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， 内向整流和ATP敏感性钾通道，发现整个心血管系统。 我们的工作整合了多个层次的研究，从通道活性的基本分子基础， 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如何 构造和功能，它们如何调节个体平滑肌和心肌，以及如何改变通道 心血管系统功能异常的病理后果。 以前，我们发现可溶性细胞质多胺引起内向整流，并证明了它们的作用。 Kir通道中的作用机制和位点。我们已经开发了纯化Kir和ATP敏感的能力， （KATP）通道，并分析这些蛋白质的结构，生化和功能。这使我们能够 发展和解决令人兴奋的新问题和假设的基本基础Kir和KATP 通道活性，包括脂质调节门控的分子机制和动态结构 伴随门控的变化。KATP通道将代谢与心脏和平滑肌中的电活动联系起来。 我们最近关于KATP通道突变在人类Cantu综合征（CS）中的因果作用的研究结果表明， 兴奋不足的多种病理后果，包括胎儿循环持续存在，心包 渗出、水肿、血管顺应性降低和肠道动力降低。开发独特的 新型转基因动物，以及独特的研究CS诊所，使我们能够产生广泛的 初步的数据，开始解释这些特点，并导致我们的新的假设，将探讨 在动物和人类中使用多种细胞生物学和生理学方法，以充分了解 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 在动物模型和动物模型中测试CS治疗的相关药理学方法的背景 人类，最终目标是开发用于CS和相关病理的特异性疗法。

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.