Ion Channel Transporter Interactions

离子通道转运体相互作用

• 批准号: 10557191
• 负责人: Geoffrey W Abbott
• 金额: $ 41.72万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557191
• 关键词: Achlorhydria; Address; Amyloid beta-Protein Precursor; Arrhythmia; Auditory system; Biochemical; Biological Process; Biology; Cells; Charge; Complex; Coupled; Diabetes Mellitus; Disease; Electrophysiology (science); Epilepsy; Epithelium; Family member; Focal Adhesions; Functional disorder; Genes; Goals; Heart; Hereditary Disease; Hypothyroidism; Ion Channel; Ions; Knock-in Mouse; Knock-out; Link; Molecular; Movement; Neurons; Neurotransmitters; Pharmaceutical Preparations; Physiological; Potassium; Process; Proteins; Radioligand Assay; Regulation; Research; Role; Signal Transduction; Sodium; Structure; System; Techniques; Tissues; Transmembrane Domain; Work; analog; base; body system; cell type; design; imaging modality; mouse model; nano; neuronal excitability; novel; solute; therapeutically effective; transcriptomics; voltage

Project Summary Voltage-gated potassium (Kv) channels are generated by tetramers of pore-forming α subunits, often in complexes with other, non-pore-forming β subunits. This project is focused on two highly important, 5-member families of Kv channel subunits: the KCNQ α subunits and the KCNE β subunits. KCNQ1 is essential in the heart and numerous epithelia; its diverse physiological roles in both excitable and non-excitable cells are facilitated by interaction with each of the 5 KCNE single-transmembrane domain β subunits. KCNE β subunits are widely expressed and regulate α subunits from most Kv subfamilies, and even other channel types. KCNQ2-5 α subunits, especially KCNQ2/3 heteromers, are best known for their essential role in generating the neuronal M-current, which regulates neuronal excitability. KCNQ2-5 are also expressed in other tissues, including the vasculature and auditory system. Reflecting their physiologic importance, disruption of KCNQ or KCNE genes causes disorders as diverse as cardiac arrhythmia, diabetes, achlorhydria, hypothyroidism, and epilepsy. We use a highly integrated approach to investigate the molecular mechanistic bases for KCNQ and KCNE biology and pathophysiology. This includes both knockout and knock-in mouse models, cellular electrophysiology, transport and radioligand assays, transcriptomics, various imaging modalities, structure- function and biochemical techniques. In the next five years, we aim to address several outstanding challenges in the field, pursuing the following novel research directions. (1) Inherited disorders linked to KCNQ or KCNE genes are often highly complex, multi-system diseases because the genes are typically expressed in multiple tissues. Yet, traditional approaches often involve focusing on a single tissue. We aim to dissect the basis for KCNQ- and KCNE-based diseases by embracing multi-system approaches and by first understanding the molecular basis for the intertwining physiological functions of these subunits. (2) We recently found that KCNQ channels form physiologically essential complexes with several different types of sodium-coupled solute transporters. We will study the molecular mechanisms and roles of novel signaling nanodomains created by “chansporter” complexes. (3) We very recently discovered that some neurotransmitters and their analogs can directly activate specific neuronal KCNQs, a paradigm shift with potentially widespread ramifications. We will investigate its physiological relevance, molecular mechanisms, and crosstalk with co-assembled transporters. (4) We will pursue the molecular basis and physiological importance of several newly discovered KCNQ and KCNE interactions involving, e.g., Amyloid Precursor Protein C99 fragment, and the focal adhesion protein, Testin. Work in this project will dissect the rich repertoire of signaling facilitated by ion channels containing KCNQ and/or KCNE subunits, in a variety of different organ systems and cell types. The goals are to understand the mechanisms underlying KCNQ/KCNE-linked biological processes, and elucidate how they are perturbed in disease states, and how they can be leveraged to develop safer, more effective therapeutics.

项目概要 电压门控钾 (Kv) 通道由成孔 α 亚基的四聚体产生，通常位于 与其他非成孔 β 亚基的复合物 该项目重点关注两个非常重要的 5 成员。 Kv 通道亚基家族：KCNQ α 亚基和 KCNE β 亚基在 KCNQ1 中至关重要。 心脏和众多上皮细胞；其在兴奋性和非兴奋性细胞中的多种生理作用 通过与 5 个 KCNE 单跨膜结构域 β 亚基的相互作用来促进。 广泛表达并调节大多数 Kv 亚家族甚至其他通道类型的 α 亚基。 KCNQ2-5 α 亚基，尤其是 KCNQ2/3 异聚体，以其在生成 调节神经元兴奋性的神经元 M 电流也在其他组织中表达。 包括脉管系统和听觉系统，反映了它们的生理重要性、KCNQ 的破坏或 KCNE 基因导致多种疾病，如心律失常、糖尿病、胃酸缺乏、甲状腺功能减退症和 我们使用高度集成的方法来研究 KCNQ 和癫痫的分子机制基础。 KCNE 生物学和病理生理学，包括敲除和敲入小鼠模型、细胞。 电生理学、转运和放射性配体测定、转录组学、各种成像方式、结构- 在未来五年中，我们的目标是解决几个突出的挑战。 (1) 与 KCNQ 或 KCNE 相关的遗传性疾病 基因通常是高度复杂的多系统疾病，因为这些基因通常在多个系统中表达。 然而，传统方法通常涉及单一组织，我们的目标是剖析其基础。 通过采用多系统方法并首先了解基于 KCNQ 和 KCNE 的疾病 (2)我们最近发现KCNQ 通道与几种不同类型的钠偶联溶质形成生理必需的复合物 我们将研究由其产生的新型信号纳米结构域的分子机制和作用。 “chansporter”复合物 (3) 我们最近发现一些神经递质及其类似物可以。 直接激活特定的神经元 KCNQ，这是一种具有潜在广泛影响的范式转变。 研究其生理相关性、分子机制以及与共组装转运蛋白的串扰。 (4) 我们将探究几个新发现的KCNQ和的分子基础和生理重要性 KCNE 相互作用，例如淀粉样蛋白前体蛋白 C99 片段和粘着斑蛋白， 该项目的测试工作将剖析由离子通道促进的丰富的信号通路，其中包含 KCNQ 和/或 KCNE 亚基，在各种不同的器官系统和细胞类型中。 了解 KCNQ/KCNE 相关生物过程的潜在机制，并阐明它们是如何发生的 疾病状态的困扰，以及如何利用它们来开发更安全、更有效的治疗方法。