲除模型和疾病模型，以及来自现有心肌病患者队列的基因组标本。酶学、电生理学、生理基因组学、高通量DNA筛选和功能蛋白质组学分析等互补技术将应用于生物体、器官、细胞和分子水平上的心脏KATP通道研究。因此，该提案将提供对心脏 KATP 通道在代谢信号解码、应激适应及其对临床医学影响中的综合理解。