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. 1988 Jul;82(1):242–247. doi: 10.1172/JCI113577

Multiple components of the A1 adenosine receptor-adenylate cyclase system are regulated in rat cerebral cortex by chronic caffeine ingestion.

V Ramkumar 1, J R Bumgarner 1, K A Jacobson 1, G L Stiles 1
PMCID: PMC303500  PMID: 3392208

Abstract

The effects of chronic caffeine on the A1 adenosine receptor-adenylate cyclase system of rat cerebral cortical membranes were studied. Caffeine treatment significantly increased the number of A1 adenosine receptors as determined with the A1 adenosine receptor antagonist radioligand [3H]xanthine amine congener (XAC). R-PIA (agonist) competition curves constructed with [3H]XAC were most appropriately described by a two affinity state model in control membranes with a KH of 2.1 +/- 0.8 and a KL of 404 +/- 330 nM with 50 +/- 4% of receptors in the high affinity state (%RH). In contrast, in membranes from treated animals, there was a marked shift towards the high affinity state. In three of seven animals all of the receptors were shifted to a unique high affinity state which was indistinguishable from the KH observed in membranes from control animals. In four of seven animals the %RH increased from 50 to 69% with KH and KL indistinguishable from the control values. Thus, the agonist specific high affinity form of the receptor was enhanced following caffeine treatment. Maximal inhibition of adenylate cyclase activity in cerebral cortical membranes by R-PIA (1 microM) was significantly increased by 28% following caffeine treatment, consistent with an increased coupling of receptor-Gi protein with adenylate cyclase. Importantly, the quantity of Gi (alpha i) in rat cerebral cortex, determined by pertussis toxin-mediated labeling, was also increased to 133% of control values by this treatment. Thus, multiple components and interactions of the A1 adenosine receptor-adenylate cyclase complex are regulated by caffeine. These changes are likely compensatory measures to offset blockade of A1 receptors in vivo by caffeine and lead to a sensitization of this inhibitory receptor system.

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Selected References

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  1. Ahlijanian M. K., Takemori A. E. Cross-tolerance studies between caffeine and (-)-N6-(phenylisopropyl)-adenosine (PIA) in mice. Life Sci. 1986 Feb 17;38(7):577–588. doi: 10.1016/0024-3205(86)90051-2. [DOI] [PubMed] [Google Scholar]
  2. Boulenger J. P., Patel J., Post R. M., Parma A. M., Marangos P. J. Chronic caffeine consumption increases the number of brain adenosine receptors. Life Sci. 1983 Mar 7;32(10):1135–1142. doi: 10.1016/0024-3205(83)90119-4. [DOI] [PubMed] [Google Scholar]
  3. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  4. Chou D. T., Khan S., Forde J., Hirsh K. R. Caffeine tolerance: behavioral, electrophysiological and neurochemical evidence. Life Sci. 1985 Jun 17;36(24):2347–2358. doi: 10.1016/0024-3205(85)90325-x. [DOI] [PubMed] [Google Scholar]
  5. Corradetti R., Pedata F., Pepeu G., Vannucchi M. G. Chronic caffeine treatment reduces caffeine but not adenosine effects on cortical acetylcholine release. Br J Pharmacol. 1986 Jul;88(3):671–676. doi: 10.1111/j.1476-5381.1986.tb10249.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Daly J. W. Adenosine receptors. Adv Cyclic Nucleotide Protein Phosphorylation Res. 1985;19:29–46. [PubMed] [Google Scholar]
  7. Daly J. W. Adenosine receptors: targets for future drugs. J Med Chem. 1982 Mar;25(3):197–207. doi: 10.1021/jm00345a001. [DOI] [PubMed] [Google Scholar]
  8. Daly J. W., Bruns R. F., Snyder S. H. Adenosine receptors in the central nervous system: relationship to the central actions of methylxanthines. Life Sci. 1981 May 11;28(19):2083–2097. doi: 10.1016/0024-3205(81)90614-7. [DOI] [PubMed] [Google Scholar]
  9. Daly J. W., Jacobson K. A., Ukena D. Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41–63. [PubMed] [Google Scholar]
  10. De Lean A., Hancock A. A., Lefkowitz R. J. Validation and statistical analysis of a computer modeling method for quantitative analysis of radioligand binding data for mixtures of pharmacological receptor subtypes. Mol Pharmacol. 1982 Jan;21(1):5–16. [PubMed] [Google Scholar]
  11. Dobmeyer D. J., Stine R. A., Leier C. V., Greenberg R., Schaal S. F. The arrhythmogenic effects of caffeine in human beings. N Engl J Med. 1983 Apr 7;308(14):814–816. doi: 10.1056/NEJM198304073081405. [DOI] [PubMed] [Google Scholar]
  12. Fredholm B. B. Adenosine actions and adenosine receptors after 1 week treatment with caffeine. Acta Physiol Scand. 1982 Jun;115(2):283–286. doi: 10.1111/j.1748-1716.1982.tb07078.x. [DOI] [PubMed] [Google Scholar]
  13. Fredholm B. B., Jonzon B., Lindgren E. Inhibition of noradrenaline release from hippocampal slices by a stable adenosine analogue. Acta Physiol Scand Suppl. 1983;515:7–10. [PubMed] [Google Scholar]
  14. Fredholm B. B., Persson C. G. Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol. 1982 Jul 30;81(4):673–676. doi: 10.1016/0014-2999(82)90359-4. [DOI] [PubMed] [Google Scholar]
  15. Graham D. M. Caffeine--its identity, dietary sources, intake and biological effects. Nutr Rev. 1978 Apr;36(4):97–102. doi: 10.1111/j.1753-4887.1978.tb03717.x. [DOI] [PubMed] [Google Scholar]
  16. Greden J. F., Victor B. S., Fontaine P., Lubetsky M. Caffeine-withdrawal headache: a clinical profile. Psychosomatics. 1980 May;21(5):411-3, 417-8. doi: 10.1016/S0033-3182(80)73670-8. [DOI] [PubMed] [Google Scholar]
  17. Green R. M., Stiles G. L. Chronic caffeine ingestion sensitizes the A1 adenosine receptor-adenylate cyclase system in rat cerebral cortex. J Clin Invest. 1986 Jan;77(1):222–227. doi: 10.1172/JCI112280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hancock A. A., DeLean A. L., Lefkowitz R. J. Quantitative resolution of beta-adrenergic receptor subtypes by selective ligand binding: application of a computerized model fitting technique. Mol Pharmacol. 1979 Jul;16(1):1–9. [PubMed] [Google Scholar]
  19. Hollins C., Stone T. W. Adenosine inhibition of gamma-aminobutyric acid release from slices of rat cerebral cortex. Br J Pharmacol. 1980 May;69(1):107–112. doi: 10.1111/j.1476-5381.1980.tb10888.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jacobson K. A., Ukena D., Kirk K. L., Daly J. W. [3H]xanthine amine congener of 1,3-dipropyl-8-phenylxanthine: an antagonist radioligand for adenosine receptors. Proc Natl Acad Sci U S A. 1986 Jun;83(11):4089–4093. doi: 10.1073/pnas.83.11.4089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  22. Londos C., Cooper D. M., Schlegel W., Rodbell M. Adenosine analogs inhibit adipocyte adenylate cyclase by a GTP-dependent process: basis for actions of adenosine and methylxanthines on cyclic AMP production and lipolysis. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5362–5366. doi: 10.1073/pnas.75.11.5362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Maitre M., Chesielski L., Lehmann A., Kempf E., Mandel P. Protective effect of adenosine and nicotinamide against audiogenic seizure. Biochem Pharmacol. 1974 Oct 15;23(20):2807–2816. doi: 10.1016/0006-2952(74)90054-9. [DOI] [PubMed] [Google Scholar]
  24. Marley E., Nistico G. Effects of catecholamines and adenosine derivatives given into the brain of fowls. Br J Pharmacol. 1972 Dec;46(4):619–636. doi: 10.1111/j.1476-5381.1972.tb06888.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Michaelis M. L., Michaelis E. K., Myers S. L. Adenosine modulation of synaptosomal dopamine release. Life Sci. 1979 May 28;24(22):2083–2092. doi: 10.1016/0024-3205(79)90082-1. [DOI] [PubMed] [Google Scholar]
  26. Milligan G., Streaty R. A., Gierschik P., Spiegel A. M., Klee W. A. Development of opiate receptors and GTP-binding regulatory proteins in neonatal rat brain. J Biol Chem. 1987 Jun 25;262(18):8626–8630. [PubMed] [Google Scholar]
  27. Moss J., Stanley S. J., Watkins P. A., Burns D. L., Manclark C. R., Kaslow H. R., Hewlett E. L. Stimulation of the thiol-dependent ADP-ribosyltransferase and NAD glycohydrolase activities of Bordetella pertussis toxin by adenine nucleotides, phospholipids, and detergents. Biochemistry. 1986 May 6;25(9):2720–2725. doi: 10.1021/bi00357a066. [DOI] [PubMed] [Google Scholar]
  28. Osborne J. C., Jr, Stanley S. J., Moss J. Kinetic mechanisms of two NAD:arginine ADP-ribosyltransferases: the soluble, salt-stimulated transferase from turkey erythrocytes and choleragen, a toxin from Vibrio cholerae. Biochemistry. 1985 Sep 10;24(19):5235–5240. doi: 10.1021/bi00340a042. [DOI] [PubMed] [Google Scholar]
  29. Owens J. R., Frame L. T., Ui M., Cooper D. M. Cholera toxin ADP-ribosylates the islet-activating protein substrate in adipocyte membranes and alters its function. J Biol Chem. 1985 Dec 15;260(29):15946–15952. [PubMed] [Google Scholar]
  30. Parsons W. J., Stiles G. L. Heterologous desensitization of the inhibitory A1 adenosine receptor-adenylate cyclase system in rat adipocytes. Regulation of both Ns and Ni. J Biol Chem. 1987 Jan 15;262(2):841–847. [PubMed] [Google Scholar]
  31. Pedata F., Giovannelli L., De Sarno P., Pepeu G. Effect of adenosine, adenosine derivatives, and caffeine on acetylcholine release from brain synaptosomes: interaction with muscarinic autoregulatory mechanisms. J Neurochem. 1986 May;46(5):1593–1598. doi: 10.1111/j.1471-4159.1986.tb01781.x. [DOI] [PubMed] [Google Scholar]
  32. Perkins M. N., Stone T. W. Blockade of striatal neurone responses to morphine by aminophylline: evidence for adenosine mediation of opiate action. Br J Pharmacol. 1980 May;69(1):131–137. doi: 10.1111/j.1476-5381.1980.tb10892.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Phillis J. W., Edstrom J. P., Kostopoulos G. K., Kirkpatrick J. R. Effects of adenosine and adenine nucleotides on synaptic transmission in the cerebral cortex. Can J Physiol Pharmacol. 1979 Nov;57(11):1289–1312. doi: 10.1139/y79-194. [DOI] [PubMed] [Google Scholar]
  34. Pincomb G. A., Lovallo W. R., Passey R. B., Whitsett T. L., Silverstein S. M., Wilson M. F. Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men. Am J Cardiol. 1985 Jul 1;56(1):119–122. doi: 10.1016/0002-9149(85)90578-8. [DOI] [PubMed] [Google Scholar]
  35. Robertson D., Wade D., Workman R., Woosley R. L., Oates J. A. Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest. 1981 Apr;67(4):1111–1117. doi: 10.1172/JCI110124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Roller L. Caffeinism: subjective quantitative aspect of withdrawal syndrome. Med J Aust. 1981 Feb 7;1(3):146–146. doi: 10.5694/j.1326-5377.1981.tb135407.x. [DOI] [PubMed] [Google Scholar]
  37. Salomon Y., Londos C., Rodbell M. A highly sensitive adenylate cyclase assay. Anal Biochem. 1974 Apr;58(2):541–548. doi: 10.1016/0003-2697(74)90222-x. [DOI] [PubMed] [Google Scholar]
  38. Smits P., Boekema P., De Abreu R., Thien T., van 't Laar A. Evidence for an antagonism between caffeine and adenosine in the human cardiovascular system. J Cardiovasc Pharmacol. 1987 Aug;10(2):136–143. doi: 10.1097/00005344-198708000-00002. [DOI] [PubMed] [Google Scholar]
  39. Snyder S. H., Katims J. J., Annau Z., Bruns R. F., Daly J. W. Adenosine receptors and behavioral actions of methylxanthines. Proc Natl Acad Sci U S A. 1981 May;78(5):3260–3264. doi: 10.1073/pnas.78.5.3260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Spignoli G., Pedata F., Pepeu G. A1 and A2 adenosine receptors modulate acetylcholine release from brain slices. Eur J Pharmacol. 1984 Jan 27;97(3-4):341–342. doi: 10.1016/0014-2999(84)90475-8. [DOI] [PubMed] [Google Scholar]
  41. Stiles G. L., Daly D. T., Olsson R. A. The A1 adenosine receptor. Identification of the binding subunit by photoaffinity cross-linking. J Biol Chem. 1985 Sep 5;260(19):10806–10811. [PubMed] [Google Scholar]
  42. Stone T. W., Perkins M. N. Is adenosine the mediator of opiate action on neuronal firing rate? Nature. 1979 Sep 20;281(5728):227–228. doi: 10.1038/281227a0. [DOI] [PubMed] [Google Scholar]
  43. Sutherland D. J., McPherson D. D., Renton K. W., Spencer C. A., Montague T. J. The effect of caffeine on cardiac rate, rhythm, and ventricular repolarization. Analysis of 18 normal subjects and 18 patients with primary ventricular dysrhythmia. Chest. 1985 Mar;87(3):319–324. doi: 10.1378/chest.87.3.319. [DOI] [PubMed] [Google Scholar]
  44. Weiner M., Olson J. W. Single-dose tolerance to the behavioral effects of dibutyryl cyclic AMP in mice. Psychopharmacology (Berl) 1977 Aug 31;54(1):61–65. doi: 10.1007/BF00426543. [DOI] [PubMed] [Google Scholar]
  45. White B. C., Lincoln C. A., Pearce N. W., Reeb R., Vaida C. Anxiety and muscle tension as consequences of caffeine withdrawal. Science. 1980 Sep 26;209(4464):1547–1548. doi: 10.1126/science.7433978. [DOI] [PubMed] [Google Scholar]
  46. Whitsett T. L., Manion C. V., Christensen H. D. Cardiovascular effects of coffee and caffeine. Am J Cardiol. 1984 Mar 15;53(7):918–922. doi: 10.1016/0002-9149(84)90525-3. [DOI] [PubMed] [Google Scholar]

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