HEART ATRIAL MUSCARINIC RECEPTOR

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The m2 muscarinic acetylcholine receptor subtype mediates the regulation of the heartbeat by the parasympathetic nervous system and is of interest as a possible target for antiarrhythmia drugs. The long-term objective of this proposal is to understand the molecular mechanism of m2 receptor signal transduction in as much detail as possible. The recombinant m2 receptor expressed in Chinese Hamster ovary cells provides a useful system to accomplish this goal. Site-directed mutagenesis is combined with ligand binding and kinetic approaches to examine structure/function relationships for receptor amino acids and to develop quantitative mechanisms describing the manner in which the receptor binds ligands and couples to stimulation of phosphatidylinositol metabolism and inhibition of cAMP formation. The recombinant protein can also be purified from overexpressing cell lines in sufficient quantities for biophysical studies such as far ultraviolet circular dichroism and Fourier transform infrared spectroscopy to analyze receptor structure. These studies should contribute to our understanding of m2 receptor structure and the mechanism of m2 muscarinic receptor signal transduction from a quantitative perspective and may result in the rational design of more effective antiarrhythmic agents.