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

钾通道催化钾离子跨细胞渗透 膜。以这种方式，它们介导可兴奋组织的功能， 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孔形成P结构域的存在。在 1995年，我们从芽殖酵母中克隆出第一个 一个新的K+通道超家族成员，内部携带2个P结构域 在连续多肽上。/ 1在1996年，我们分离出了第二个 果蝇2 P结构域K/+通道谱系2我们 对这两个通道的研究揭示了以前被认为是 在克隆的通道中未被识别，并显示新的超家族是 在结构和功能上都很独特。现在，我们已经分离出2 P 结构域K/+通道基因。在这个项目中，我们建议 第一个研究小鼠OAT，一个心脏特异性，pH敏感性，2 P结构域 K/+通道及其人类同源物。我们的长期目标是 三重：探索OAT渠道功能的结构基础， 确定OAT基因表达的决定因素，并阐明 OAT通道在心脏发育和生理学中的作用。我们的六个目标 目的：（1）研究小鼠OAT的功能和药理作用 （2）研究细胞膜的拓扑结构和亚基化学计量， OAT通道;（3）表征鼠OAT的细胞调节 通道;（4）确定表达模式、天然组成和 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物（称为Ik/p）;（5）鉴定顺式- 调节鼠OAT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OAT的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， 如果要诊断心脏疾病，必须了解成熟的心脏， 治疗和治愈。我们的动机是知道OAT渠道是 在发育和自然心脏中高水平表达。因为 超家族及其心脏变异的鉴定是最近的，基本的 对它们在健康和疾病中的作用的理解还有待于实现。我们现在有 工具来实现这种理解。

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.