Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1994 Sep 15;302(Pt 3):949–955. doi: 10.1042/bj3020949

Elevated intracellular cyclic AMP exerts different modulatory effects on cytosolic free Ca2+ oscillations induced by ADP and ATP in single rat hepatocytes.

A K Green 1, P H Cobbold 1, C J Dixon 1
PMCID: PMC1137322  PMID: 7945225

Abstract

Single aequorin-injected hepatocytes respond to agonists acting via the phosphoinositide signalling pathway by the generation of oscillations in cytosolic free Ca2+ concentration ([Ca2+]free). The duration of [Ca2+]free transients is characteristic of the stimulating agonist. We have previously reported that ADP and ATP, which are believed to act through a single P(2y)-purinoceptor species, induce very different oscillatory [Ca2+]free responses in the majority of hepatocytes. We have interpreted these data as evidence for two separate Ca(2+)-mobilizing purinoceptors for these nucleotides. We show here that the elevation of intracellular cyclic AMP concentration, by the co-application of either dibutyryl cyclic AMP or 7 beta-desacetyl-7 beta-[gamma-(N-methylpiperazino)butyryl]- forskolin (L858051), exerts different modulatory effects on [Ca2+]free oscillations induced by ADP and ATP in single rat hepatocytes. Elevated intracellular cyclic AMP levels enhance the frequency and peak [Ca2+]free of transients induced by ADP. In contrast, the elevation of intracellular cyclic AMP levels in hepatocytes producing [Ca2+]free oscillations in response to ATP stimulates either an increase in the duration of transients or a sustained rise in [Ca2+]free. The data illustrate a further difference between the oscillatory [Ca2+]free responses of hepatocytes to ADP and ATP, thus further arguing against ADP and ATP acting via a single purinoceptor species.

Full text

PDF
949

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Altin J. G., Bygrave F. L. Synergistic stimulation of Ca2+ uptake by glucagon and Ca2+-mobilizing hormones in the perfused rat liver. A role for mitochondria in long-term Ca2+ homoeostasis. Biochem J. 1986 Sep 15;238(3):653–661. doi: 10.1042/bj2380653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Altin J. G., Bygrave F. L. The influx of Ca2+ induced by the administration of glucagon and Ca2+-mobilizing agents to the perfused rat liver could involve at least two separate pathways. Biochem J. 1987 Feb 15;242(1):43–50. doi: 10.1042/bj2420043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berridge M. J. Calcium oscillations. J Biol Chem. 1990 Jun 15;265(17):9583–9586. [PubMed] [Google Scholar]
  4. Blackmore P. F., 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. 1986 Aug 25;261(24):11056–11063. [PubMed] [Google Scholar]
  5. Bouvier M., Leeb-Lundberg L. M., Benovic J. L., Caron M. G., Lefkowitz R. J. Regulation of adrenergic receptor function by phosphorylation. II. Effects of agonist occupancy on phosphorylation of alpha 1- and beta 2-adrenergic receptors by protein kinase C and the cyclic AMP-dependent protein kinase. J Biol Chem. 1987 Mar 5;262(7):3106–3113. [PubMed] [Google Scholar]
  6. Brown H. A., Lazarowski E. R., Boucher R. C., Harden T. K. Evidence that UTP and ATP regulate phospholipase C through a common extracellular 5'-nucleotide receptor in human airway epithelial cells. Mol Pharmacol. 1991 Nov;40(5):648–655. [PubMed] [Google Scholar]
  7. Burgess G. M., Bird G. S., Obie J. F., Putney J. W., Jr The mechanism for synergism between phospholipase C- and adenylylcyclase-linked hormones in liver. Cyclic AMP-dependent kinase augments inositol trisphosphate-mediated Ca2+ mobilization without increasing the cellular levels of inositol polyphosphates. J Biol Chem. 1991 Mar 15;266(8):4772–4781. [PubMed] [Google Scholar]
  8. Burnstock G., Kennedy C. Is there a basis for distinguishing two types of P2-purinoceptor? Gen Pharmacol. 1985;16(5):433–440. doi: 10.1016/0306-3623(85)90001-1. [DOI] [PubMed] [Google Scholar]
  9. Bygrave F. L., Benedetti A. Calcium: its modulation in liver by cross-talk between the actions of glucagon and calcium-mobilizing agonists. Biochem J. 1993 Nov 15;296(Pt 1):1–14. doi: 10.1042/bj2960001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bygrave F. L., Gamberucci A., Fulceri R., Benedetti A. Evidence that stimulation of plasma-membrane Ca2+ inflow is an early action of glucagon and dibutyryl cyclic AMP in rat hepatocytes. Biochem J. 1993 May 15;292(Pt 1):19–22. doi: 10.1042/bj2920019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Charest R., Blackmore P. F., Exton J. H. Characterization of responses of isolated rat hepatocytes to ATP and ADP. J Biol Chem. 1985 Dec 15;260(29):15789–15794. [PubMed] [Google Scholar]
  12. Cobbold P. H., Sanchez-Bueno A., Dixon C. J. The hepatocyte calcium oscillator. Cell Calcium. 1991 Feb-Mar;12(2-3):87–95. doi: 10.1016/0143-4160(91)90011-3. [DOI] [PubMed] [Google Scholar]
  13. Cockcroft S., Stutchfield J. The receptors for ATP and fMetLeuPhe are independently coupled to phospholipases C and A2 via G-protein(s). Relationship between phospholipase C and A2 activation and exocytosis in HL60 cells and human neutrophils. Biochem J. 1989 Nov 1;263(3):715–723. doi: 10.1042/bj2630715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Crane J. K., Campanile C. P., Garrison J. C. The hepatic angiotensin II receptor. II. Effect of guanine nucleotides and interaction with cyclic AMP production. J Biol Chem. 1982 May 10;257(9):4959–4965. [PubMed] [Google Scholar]
  15. Cuthbertson K. S., Cobbold P. H. Phorbol ester and sperm activate mouse oocytes by inducing sustained oscillations in cell Ca2+. Nature. 1985 Aug 8;316(6028):541–542. doi: 10.1038/316541a0. [DOI] [PubMed] [Google Scholar]
  16. Dixon C. J., Cobbold P. H., Green A. K. Adenosine 5'-[alpha beta-methylene]triphosphate potentiates the oscillatory cytosolic Ca2+ responses of hepatocytes to ATP, but not to ADP. Biochem J. 1993 Aug 1;293(Pt 3):757–760. doi: 10.1042/bj2930757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dixon C. J., Woods N. M., Cuthbertson K. S., Cobbold P. H. Evidence for two Ca2(+)-mobilizing purinoceptors on rat hepatocytes. Biochem J. 1990 Jul 15;269(2):499–502. doi: 10.1042/bj2690499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dulon D., Mollard P., Aran J. M. Extracellular ATP elevates cytosolic Ca2+ in cochlear inner hair cells. Neuroreport. 1991 Feb;2(2):69–72. doi: 10.1097/00001756-199102000-00001. [DOI] [PubMed] [Google Scholar]
  19. Gonzalez F. A., Alfonzo R. G., Toro J. R., Heppel L. A. Receptor specific for certain nucleotides stimulates inositol phosphate metabolism and Ca2+ fluxes in A431 cells. J Cell Physiol. 1989 Dec;141(3):606–617. doi: 10.1002/jcp.1041410320. [DOI] [PubMed] [Google Scholar]
  20. Gonzalez F. A., Rozengurt E., Heppel L. A. Extracellular ATP induces the release of calcium from intracellular stores without the activation of protein kinase C in Swiss 3T6 mouse fibroblasts. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4530–4534. doi: 10.1073/pnas.86.12.4530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gordon J. L. Extracellular ATP: effects, sources and fate. Biochem J. 1986 Jan 15;233(2):309–319. doi: 10.1042/bj2330309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Guillon G., Gallo-Payet N., Balestre M. N., Lombard C. Cholera-toxin and corticotropin modulation of inositol phosphate accumulation induced by vasopressin and angiotensin II in rat glomerulosa cells. Biochem J. 1988 Aug 1;253(3):765–775. doi: 10.1042/bj2530765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hajnóczky G., Gao E., Nomura T., Hoek J. B., Thomas A. P. Multiple mechanisms by which protein kinase A potentiates inositol 1,4,5-trisphosphate-induced Ca2+ mobilization in permeabilized hepatocytes. Biochem J. 1993 Jul 15;293(Pt 2):413–422. doi: 10.1042/bj2930413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hanoune J., Stengel D., Lacombe M. L., Feldmann G., Coudrier E. Proteolytic activation of rat liver adenylate cyclase by a contaminant of crude collagenase from Clostridium histolyticum. J Biol Chem. 1977 Mar 25;252(6):2039–2045. [PubMed] [Google Scholar]
  25. Keppens S., De Wulf H. Characterization of the liver P2-purinoceptor involved in the activation of glycogen phosphorylase. Biochem J. 1986 Dec 1;240(2):367–371. doi: 10.1042/bj2400367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Keppens S., De Wulf H. P2-purinergic control of liver glycogenolysis. Biochem J. 1985 Nov 1;231(3):797–799. doi: 10.1042/bj2310797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kuroki M., Takeshige K., Minakami S. ATP-induced calcium mobilization in human neutrophils. Biochim Biophys Acta. 1989 Jun 15;1012(1):103–106. doi: 10.1016/0167-4889(89)90017-7. [DOI] [PubMed] [Google Scholar]
  28. Laurenza A., Khandelwal Y., De Souza N. J., Rupp R. H., Metzger H., Seamon K. B. Stimulation of adenylate cyclase by water-soluble analogues of forskolin. Mol Pharmacol. 1987 Jul;32(1):133–139. [PubMed] [Google Scholar]
  29. Lustig K. D., Shiau A. K., Brake A. J., Julius D. Expression cloning of an ATP receptor from mouse neuroblastoma cells. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5113–5117. doi: 10.1073/pnas.90.11.5113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mauger J. P., Poggioli J., Claret M. Synergistic stimulation of the Ca2+ influx in rat hepatocytes by glucagon and the Ca2+-linked hormones vasopressin and angiotensin II. J Biol Chem. 1985 Sep 25;260(21):11635–11642. [PubMed] [Google Scholar]
  31. Morgan N. G., Charest R., Blackmore P. F., Exton J. H. Potentiation of alpha 1-adrenergic responses in rat liver by a cAMP-dependent mechanism. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4208–4212. doi: 10.1073/pnas.81.13.4208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Morgan N. G., Exton J. H., Blackmore P. F. Angiotensin II inhibits hepatic cAMP accumulation induced by glucagon and epinephrine and their metabolic effects. FEBS Lett. 1983 Mar 7;153(1):77–80. doi: 10.1016/0014-5793(83)80122-7. [DOI] [PubMed] [Google Scholar]
  33. Murgo A. J., Sistare F. D. K562 leukemia cells express P2T (adenosine diphosphate) purinergic receptors. J Pharmacol Exp Ther. 1992 May;261(2):580–585. [PubMed] [Google Scholar]
  34. Okajima F., Tokumitsu Y., Kondo Y., Ui M. P2-purinergic receptors are coupled to two signal transduction systems leading to inhibition of cAMP generation and to production of inositol trisphosphate in rat hepatocytes. J Biol Chem. 1987 Oct 5;262(28):13483–13490. [PubMed] [Google Scholar]
  35. Pittner R. A., Fain J. N. Exposure of cultured hepatocytes to cyclic AMP enhances the vasopressin-mediated stimulation of inositol phosphate production. Biochem J. 1989 Jan 15;257(2):455–460. doi: 10.1042/bj2570455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pittner R. A., Fain J. N. Vasopressin and norepinephrine stimulation of inositol phosphate accumulation in rat hepatocytes are modified differently by protein f1nase C and protein kinase A. Biochim Biophys Acta. 1990 Apr 2;1043(2):211–217. doi: 10.1016/0005-2760(90)90298-c. [DOI] [PubMed] [Google Scholar]
  37. Poggioli J., Mauger J. P., Claret M. Effect of cyclic AMP-dependent hormones and Ca2+-mobilizing hormones on the Ca2+ influx and polyphosphoinositide metabolism in isolated rat hepatocytes. Biochem J. 1986 May 1;235(3):663–669. doi: 10.1042/bj2350663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sage S. O., Reast R., Rink T. J. ADP evokes biphasic Ca2+ influx in fura-2-loaded human platelets. Evidence for Ca2+ entry regulated by the intracellular Ca2+ store. Biochem J. 1990 Feb 1;265(3):675–680. doi: 10.1042/bj2650675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sanchez-Bueno A., Cobbold P. H. Agonist-specificity in the role of Ca(2+)-induced Ca2+ release in hepatocyte Ca2+ oscillations. Biochem J. 1993 Apr 1;291(Pt 1):169–172. doi: 10.1042/bj2910169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sanchez-Bueno A., Marrero I., Cobbold P. H. Different modulatory effects of elevated cyclic AMP on cytosolic Ca2+ spikes induced by phenylephrine or vasopressin in single rat hepatocytes. Biochem J. 1993 Apr 1;291(Pt 1):163–168. doi: 10.1042/bj2910163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Schöfl C., Sanchez-Bueno A., Brabant G., Cobbold P. H., Cuthbertson K. S. Frequency and amplitude enhancement of calcium transients by cyclic AMP in hepatocytes. Biochem J. 1991 Feb 1;273(Pt 3):799–802. doi: 10.1042/bj2730799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Somogyi R., Zhao M., Stucki J. W. Modulation of cytosolic-[Ca2+] oscillations in hepatocytes results from cross-talk among second messengers. The synergism between the alpha 1-adrenergic response, glucagon and cyclic AMP, and their antagonism by insulin and diacylglycerol manifest themselves in the control of the cytosolic-[Ca2+] oscillations. Biochem J. 1992 Sep 15;286(Pt 3):869–877. doi: 10.1042/bj2860869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Webb T. E., Simon J., Krishek B. J., Bateson A. N., Smart T. G., King B. F., Burnstock G., Barnard E. A. Cloning and functional expression of a brain G-protein-coupled ATP receptor. FEBS Lett. 1993 Jun 14;324(2):219–225. doi: 10.1016/0014-5793(93)81397-i. [DOI] [PubMed] [Google Scholar]
  44. Woods N. M., Cuthbertson K. S., Cobbold P. H. Agonist-induced oscillations in cytoplasmic free calcium concentration in single rat hepatocytes. Cell Calcium. 1987 Feb;8(1):79–100. doi: 10.1016/0143-4160(87)90038-8. [DOI] [PubMed] [Google Scholar]
  45. Woods N. M., Cuthbertson K. S., Cobbold P. H. Repetitive transient rises in cytoplasmic free calcium in hormone-stimulated hepatocytes. Nature. 1986 Feb 13;319(6054):600–602. doi: 10.1038/319600a0. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES