The applicant's laboratory has made significant contributions to understanding the cellular basis of the phenomenon of postjunctional supersensitivity. This phenomenon is the expression of a cellular homeostatic mechanism by which cells compensate for chronic changes in the net stimulus the cells receive, generally via their innervation. Our long term goals have been and continue to be to understand the cellular and molecular bases of these changes in sensitivity and their biological significance. The proposed work is directly in line with these goals. There are three components to the proposal. (1) Identify the cellular bases of supersensitivity in the heart. (2) Determine if sensitivity changes in vascular smooth muscle contribute to renal hypertension in rats. (3) Determine if sensitivity changes in discrete regions of the brain contribute to the seizure state in rat models of epilepsy. The broad goals of this proposal necessitate the use of a wide range of methodologies. Most of the methods to be employed are established in the laboratory of the responsible investigator and include pharmacological techniques (e.g. construction and interpretation of concentration-response curves), biochemical procedures (e.g. radioactive ligand binding, rubidium uptake, assay of adenylate cyclase activity and cyclic AMP levels and measurement of Na+, K+ -ATPase activity). A major portion of the proposal also involves various electrophysiological techniques (e.g. intracellular recording from cardiac and smooth muscle cells; extracellular recording of individual neuronal activity in situ and microiontophoretic application of drugs to individual neurons). Studies of the proteins involved in the coupling of cardiac receptors to adenylate cyclase will be undertaken in collaboration with Dr. Theodore Torphy and Jeffrey Stadel of Smith, Kline, Beckman as a consultant.
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