Modulation of the cardiac G protein-gated K+ channel

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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.