Regulation of KCNH ion channels

KCNH 离子通道的调节

• 批准号: 8758371
• 负责人: William N Zagotta
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-04 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758371
• 关键词: Action Potentials; Affect; Antibodies; Arrhythmia; Binding; Binding Sites; Brain; C-terminal; Calmodulin; Cardiac Myocytes; Cartoons; Cognition; Cognitive; Complex; Congenital Heart Defects; Couples; Cyclic Nucleotides; DNA Sequence Rearrangement; DNA biosynthesis; Defect; Disease; Electrophysiology (science); Ethers; Family; Fluorescence; Gene Mutation; Genes; Goals; Health; Heart; Heart Diseases; Human; Ion Channel; Ligands; Link; Long QT Syndrome; Malignant Neoplasms; Measures; Mediating; Mental disorders; Molecular; Mutate; N-terminal; Neurons; Phosphorylation; Play; Potassium Channel; Property; Protein Isoforms; Regulation; Risk; Roentgen Rays; Role; Schizophrenia; Shapes; Small Interfering RNA; Structure; Testing; Ventricular; X-Ray Crystallography; desensitization; disease-causing mutation; neoplastic cell; public health relevance; research study; sudden cardiac death; therapy design; therapy development; voltage

DESCRIPTION (provided by applicant): Ion channels underlie all electrical excitability in the brain and heart, and defects in ion channels are the cause of many human disorders. The KCNH family of channels, ERG, ELK, and EAG, are voltage-dependent potassium channels that are specialized for their role in shaping the electrical activity of neurons and cardiomyocytes. Defects in KCNH channels have been shown to be linked to cognitive defects, increased risk of schizophrenia, cardiac arrhythmias, and cancer. Recently it has become clear that the specialized gating of KCNH channels arises from their unique intracellular domains, the N-terminal eag domain, and the C-terminal C-linker/CNBHD. In this proposal, we will test the hypothesis that the C-linker/CNBHD of KCNH channels is a key regulatory domain that mediates the action of the eag domain and other intracellular regulators. We will build on three exciting new X-ray crystal structures we have solved of the intracellular domains of three different KCNH channels: 1) the C-linker/CNBHD of ELK, 2) the C-linker/CNBHD of ERG, and 3) a complex of the CNBHD and eag domain of EAG. These new structures reveal unexpected features like a direct interaction between the eag domain and the CNBHD, and an intrinsic ligand in the binding site of the CNBHD that regulates gating. They provide a framework to better understand the mechanisms of the gating and regulation of KCNH channels. Toward this goal, we will leverage the power of X-ray crystallography, electrophysiology, and fluorescence to study the structure and rearrangements of the eag domain and C-linker/CNBHD during gating of KCNH channels.

描述（由申请人提供）：离子通道是大脑和心脏中所有电兴奋性的基础，而离子通道中的缺陷是许多人类疾病的原因。 KCNH的通道家族，ERG，ELK和EAG是电压依赖性的钾通道，它们在塑造神经元和心肌细胞的电活动中的作用专门起作用。 KCNH通道中的缺陷已显示与认知缺陷，精神分裂症，心律不齐和癌症的风险增加有关。最近，很明显，KCNH通道的专门门控源于其独特的细胞内结构域，N末端EAG结构域和C端C-Linker/CNBHD。在此提案中，我们将检验以下假设：KCNH通道的C-LINKER/CNBHD是介导EAG域和其他细胞内调节剂的作用的关键调节域。我们将建立在三个令人兴奋的新X射线晶体结构上，我们已经在三个不同的KCNH通道的细胞内结构域解决：1）ELK的C-Linker/CNBHD，2）ERG的C-LINKER/CNBHD和3）和3） EAG的CNBHD和EAG域的复合物。这些新结构揭示了意外的特征，例如EAG结构域和CNBHD之间的直接相互作用，以及调节门控的CNBHD结合位点中的内在配体。它们提供了一个框架，以更好地了解KCNH通道的门控和调节的机制。为了实现这一目标，我们将利用X射线晶体学，电生理学和荧光的功能研究KCNH通道门控过程中EAG域和C-Linker/CNBHD的结构和重排。