Role of Guanine Nucleotide Regulatory Proteins and Inositol Phosphates in the Hormone Induced Mobilization of Hepatocyte Calcium

  • Peter F. Blackmore
  • Christopher J. Lynch
  • Ronald J. Uhing
  • Thomas Fitzgerald
  • Stephen B. Bocckino
  • John H. Exton
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 232)


Many hormones and neurotransmitters exert their effects in the liver by increasing the concentration of free ionized Ca2+ in the cytoplasm.1,2,3 Examples of such agonists are norepinephrine and epinephrine acting via α1-adrenergic receptors, vasopressin acting on V1 receptors, ATP and ADP acting on P2 purinergic receptors and angiotensin II. Each agonist, after binding to its specific cell surface receptor, provokes the hydrolysis of PI 4,5-P2 by a phospholipase C activity to give rise to DAG and Ins 1,4,5-P3.4,5 The DAG functions to activate protein kinase C while Ins 1,4,5-P3 mobilizes Ca2+ from elements of the endoplasmic reticulum.4,5 Recent studies have implicated the involvement of a guanine nucleotide binding protein which couples the various hormone receptors to the PI 4,5-p2 specific phospholipase C6. The existence of a novel inositol phosphate ester, Ins 1,3,4,5-P4, has also been described.7 The purpose of this article is to present our data on these two aspects of hormone action in the liver.


Cholera Toxin Guanine Nucleotide Pertussis Toxin Inositol Phosphate GTPase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Williamson, J.R., Cooper, R.H., Joseph, S.K., and Thomas, A,P. Inositol triphosphate and diacylglycerol as intracellular second messengers in liver. Am. J. Physiol. 248:C203–C216 (1985).PubMedGoogle Scholar
  2. 2.
    Exton, J.H, Role of calcium and phosphoinositides in the actions of certain hormones and neurotransmitters. J. Clin. Invest. 73:1753–1757, 1985.CrossRefGoogle Scholar
  3. 3.
    Blackmore, P.F. Effects of ?-adrenergic agents on hepatic Ca2+ distribution. CRC Critical Rev. Biochem. (N. Kraus-Friedmann, ed.), Chemical Rubber Co., pp. 183–193, 1986.Google Scholar
  4. 4.
    Berridge, M.J. Inositol trisphosphate and diacylglycerol as second messengers. Biochem. J. 220:345–360 (1984).PubMedGoogle Scholar
  5. 5.
    Berridge, M.J. and Irvine, R.F. Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312:315–321 (1984).PubMedCrossRefGoogle Scholar
  6. 6.
    Gomperts, B.D. Calcium shares the limelight in stimulus-secretion coupling. TIBS 11:290–292 (1986).Google Scholar
  7. 7.
    Batty, I.R., Nahorski, S.R., and Irvine, R.F. Rapid formation of inositol 1,3,4,5-tetrakisphosphate following muscarinic receptor stimulation of rat cerebral cortical slices. Biochem. J. 232:211–215 (1985).PubMedGoogle Scholar
  8. 8.
    Lynch, C.J., Charest, R., Blackmore, P.F., and Exton, J.H. Studies on the hepatic α1-adrenergic receptor: modulation of guanine nucleotide effects by calcium, temperature, and age. J. Biol. Chem. 260:15393–1600 (1985).Google Scholar
  9. 9.
    Gomperts, B.D. Involvement of guanine nucleotide-binding protein in the gating of Ca2+ by receptors. Nature 306:64–66 (1983).PubMedCrossRefGoogle Scholar
  10. 10.
    Hinkle, P.M. and Phillips, W.J. Thyrotropin-releasing hormone stimulates GTP hydrolysis by membranes from GH4C1 rat pituitary tumor cells. Proc. Natl. Acad. Sci. U.S.A. 81:6183–6187 (1984).PubMedCrossRefGoogle Scholar
  11. 11.
    Lad, P.M., Olson, C.V., and Smiley, P.A. Association of the N-formyl-Met-Leu-Phe receptor in human neutrophils with a GTP-binding protein sensitive to pertussis toxin. Proc. Natl. Acad. Sci. U.S.A. 82:869–873 (1985).PubMedCrossRefGoogle Scholar
  12. 12.
    Sternweis, P.C. and Gilman, A.G. Aluminum: a requirement for activation of the regulatory component of adenylate cyclase by fluoride. Proc. Natl. Acad. Sci. U.S.A. 79:4888–4891 (1982).PubMedCrossRefGoogle Scholar
  13. 13.
    Kanaho, Y., Moss, J., and Vaughan, M. Mechanism of inhibition of transducin GTPase activity by fluoride and aluminum. J. Biol. Chem. 260:11493–11497 (1985).PubMedGoogle Scholar
  14. 14.
    Blackmore, P.F., Bocckino, S.B., Waynick, L.E. and Exton, J.H. Role of a guanine nucleotide-binding regulatory protein in the hydrolysis of hepatocyte phosphatidylinositol 4,5-bisphosphate by calcium-mobilizing hormones and the control of cell calcium: studies utilizing aluminum fluoride. J. Biol. Chem. 260:14477–14483 (1985).PubMedGoogle Scholar
  15. 15.
    Blackmore, P.F. and Exton, J.H. Studies on the hepatic calcium-mobilizing activity of aluminum fluoride and glucagon: modulation by cAMP and phorbol myristate acetate. J. Biol. Chem. 261:11056–11063 (1986).PubMedGoogle Scholar
  16. 16.
    Smith, C.D., Lane, B.C., Kusaka, I., Verghese, M.W., and Snyderman, R. Chemoattractant receptor-induced hydrolysis of phosphatidylinositol 4,5-bisphosphate in human polymorphonuclear leukocyte membranes: requirement for a guanine nucleotide regulatory protein. J. Biol. Chem. 260:5875–5878 (1985).PubMedGoogle Scholar
  17. 17.
    Nakamura, T., and Ui, M. Simultaneous inhibitions of inositol phospholipid breakdown, arachidonic acid release, and histamine secretion in mast cells by islet-activating protein, pertussis toxin: a possible involvement of the toxin-specific substrate in the Ca2+-mobilizing receptor-mediated biosignaling system. J. Biol. Chem. 260:3584–3593 (1985).PubMedGoogle Scholar
  18. 18.
    Bokoch, G.M., and Gilman, A.G. Inhibition of receptor-mediated release of arachidonic acid by pertussis toxin. Cell 39, 301–308 (1984).PubMedCrossRefGoogle Scholar
  19. 19.
    Molski, T.F.P., Naccache, P.H., Marsh, M.L., Kermode, J., Becker, E.L., and Sha’afi, R.I. Pertussis toxin inhibits the rise in the intracellular concentration of free calcium that is induced by chemotactic factors in rabbit neutrophils: possible role of the “G proteins” in calcium mobilization. Biochem. Biophys. Res. Commun. 124:644–650 (1984).PubMedCrossRefGoogle Scholar
  20. 20.
    Volpi, M., Naccache, P.H., Molski, T.F.P., Shefcyk, J., Huang, C.-K., Marsh, M.L., Munoz, J., Becker, E.L., and Sha’afi, R.I. Pertussis toxin inhibits fMet-Leu-Phe-but not phorbol ester-stimulated changes in rabbit neutrophils: role of G proteins in excitation response coupling. Proc. Natl. Acad. Sci. U.S.A. 82:2708–2712 (1985).PubMedCrossRefGoogle Scholar
  21. 21.
    Lynch, C.J., Prpic, V., Blackmore, P.F., and Exton, J.H. Effect of islet-activating pertussis toxin on the binding characteristics of Ca2+-mobilizing hormones and on agonist activation of Phosphorylase in hepatocytes. Mol. Pharmacol. 29:196–203, 1986.PubMedGoogle Scholar
  22. 22.
    Cockcroft, S. and Gomperts, B.D. Role of guanine nucleotide binding protein in the activation of polyphosphoinositide phosphodiesterase. Nature 314:534–536 (1985).PubMedCrossRefGoogle Scholar
  23. 23.
    Litosch, I., Wallis, C., and Fain, J.N. 5-Hydroxytryptamine stimulates inositol phosphate production in a cell-free system from blowfly salivary glands: evidence for a role of GTP in coupling receptor activation to phosphoinositide breakdown. J. Biol. Chem. 260:5464–5471 (1985).PubMedGoogle Scholar
  24. 24.
    Uhing, R.J., Jiang, H., Prpic, V. and Exton, J.H. Regulation of a liver plasma memmbrane phosphoinositide phosphodiesterase by guanine nucleotides and calcium. FEBS Lett. 188:317–320, 1985.PubMedCrossRefGoogle Scholar
  25. 25.
    Lynch, C.J., Blackmore, P.F., Charest, R., and Exton, J.H. The relationships between receptor binding capacity for norepinephrine, angiotensin II, and vasopressin and release of inositol trisphosphate, Ca2+ mobilization, and Phosphorylase activation in rat liver. Mol. Pharmacol. 28:93–99 (1985).PubMedGoogle Scholar
  26. 26.
    Salomon, Y., Lin, M.C., Londos, C., Rendell, M., and Rodbell, M. The hepatic adenylate cyclase system: evidence for transition states and structural requirements for guanine nucleotide activation. J. Biol. Chem. 250:4239–4245 (1975).PubMedGoogle Scholar
  27. 27.
    Eckstein, F., Cassel, D., Levkovits, H., Lowe, M., and Selinger, Z. Guanosine 5′-0-(2-thiodiphosphate): an inhibitor of adenylate cyclase stimulation by guanine nucleotides and fluoride ions. J. Biol. Chem. 254:9829–9834 (1979).PubMedGoogle Scholar
  28. 28.
    Fitzgerald, T.J., Uhing, R.J., and Exton, J.H. Solubilization of the vasopressin receptor from rat liver plasma membranes: evidence for a receptor-GTP-binding protein complex. J. Biol. Chem. 261:(in press)(1986).Google Scholar
  29. 29.
    Blackmore, P.F., Bocckino, S., Jiang, H., and Exton, J.H. Agonist induced formation of myoinositol 1,4,5-P3, myoinositol 1,3,4-P3 and myoinositol-P4 in rat liver parenchymal cells. Fed. Proc. 45:1688 (1986).Google Scholar
  30. 30.
    Charest, R., Prpic, V., Exton, J.H., and Blackmore, P.F. Stimulation of inositol trisphosphate formation in hepatocytes by vasopressin, adrenaline and angiotensin II and its relationship to changes in cytosolic free Ca2+. Biochem. J. 227:79–90 (1985).PubMedGoogle Scholar
  31. 31.
    Johnson, R.M., Connelly, P.A., Sisk, R.B., Pobiner, B.F., Hewlett, E.L., and Garrison, J.C. Pertussis toxin or phorbol 12-myristate 13-acetate can distinguish between epidermal growth factor-and angiotensin-stimulated signals in hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 83:2032–2036 (1986).PubMedCrossRefGoogle Scholar
  32. 32.
    Bosch, F., Bouscarel, B., Slaton, J., Blackmore, P.F., and Exton, J.H. Epidermal growth factor mimics insulin effects in rat hepatocytes. Biochem. J. 239:523–530 (1986).PubMedGoogle Scholar
  33. 33.
    Uhing, R.J., Prpic, V., Jiang, H., and Exton, J.H. Hormone-stimulated polyphosphoinositide breakdown in rat liver plasma membranes: roles of guanine nucleotides and calcium. J. Biol. Chem. 261:2140–2146 (1986).PubMedGoogle Scholar
  34. 34.
    Irvine, R.F., Letcher, A.J., Heslop, J.P., and Berridge, M.J. The inositol tris/tetrakisphosphate pathway — demonstration of Ins(l,4,5)P3 3-kinase activity in animal tissues. Nature 320:631–634 (1986).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Peter F. Blackmore
    • 1
  • Christopher J. Lynch
    • 1
  • Ronald J. Uhing
    • 1
  • Thomas Fitzgerald
    • 1
  • Stephen B. Bocckino
    • 1
  • John H. Exton
    • 1
  1. 1.Howard Hughes Medical Institute and Department of Molecular Physiology and BiophysicsVanderbilt University School of MedicineNashvilleUSA

Personalised recommendations