The long-term goal of this research is to elucidate at the molecular level the factors involved in the development, function, and regulation of muscarinic acetylcholine receptors in the heart. This proposal will study chick cardiac mAChR during chick embryonic development in vivo and in cardiac muscle cell culture. This project will extend our recent findings that physiologically inactive muscarinic receptors present in 3-4 day embryonic chick heart exhibit a defect in regulation of guanyl nucleotides by determining the molecular nature of the defect associated with these inactive receptors. Newly synthesized receptors in hearts from older embryos appear to undergo a maturation or increase in physiological sensitivity which is distinct from that which occurs in very young embryos. This proposal will study the synthesis, biochemistry, and physiological activity of muscarinic receptors both in vivo and in culture in order to determine the factors regulating the synthesis and coupling of the muscarinic receptor to physiological activity. Cardiac muscle cultures will also be treated with specific inhibitors of guanine nucleotide biosynthesis in order to elucidate the role of guanine nucleotides in situ in the regulation and action of the muscarinic acetylcholine receptor. This research should delinate the factors involved in cardiac muscarinic receptor development, regulation, and function, and may aid in the understanding of a number of cardiac abnormalities.
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