Decreased bioactivity of the guanine nucleotide-binding protein that stimulates adenylate cyclase in hearts from cardiomyopathic Syrian hamsters.
We investigated regulation of cardiac adenylate cyclase in 29-d-old BIO 14.6 Syrian hamsters, which inherit cardiomyopathy as an autosomal recessive trait. Pharmacologic stimulation of adenylate cyclase in cardiac membranes with isoproterenol, fluoride ion, guanine nucleotide, forskolin, and manganous ion indicated that there was defective coupling of the guanine nucleotide-binding protein that stimulates adenylate cyclase (Gs) to adenylate cyclase. Cyc complementation assays revealed congruent to 50% less Gs activity in cardiac and skeletal muscle from cardiomyopathic hamsters. Despite this decrease in functional Gs, there were no changes in immunologic levels of the alpha-subunit of Gs (alpha Gs) or in levels of mRNA encoding alpha Gs. The defect in Gs bioactivity was limited to cardiac and skeletal muscle, occurred only in animals homozygous for the dystrophic trait, and was demonstrable before any cardiac abnormalities were evident on light microscopy. By contrast, cardiac levels of beta-adrenergic receptors were not different in cardiac membranes from BIO 14.6 hamsters. We conclude that a functional defect in alpha Gs may contribute to a contractile abnormalities in the cardiomyopathic BIO 14.6 hamster. However, the etiology of the alpha Gs defect remains obscure.
Kessler
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PD
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
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Van Dop
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Feldman
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D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D015152:Blotting, Northern; D009202:Cardiomyopathies / Q000151:congenital / Q000378:metabolism*; D002772:Cholera Toxin; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D005459:Fluorides / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006150:Guanine Nucleotides / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008345:Manganese / Q000494:pharmacology; D008647:Mesocricetus; D009206:Myocardium / Q000201:enzymology*; D011943:Receptors, Adrenergic, beta / Q000032:analysis; D010566:Virulence Factors, Bordetella
D037361:Adenylate Cyclase Toxin; D006150:Guanine Nucleotides; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D008345:Manganese; D002772:Cholera Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D005459:Fluorides