OAT--A NOVEL CARDIAC POTASSIUM CHANNEL WITH 2 P DOMAINS

钾离子通道催化K/+离子跨细胞渗透 膜。通过这种方式，它们调节可兴奋组织的功能，如 心肌。直到1995年，所有公认的K/+的定义属性 通道亚基是一个单一的形成孔的P结构域。在……里面 1995年，我们从发芽酵母中克隆出第一株酿酒酵母 一个新的K+通道超家族的成员，它携带2P结构域 在连续多肽./1上，1996年，我们分离出了第二个 果蝇2P结构域K/+通道的谱系 对这两个渠道的研究揭示了以前的表型 在克隆的频道中未被识别，并表明新的超家族是 在结构和功能上都很独特。现在，我们已经分离出两个P 小鼠和人的K/+结构域通道基因。在这个项目中，我们建议 首次研究小鼠OAT，心脏特异的、pH敏感的2P结构域 K/+通道，以及随后的人类同源物。我们的长期目标是 三：探索燕麦通道功能的结构基础， 确定燕麦蛋白基因表达的决定因素，并阐明 燕麦蛋白通道在心脏发育和生理中的作用。我们的六个目标 主要内容有：(1)研究燕麦的功能和药理作用 (2)膜拓扑结构和亚基化学计量学的研究 燕麦通道；(3)研究小鼠燕麦细胞的调控 渠道；(4)确定表达模式、自然成分和 OAT通道在体内的作用(从而确定OAT是否是 心脏电流的分子相关称为Ik/p)；(5)识别顺式- 调节小鼠燕麦蛋白基因的肌动蛋白序列和反式肌动蛋白因子； 以及，(6)评估小鼠燕麦显著属性是如何概括的 在人类身上。心脏生理学与K/+通道功能密切相关。 它遵循离子通道功能的基本方面在开发和 如果要诊断心脏疾病，必须了解成熟的心脏， 治疗和治愈。我们的动机是了解OAT渠道是 在发育中和自然的心脏中高水平表达。因为 对超家族及其心脏变异体的鉴定是最近的基础 了解它们在健康和疾病中的作用是摆在我们面前的。我们现在有 实现这一理解的工具。

Potassium channels catalyze the permeation of K/+ ions across cell membranes. In this way, they mediate function of excitable tissues such as cardiac muscle. Until 1995, the defining attribute of all recognized K/+ channel subunits was the presence of a single pore-forming P domain. In 1995, we cloned from the budding yeast Saccharomyces cerevisiae the first member of a new superfamily of K+ channels that carry 2 P domains within on continuous polypeptide./1 In 1996, we isolated an example of a second lineage of 2 P domain K/+ channels from Drosophila melanogaster./2 Our studies of these two channels revealed phenotypes that were previously unrecognized among cloned channels and showed the new superfamily to be distinctive in both structure and function. Now, we have isolated 2 P domain K/+ channel genes from mouse and human. In this project, we propose first to study murine OAT, a cardiac-specific, pH-sensitive, 2 P domain K/+ channel and, subsequently, its human homolog. Our long-term goals are three-fold: to explore the structural basis for OAT channel function, to identify the determinants of OAT gene expression, and, to elucidate the role of OAT channels in cardiac development and physiology. Our six aims are: (1) to characterize the function and pharmacology of murine OAT channels; (2) to study the membrane topology and subunit stoichiometry of OAT channels; (3) to characterize cellular modulation of murine OAT channels; (4) to determine the expression pattern, native composition and role of OAT channels in vivo (and, thereby, to determine if OAT is the molecular correlate of cardiac current called Ik/p); (5) to identify cis- actin sequences and trans-actin factors that regulate the murine OAT gene; and, (6) to assess how salient attributes of murine OAT are recapitulated in humans. Cardiac physiology is intimately tied to K/+ channel function. It follows the basic aspects of ion channel function in developing and mature heart must be understood if cardiac disorders are to be diagnosed, treated and cured. Our motivation is the knowledge that OAT channels are expressed at high levels in developing and nature heart. Because identification of the superfamily and its cardiac variant is recent, basic understanding of their role in health and disease lies ahead. We now have the tools to achieve this understanding.