Modulation of the cardiac G protein-gated K+ channel

描述(申请人提供)：这项研究的目的是了解心脏G蛋白门控钾通道的功能和调节的外在影响和内在结构。第一个目的是确定磷酸酶是否以亚单位依赖的方式影响GIRK通道的功能。GIRK1/GIRK4异多聚体(IKAch)和GIRK4同源多聚体(GIRK4)分别在野生型和GIRK1基因敲除小鼠的心房肌细胞中被研究，显示出不同的功能特性，包括在细胞附着的斑块配置中对崩溃的不同易感性。对GIRK4同源多聚体通道表现出相对选择性的磷酸酶对这种差异负责的假设将得到检验。在这一目标中提出的实验可能揭示一种机制，即细胞分离复杂信号级联的平行分支的功能后果。第二个目标是开发一种涉及缺乏GIRK1或GIRK4的心房肌细胞的表达系统，以评估天然环境下通道结构与功能的关系。这样的系统将提供在通常支持心脏离子通道功能的环境中执行该通道的结构/功能分析的独特机会。

DESCRIPTION (provided by applicant): The goal of this research is to understand the extrinsic influences and intrinsic structures responsible for the function and modulation of the cardiac G protein-gated potassium channel. The first aim is to determine whether a phosphatase impacts the function of GIRK channels in a subunit-dependent fashion. The GIRK1/GIRK4 heteromultimer (IKAch) and the GIRK4 homomultimer studied in atrial myocytes from wild-type and GIRK1 knockout mice, respectively, exhibit distinct functional properties, including different susceptibilities to rundown in the cell-attached patch configuration. The hypothesis that a phosphatase exhibiting a relative selectivity for GIRK4 homomultimeric channels is responsible for this difference will be tested. The experiments proposed in this aim could reveal a mechanism whereby cells segregate the functional consequences of parallel branches of a complex signaling cascade. The second aim is to develop an expression system involving atrial myocytes lacking GIRK1 or GIRK4 to evaluate channel structure-function relationships in a native setting. Such a system will offer a unique opportunity to perform structure/function analyses of a cardiac ion channel in an environment that normally supports that channel's function.