Potassium Channels and Control of Cardiovascular Function

摘要 我的实验室研究离子通道的机制基础和功能后果，特别是背景知识 内向整流钾通道和ATP敏感性钾通道，在心血管系统中广泛存在。 我们的工作整合了多个层面的研究，从通道活动的基本分子基础到 与人类疾病相关的病理学的动物模型。我们感兴趣的是渠道是如何 它们如何调节个体的平滑肌和心肌，以及如何改变通道 功能参与心血管系统功能异常的病理后果。 在此之前，我们发现了细胞质中的可溶性多胺引起内向整流，并证明了它们 KIR通道的作用机制和作用部位。我们已经开发出提纯KIR和对ATP敏感的能力 (KATP)通道，并从结构、生化和功能上分析这些蛋白质。这使我们能够 开发和解决有关KIR和KATP基本基础的令人兴奋的新问题和假设 通道活性，包括脂质调节门控的分子机制和动态结构 随之而来的变化。KATP通道将新陈代谢与心肌和平滑肌的电活动联系起来。 我们最近关于KATP通道突变在人类坎图综合征(CS)中的因果作用的发现揭示了 兴奋性不足的多种病理后果，包括胎儿循环持续、心包 渗出，淋巴水肿，血管顺应性降低，肠道动力减弱。开发独特的和 新的转基因动物，以及独特的研究CS诊所，使我们能够产生广泛的 开始解释这些特征的初步数据，并引导我们提出新的假设，这些假设将被探索 在动物和人类中使用多种细胞生物学和生理学方法来充分理解 KATP依赖性兴奋性在心血管功能调节中的性质和作用。这些研究将形成 CS治疗的相关药理学方法在动物模型中和在 人类，最终目标是开发一种治疗CS和相关病理的特效疗法。

ABSTRACT My lab studies the mechanistic basis, and functional consequences, of ion channels, particularly background inward rectifier and ATP-sensitive potassium channels, that are found throughout the cardiovascular system. Our work integrates studies at multiple levels, from the fundamental molecular basis of channel activity to animal models of pathologies associated with human disease. We are interested in how channels are constructed and function, how they regulate individual smooth and cardiac muscles, and how altered channel function contributes to the pathological consequences of aberrant function in the cardiovascular system. Previously, we discovered that soluble cytoplasmic polyamines cause inward rectification and demonstrated their mechanism and sites of action in Kir channels. We have developed the capability to purify Kir and ATP-sensitive (KATP) channels and to analyze these proteins structurally, biochemically and functionally. This allows us to develop and address exciting new questions and hypotheses regarding the fundamental basis of Kir and KATP channel activity, including the molecular mechanisms by which lipids regulate gating and the dynamic structural changes that accompany gating. KATP channels link metabolism to electrical activity in cardiac and smooth muscle. Our recent findings regarding a causal role of KATP channel mutations in human Cantu Syndrome (CS) reveal multiple pathological consequences of underexcitability, including persistence of fetal circulation, pericardial effusion, lymphedema, decreased vascular compliance and decreased gut motility. Development of unique and novel genetically modified animals, as well as a unique research CS clinic, has allowed us to generate extensive preliminary data that begin to explain such features, and leads us to novel hypotheses which will be explored using multiple cell biological and physiological approaches in animals and humans to reach a full understanding of the nature and role of KATP dependent excitability in regulation of cardiovascular function. These studies will form the background to the testing of relevant pharmacological approaches to CS therapy in animal models and in humans, with the ultimate goal of developing a specific therapy for CS and related pathologies.