Reexamination of the Second Messenger Hypothesis of Glucagon and Catecholamine Action in Liver

  • J. H. Exton
  • A. D. Cherrington
  • N. J. Hutson
  • F. D. Assimacopoulos-Jeannet
Conference paper


Glucagon causes a rapid activation of cAMP-dependent protein kinase in rat liver parenchymal cells which correlates well with the accumulation of cAMP. Full activation of phosphorylase or inactivation of glycogen synthase is achieved with half-maximal activation of protein kinase. Epinephrine stimulates glycogen breakdown and gluconeogenesis in these cells mainly by mechanisms involving α-adrenergic receptors and not β-receptors. Activation of α-receptors results in rapid activation of phosphorylase and inactivation of glycogen synthase without accumulation of cAMP or activation of cAMP-dependent protein kinase. Activation of β-receptors causes a transient rise in cAMP and a short-lived activation of protein kinase with correspondingly little stimulation of glycogenolysis and gluconeogenesis.


cAMP Level Perfuse Liver Glycogen Metabolism Glucose Release Phosphorylase Activation 
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  1. 1.
    Assimacopoulos-Jeannet, F. D., Blackmore, P. F. and Exton, J. H. (1977): Studies on the α-adrenergic activation of hepatic glucose output. I II. Studies on the role of calcium in the a-adrenergic activation of phosphorylase. J. Biol. Chem. Submitted for publication.Google Scholar
  2. 2.
    Berry, M. N. and Friend, D. S. (1969): High-yield preparation of isolated rat liver parenchymal cells. J. Cell Biol. 43, 506–520.PubMedCrossRefGoogle Scholar
  3. 3.
    Birnbaum, M. J. and Fain, J. N. (1977): Activation of protein kinase and glycogen phosphorylase in isolated rat liver cells by glucagon and catecholamines. J. Biol. Chem. (in press).Google Scholar
  4. 4.
    Cherrington, A. D., Assimacopoulos, F. D., Harper, S. C., Corbin, J. D., Park, C. R. and Exton, J. H. (1976): Studies on the α-adrenergic activation of hepatic glucose output. II. Investigation of the roles of adenosine 3’;5’-monophosphate and adenosine 3’:5’-monophosphate-dependent protein kinase in the actions of phenylephrine in isolated hepatocytes. J. Biol. Chem. 251, 5209–5218.PubMedGoogle Scholar
  5. 5.
    DeWulf, H. and Keppens, S. (1975): Is calcium the second messenger in liver for cyclic AMP-independent glycogenolytic hormones? Arch. Intern. Physiol. Biochim. 84, 159–160.Google Scholar
  6. 6.
    Exton, J. H. and Harper, S. C. (1975): Role of cyclic AMP in the actions of catecholamines on hepatic carbohydrate metabolism. Adv. Cyclic Nucleotide Res. 5, 519–532.Google Scholar
  7. 7.
    Exton, J. H., Robison, G. S., Sutherland, E. W. and Park, C. R. (1971): Studies on the role of adenosine 3’,5’-monophosphate in the hepatic actions of glucagon and catecholamines. J. Biol. Chem. 246, 6166–6177.PubMedGoogle Scholar
  8. 8.
    Gilman, A. G. (1970): A protein binding assay for adenosine 31.S’-cyclic monophosphate. Proc. Natl. Acad. Sci. USA 67, 305–312.PubMedCrossRefGoogle Scholar
  9. 9.
    Hornbrook, K. R. (1970): Adrenergic receptors for metabolic responses in the liver. Fed. Proc. 29, 1381–1385.PubMedGoogle Scholar
  10. 10.
    Hutson, N. J., Brumley, F. T., Assimacopoulos, F. D., Harper, S. C. and Exton, J. H. (1976): Studies on the a-adrenergic activation of hepatic glucose output. I. Studies on the a-adrenergic activation of phosphorylase and gluconeogenesis and inactivation of glycogen synthase in isolated rat liver parenchymal cells. J. Biol. Chem. 251, 5200–5208.PubMedGoogle Scholar
  11. 11.
    Jakob, A. and Diem, S. (1976): Metabolic responses of perfused rat livers to alpha- and beta-adrenergic agonists, glucagon and cyclic AMP. Biochim. Biophys. Acta 404, 57–66.Google Scholar
  12. 12.
    Jenkinson, D. H. (1973): Classification and properties of peripheral adrenergic receptors. Brit. Med. Bull. 29, 142–147.PubMedGoogle Scholar
  13. 13.
    Khoo, J. C. and Steinberg, D. (1975): Stimulation of rat liver phosphorylase kinase by micromolar concentrations of Ca2+. FEBS Letters 57, 68–72.PubMedCrossRefGoogle Scholar
  14. 14.
    Kneer, N. M., Bosch, A. L., Clark, M. G. and Lardy, H. A. (1974): Glucose inhibition of epinephrine stimulation of hepatic gluconeogenesis by blockade of the a-receptor function. Proc. Natl. Acad. Sci. 71, 4523–4527.Google Scholar
  15. 15.
    Moran, N. C. (1975): Adrenergic receptors. In: Handbook of Physiology. Section 7: Endocrinology, Vol. 6. Adrenal Gland. H. Blaschko, G. Sayer and A. D. Smith, Eds. American Physiological Society, Washington, D. C., pp. 447–472.Google Scholar
  16. 16.
    Newton, N. E. and Hornbrook, K. R. (1972): Effects of adrenergic agents on carbohydrate metabolism of rat liver: activities of adenyl cyclase and glycogen phosphorylase. J. Pharm. Exp. Ther. 181, 479–488.Google Scholar
  17. 17.
    Okajima, F. and Ui, M. (1976): Lack of correlation between hormonal effects on cyclic AMP and glycogenolysis in rat liver. Arch. Biochem. Biophys. 175, 549–557.PubMedCrossRefGoogle Scholar
  18. 18.
    Pointer, R. H., Butcher, F. R. and Fain, J. N. (1976): Studies on the role of cyclic guanosine 3’:5’-monophosphate and extracellular Ca++ in the regulation og glycogenolysis in rat liver cells. J. Biol. Chem. 251, 2987–2992.PubMedGoogle Scholar
  19. 19.
    Saitoh, Y. and Ui, M. (1976): Stimulation of glycogenolysis and gluconeogenesis by epinephrine independent of its beta-adrenergic function in perfused rat liver. Biochem. Pharmacol. 25, 841–845.PubMedCrossRefGoogle Scholar
  20. 20.
    Sherline, P., Lynch, A. and Glinsmann, W. H. (1972): Cyclic AMP and adrenergic receptor control of rat liver glycogen metabolism. Endocrinology 91, 680–690.PubMedCrossRefGoogle Scholar
  21. 21.
    Shimazu, T. and Amakawa, A. (1975): Regulation of glycogen metabolism in liver by the autonomic nervous system. VI. Possible mechanism of phosphorylase activation by the splanchnic nerve. Biochim. Biophys. Acta 385, 242–256.PubMedGoogle Scholar
  22. 22.
    Soderling, T. R. and Park, C. R. (1974): Recent advances in glycogen metabolism. In: Advances in Cyclic Nucleotide Research, Vol. 4. P. Greengard and G. A. Robison, Eds. Raven Press, New York, pp. 283–333.Google Scholar
  23. 23.
    Stalmans, W. and Hers, H. G. (1975): The stimulation of liver phosphorylase b by AMP, fluoride and sulfate. Eur. J. Biochem. 54, 341–350.PubMedCrossRefGoogle Scholar
  24. 24.
    Thomas, J. A., Schlender, K. K. and Larner, J. (1968): A rapid filter paper assay for UDP glucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14c-glucose. Anal. Biochem. 486–499.Google Scholar
  25. 25.
    Tolbert, M. E. M., Butcher, F. R. and Fain, J. N. (1973): Lack of correlation between catecholamine effects on cyclic adenosine 3’:5’-monophosphate and gluconeogenesis in isolated rat liver cells. J. Biol. Chem. 248, 5686–5692.PubMedGoogle Scholar
  26. 26.
    Vandenheede, J. R., Keppens, S. and DeWulf, H. (1976): The activation of liver phosphorylase b kinase by glucagon. FEBS Letters 61, 213–217.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 1977

Authors and Affiliations

  • J. H. Exton
    • 1
    • 2
  • A. D. Cherrington
    • 1
    • 2
  • N. J. Hutson
    • 1
    • 2
  • F. D. Assimacopoulos-Jeannet
    • 1
    • 2
  1. 1.Laboratories for the Studies of Metabolic DisordersHoward Hughes Medical InstituteUSA
  2. 2.Department of PhysiologyVanderbilt University Medical SchoolNashvilleUSA

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