This application is for the renewal of a program project that was initiated in 1986. The proposed program is now focused on the structure- function relationships of the ion pumps that are sensitive to cardiac glycosides, and on the elucidation of mechanisms by which cardiac glycosides and intracellular calcium ion regulate the growth of cardiac cells. The participating investigators with expertise in membrane biochemistry, molecular genetics, protein chemistry, cell biology, and cardiac physiology will combine their efforts to conduct the following studies: Project I deal with NAK-ATPase which is the receptor for the positive inotropic actions of cardiac glycoside. The proposed studies are designed to reveal the structures of the ATP-sensitive occlusion pockets and their roles in the transport function of NaK-ATPase. Studies of Project II are aimed to characterize the structure of a newly discovered human HK-ATPase that is also sensitive to cardiac glycosides, and to reveal the structural bases of the ion selectivities of this and related ion transporting ATPases. Studies of Project III are based on the recent discovery that cardiac glycosides induce hypertrophy in cultured cardiac myocytes, and are aimed to define the specific signal transduction pathways that begin with the partial inhibition of NaK-ATPase and lead to Ca2+-dependent transcriptional regulations of cardiac myocyte genes. Project IV focuses on the molecular mechanisms through which intracellular Ca2+-dependent proteases (calpains) regulate the signal transduction pathways involved in the proliferative growth of fibroblasts associated with pathological cardiac hypertrophy. The proposed studies are expected to advance our knowledge of the basic mechanisms that are central to the regulation of cardiac contractility and growth in the normal and the failing hearts.
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