The renin-angiotensin system is a complex biochemical pathway that maintains homeostasis of blood pressure, blood volume and electrolyte composition. The active product of this pathway, angiotensin II, has effects on tissues throughout the body. Studies have demonstrated that virtually all of the physiologic actions of angiotensin II are mediated by the AT1 receptor. It is remarkable that angiotensin II binding to the identical receptor in the adrenal, the kidney, the liver and vascular smooth muscle cells causes such a diversity of tissue specific effects. This clearly suggests that the angiotensin II-AT1 receptor association is only the first step in a cascade of intracellular signals that progresses from the cell surface into the cytoplasm and the nucleus. It is these signals that stimulate tissue specific responses. Recently, it has become clear that tyrosine phosphorylation plays an important role in the early signalling responses mediated by angiotensin II. This grant is to study how angiotensin II, in binding to the seven-transmembrane AT1 receptor, stimulates the tyrosine phosphorylation of downstream kinases and heterotrimeric G-proteins in angiotensin II mediated tyrosine phosphorylation of phospholipase C, the JAK pathway and the Ras signaling pathways.
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