The long term objective of this project is to understand in a more detailed sense the mechanism of action of cGMP in eukaryotic cells. Specifically it will be the goals of this study to delineate the biochemical mechanism of cGMP-induced relaxation of vascular smooth muscle in the hope that this will increase our understanding of vascular smooth muscle function. Using the recent findings on the physiological actions of cGMP derivatives on Ca2+ metabolism in smooth muscle as a starting point, the effects of cGMP and agents which raise cGMP levels on the Ca2+ regulated enzymes myosin light chain kinase and phosphorylase kinase, will be studied. An attempt will be made to correlate the effects of cGMP on tension and Ca2+ regulated enzyme activity in order to probe the effects of cGMP on Ca2+ metabolism. In addition, the effects of specific cGMP-dependent phosphorylation on Ca2+ accumulation in crude, partially purified, and purified membrane fractions from vascular smooth muscle will be studied. The correlation of changes in Ca2+ uptake by these structures with Ca2+ regulated enzyme activity should provide key insights into the mechanism of action of cGMP. And finally, the purification and identification of specific cGMP-protein kinase substrate(s) and its (their) roles(s) in Ca2+ metabolism will be studied. By understanding the biochemical mechanism of action of cGMP in normal smooth muscle physiology, predictions and hypotheses can be tested on what role this system has in vascular abnormalities which occur in pathological situations such as essential hypertension. Furthermore, an understanding of the actions of cGMP in smooth muscle will aid in our knowledge of its role in other systems where the nucleotide and its receptors are prominent, i.e., brain, heart, and secretory tissues.
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