The long-range objective of the proposed research is to identify factors that contribute to the regulation of the function of the cardiac sarcoplasmic reticulum (SR). The SR is thought to play a key role in determining the availability of calcium to the contractile proteins and hence in determining the contractile properties of the heart. An effect of cAMP-dependent protein kinase to increase the rate of calcium transport in isolated SR, as shown previously by this and other laboratories, can account, at least in part, for the relaxation-promoting effects of catecholamines on the heart. More recently, increased rates of calcium transport have been demonstrated in SR Membranes with calmodulin-dependent protein kinase and phospholipid-dependent, Ca++ sensitive protein kinase. In the proposed research, the regulation of cardiac SR membrane function by cAMP-, calmodulin-, and phospholipid-dependent protein kinases will be studied in the fetal, neonatal, and aging heart. SR membrane regulation will be assessed in terms of calcium transport rate, (Ca++ + Mg++)-activated ATPase activity, membrane phosphorylation, calcium efflux, and calcium capacity. The last two measurements may have bearing on a postulated role of the SR in the inotropic effect of catecholamines. We will also further explore the relationship between changes in phospholipid metabolism and changes in calcium transport induced by varying Ca++ concentrations and the presence of different protein kinases. Studies will be carried out in vitro with isolated SR preparations or whole muscle homogenates. Animal tissues to be utilized are canine and rat myocardium, and for comparison, rabbit skeletal muscle. The proposed studies should provide basic new information about the physiologic and pharmacologic regulation of calcium fluxes across cardiac subcellular membranes with special emphasis on the developing and aging heart. This information may be useful in understanding the biochemical basis for the action of catecholamines and catecholamine antagonists on the human myocardium during development and aging.
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