Ion Channel Transporter Interactions

项目摘要 电压门控钾离子通道由成孔α亚基的四聚体产生，通常在 与其他非孔形成β亚基的复合物。该项目的重点是两个非常重要的，5名成员 Kv通道亚基家族：KCNQ α亚基和KCNE β亚基。KCNQ 1在 心脏和许多上皮细胞;其在可兴奋和不可兴奋细胞中的多种生理作用， 通过与5个KCNE单跨膜结构域β亚基中的每一个的相互作用而促进。KCNE β亚基 广泛表达并调节大多数Kv亚家族的α亚基，甚至其他通道类型。 KCNQ 2 -5 α亚基，尤其是KCNQ 2/3异聚体，因其在产生KCNQ 2 - 5 α亚基中的重要作用而闻名。 神经元M电流，调节神经元兴奋性。KCNQ 2 -5也在其他组织中表达， 包括脉管系统和听觉系统。反映其生理重要性，KCNQ或 KCNE基因引起的疾病多种多样，如心律失常、糖尿病、缺氯症、甲状腺功能减退症， 癫痫我们使用高度集成的方法来研究KCNQ的分子机制基础， KCNE生物学和病理生理学这包括基因敲除和基因敲入小鼠模型，细胞免疫学和细胞免疫学。 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- 功能和生化技术。在未来五年，我们的目标是应对几个突出的挑战 在该领域，追求以下新的研究方向。(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，因为基因通常在多个系统中表达。 组织中然而，传统的方法通常涉及集中在单个组织上。我们的目标是剖析 KCNQ和KCNE为基础的疾病，通过拥抱多系统的方法，并首先了解 这些亚基相互交织的生理功能的分子基础。(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 运输机我们将研究由纳米结构域产生的新型信号传导纳米结构域的分子机制和作用。 “chansporter”情结。(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分支的范式转变。我们将 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)我们将探讨几个新发现的KCNQ的分子基础和生理重要性， KCNE相互作用涉及，例如，淀粉样前体蛋白C99片段，和粘着斑蛋白， 测试在这个项目中的工作将剖析丰富的剧目信号促进离子通道， KCNQ和/或KCNE亚基，在各种不同的器官系统和细胞类型。这些目标 了解KCNQ/KCNE相关生物过程的机制，并阐明它们是如何 以及如何利用它们来开发更安全，更有效的治疗方法。

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.