This project seeks to enhance our understanding of the physiological, pharmacological, and pathophysiological properties of heart and smooth muscle membranes. The Program Project includes studies of ionic currents in whole cells, ion fluxes in isolated membrane vesicles, structure-function relationships in individual membrane proteins, and the regulation of single channel currents generated by native ion channels in intact cells and ion channel proteins reconstituted into planar lipid bilayers. The interrelated Projects provide a concerted effort to characterize cardiovascular membrane structure and function as part of a long term effort to elucidate the relationship of fundamental membrane properties to the pathogenesis and therapy of cardiovascular disease. The central theme is to examine the interplay between biochemical, biophysical and molecular mechanisms controlling ion fluxes and other aspects of membrane function, and to elucidate the role of membrane proteins in determining the behavior of cardiac, skeletal, and smooth muscle. Surface (plasma) and intracellular membranes will be utilized to identify and characterize structural and functional properties of membrane proteins in the regulation of active and passive ion fluxes across cardiovascular membranes. Electrophysiological and biochemical studies of intact cells and purified membranes will define the properties of populations of ion pumps and channels. These data will be evaluated at a molecular level in collaborative studies of single ion channels and related membrane proteins reconstituted into lipid bilayers. Data from normal membranes will provide a basis for studies of drug actions on selected ion channels and pumps. Calcium metabolism will be examined in cells isolated from chronically overloaded hearts to evaluate the functional role of altered expression of genes encoding specific membrane proteins of the hypertrophied left ventricle in an effort to understand the pathogenesis of the clinical syndromes of heart failure.
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