CHARACTERIZATION OF HEART ATRIAL MUSCARINIC RECEPTOR

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Muscarinic cholinergic receptors in the atria mediate the regulation of the heart by the parasympathetic nervous systems. In order to obtain detailed information regarding the molecular mechanism of atrial muscarinic receptor signal transduction two approaches are proposed. The first is to use site- directed mutagenesis to explore the roles of specific amino acids in ligand binding, thermal stability and coupling to either endogenous Chinese Hamster ovary (CHO) cell G proteins or to atrial Gi reconstituted into CHO cell membranes. The second approach is to use biophysical methods such as circular dichroism and transient kinetics to examine changes in secondary structure that occur when ligands bind to the purified recombinant protein or to detect and analyze protein conformational changes that occur in the membrane-bound or purified preparations. Interaction of defined Gialpha1,2,3, with atrial Gibetagamma and muscarinic receptors, by resolving purified atrial gi into gil and Gi3 or by purifying Gi1,2,3 from brain and erythrocytes. The detailed knowledge of muscarinic mechanisms in the heart may be useful in the rational design of drugs for use in treating cardiac arrhymias as tachycardia.