Modulation of the cardiac G protein-gated K+ channel

描述（由申请人提供）：本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基依赖的方式影响GIRK通道的功能。分别在野生型和GIRK1敲除小鼠心房肌细胞中研究的GIRK1/GIRK4异聚体（IKAch）和GIRK4同聚体表现出不同的功能特性，包括对细胞附着贴片结构的破坏的不同敏感性。这一假设，表现出对GIRK4同质通道的相对选择性的磷酸酶是负责这种差异将被测试。在这个目标中提出的实验可以揭示一个机制，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-功能关系。这样的系统将提供一个独特的机会，在通常支持心脏离子通道功能的环境中执行心脏离子通道的结构/功能分析。

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.