Neurochemical Research

, Volume 1, Issue 2, pp 217–227 | Cite as

Release of phosphodiesterase activator from particulate fractions of cerebellum and striatum by putative neurotransmitters

  • A. Revuelta
  • P. Uzunov
  • E. Costa


The endogenous phosphodiesterase activator (PDEA) described by Cheung (1,2) is, in part, stored as a membrane-bound protein (12,13). PDEA can be released from the membranes by a cAMP-dependent phosphorylation of a protein that may function as PDEA binding site (13). We found that PDEA can be released from brain particulate fraction by 1 μM norepinephrine, dopamine, adenosine, and histamine in the presence of ATP and a purified cAMP-dependent protein kinase; in similar conditions, serotonin is ineffective in concentrations up to 0.1 mM. Norepinephrine and dopamine activate the adenylate cyclase activity of those preparations from which they release the PDEA. Norepinephrine is more potent than dopamine in releasing PDEA from the particulate fraction of cerebellum, whereas dopamine is more active than norepinephrine in releasing PDEA from the particulate fraction of striatum. The release of PDEA elicited by both neurotransmitters is concentration-dependent; increasing the transmitter concentrations above a certain limit decreases the rate of PDEA release.


Dopamine Protein Kinase Adenosine Serotonin Histamine 
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.
    Cheung, W.Y. (1970) Cyclic 3′,5′-nucleotide phosphodiesterase: demonstration of an activator. Biochem. Biophys. Res. Commun. 38, 533–538.PubMedGoogle Scholar
  2. 2.
    Cheung, W.Y. (1971) Cyclic 3′,5′-nucleotide phosphodiesterase: evidence for and properties of a protein activator. J. Biol. Chem. 246, 2859–2869.PubMedGoogle Scholar
  3. 3.
    Liu, Y.P., Lin, Y.M., andCheung, W.Y. (1974) Active form of protein activator of cAMP phosphodiesterase is a Ca++-activator complex. Fed. Proc. Fed. Am. Soc. Exp. Biol. 33, 1391.Google Scholar
  4. 4.
    Lin, Y.M., Liu, Y.P., andCheung, W.Y. (1974) Purification and characterization of a protein activator of cyclic nucleotide phosphodiesterase from bovine brain.In Hardman, J.G., andO'Malley, B.W. (eds.), Methods in Enzymology, Vol. 38, Academic Press, Inc. New York, pp. 262–283.Google Scholar
  5. 5.
    Lin, Y.M., Liu, Y.P., andCheung, W.Y. (1974) Cyclic 3′,5′-nucleotide phosphodiesterase. Purification, characterization, and active form of the protein activator from bovine brain. J. Biol. Chem. 249, 4943–4954.PubMedGoogle Scholar
  6. 6.
    Kakiuchi, S., andYamazaki, R. (1970) Calcium dependent phosphodiesterase activity and its, activating factor (PAF) from brain: studies on cyclic 3′,5′-nucleotide phosphodiesterase (III). Biochem. Biophys. Res. Commun. 41, 1104–1110.PubMedGoogle Scholar
  7. 7.
    Kakiuchi, S., Yamazaki, R., andNakajima, H. (1970) Properties of a heat-stable phosphodiesterase activating factor isolated from brain extract: studies on cyclic 3′,5′-nucleotide phosphodiesterase (II). Proc. Jpn. Acad. 46, 587–592.Google Scholar
  8. 8.
    Kakiuchi, S., Yamazaki, R., andTeshima, Y. (1972) Regulation of brain phosphodiesterase activity: Ca2+ plus Mg2+-dependent phosphodiesterase and its activating factor from rat brain.In Greengard, P., Paoletti, R., andG.A. Robison, (eds.), Advances in Cyclic Nucleotide Research, Vol. 1, Raven Press, New York, pp. 455–477.Google Scholar
  9. 9.
    Kakiuchi, S., Yamazaki, R., Teshima, Y., andUenishi, K. (1973) Regulation of nucleoside cyclic 3′,5′-monophosphate phosphodiesterase activity from rat brain by a modulator and Ca2+. Proc. Natl. Acad. Sci. U.S.A. 70, 3526–3530.PubMedGoogle Scholar
  10. 10.
    Uzunov, P., Revuelta, A.V., andCosta, E. (1975)In vitro regulation of cyclic 3′,5′-adenosine-monophosphate content by changes in the endogenous phosphodiesterase activator. Fed. Proc. Fed. Am. Soc. Exp. Biol. 34, 261.Google Scholar
  11. 11.
    Uzunov, P., Revuelta, A., andCosta, E. (1975) A role for the endogenous activator of 3′,5′-nucleotide phosphodiesterase in rat adrenal medulla. Mol. Pharmacol. 11, 506–510.Google Scholar
  12. 12.
    Uzunov, P., Gnegy, M., Lehne, R., Revuelta, A., andCosta, E. (1976) A neurobiological role for a protein activator of cyclic nucleotide phosphodiesterase.In Costa, E., Paoletti, R., andGiacobini, E. (eds.), Advances in Biochemical Psychopharmacology, Vol. 16, Raven Press, New York (in press).Google Scholar
  13. 13.
    Gnegy, M., Costa, E., andUzunov, P. (1976) The regulation of the transsynaptically elicited increase of 3′,5′-cyclic AMP by the endogenous phosphodiesterase activator. Proc. Nat. Acad. Sci. U.S.A. 73, 352–355.Google Scholar
  14. 14.
    Kuo, J.F. andGreengard, P. (1972) An assay method for cyclic AMP and cyclic GMP based upon their abilities to activate cyclic GMP-dependent protein kinase.In Greengard, P., Robison, G.A., andPaoletti, R. (eds.), Advances in Cyclic Nucleotide Research, Vol. 2, Raven Press, New York, pp. 41–50.Google Scholar
  15. 15.
    Filburn, C.R., andKarn, J. (1973) An isotopic assay of cyclic 3′,5′-nucleotide phosphodiesterase with aluminum oxide columns. Anal. Biochem. 52, 505–516.PubMedGoogle Scholar
  16. 16.
    Krishna, G., Weiss, B., andBrodie, B.B. (1968) A simple sensitive method for the assay of adenyl cyclase. J. Pharmacol. Exp. Ther. 163, 379–385.PubMedGoogle Scholar
  17. 17.
    Kakiuchi, S., andRall, T.W. (1965) Effects of norepinephrine (NE) and histamine (H) on levels of adenosine 3′,5′-phosphate (3,5-AMP) in brain slices. Fed. Proc. Fed. Am. Soc. Exp. Bicl. 24, 150.Google Scholar
  18. 18.
    Kakiuchi, S., andRall, T.W. (1968) The influence of chemical agents on the accumulation of adenosine 3′,5′-phosphate in slices of rabbit cerebellum. Mol. Pharmacol. 4, 367–378.PubMedGoogle Scholar
  19. 19.
    Huang, M., andDaly, J.W. (1972) Accumulation of cyclic adenosine monophosphate in incubated slices of brain tissue. I. Structure-activity relationships of agonists and antagonists of biogenic amines and of tricyclic tranquilizers and antidepressants. J. Med. Chem. 15, 458–461.PubMedGoogle Scholar
  20. 20.
    Palmer, G.C., Sulser, F. andRobison, G.A. (1969) The effect of neurohumoral agents on the level of cAMP in different brain areas in vitro. Pharmacologist 11, 258.Google Scholar
  21. 21.
    Walker, J.B., andWalker, J.P. (1973) Neurohumoral regulation of adenylate cyclase activity in rat striatum. Brain Res. 54, 386–390.PubMedGoogle Scholar
  22. 22.
    Shimizu, H., Daly, J.W., andCreveling, C.R. (1969) A radioisotopic method for measuring the formation of adenosine 3′,5′-cyclic monophosphate in incubated slices of brain. J. Neurochem. 16, 1609–1619.PubMedGoogle Scholar
  23. 23.
    Shimizu, H., Creveling, C.R., andDaly, J.W. (1970) Stimulated formation of adenosine 3′,5′-cyclic phosphate in cerebral cortex: synergism between electrical activity and biogenic amines. Proc. Nat. Acad. Sci. U.S.A. 65, 1033–1040.Google Scholar
  24. 24.
    Perkins J.P., andMoore, M.M. (1973) Characterization of the adrenergic receptors mediating a rise in cyclic 3′,5′-adenosine monophosphate in rat cerebral cortex. J. Pharmacol. Exp. Therap. 185, 371–378.Google Scholar
  25. 25.
    Ferrendelli, J.A., Kinscherf, D.A., andChang, M.M. (1973) Regulation of levels of guanosine cyclic 3′,5′-monophosphate in the central nervous system: effects of depolarizing agents. Mol. Pharmacol. 9, 445–454.PubMedGoogle Scholar
  26. 26.
    Shimizu, H., Creveling, C.R., andDaly, J.W. (1970) The effect of histamines and other compounds on the formation of adenosine 3′,5′-monophosphate in slices from cerebral cortex. j. Neurochem. 17, 441–444PubMedGoogle Scholar
  27. 27.
    Forn, J., andKrishna, G. (1970) Effects of biological amines on the rate of adenosine 3′,5′-monophosphate (3′,5′-AMP) formation in brain slices of different animal species. Fed. Proc. Fed. Am. Soc. Exp. Biol. 29, 480.Google Scholar
  28. 28.
    Uzunov, P., andWeiss, B (1972) Psychopharmacological agents and the cyclic AMP system of rat brain.In Greengard, P., andRobison, G.A. (eds.), Advances in Cyclic Nucleotide Research, Vol. 1, Raven Press, New York pp. 435–453.Google Scholar
  29. 29.
    Klainer, L.M., Chi, Y.-M., Freidberg, S.L., Rall, T.W., andSutherland, E.W. (1962) Adenylcyclase. IV. The effects of neurohormones on the formation of adenosine 3′,5′-phosphate by preparations from brain and other tissues. J. Biol. Chem. 237, 1239–1243.PubMedGoogle Scholar
  30. 30.
    Voigt, K.M., andKrishna, G. (1967) Correlation between the distribution of adenyl cyclase, cyclic 3′,5′AMP phosphodiesterase and various biological amines in various areas of the brain. Pharmacologist 9, 239.Google Scholar
  31. 31.
    Burkard, W.P., andGey, K.F. (1968) Adenylcyclase in Rattenherz. Helv. Physiol. Pharmacol. Acta 26, CR197-CR198.PubMedGoogle Scholar
  32. 32.
    Williams, R.H. Little, S.A., andEnsinck, J.W. (1969) Adenyl cyclase and phosphodiesterase activities in brain areas of man, monkey and rat. Am. J. Med. Sci. 258, 190–202.PubMedGoogle Scholar
  33. 33.
    McCune, R.W., Gill, T.H., von Hungen, K., andRoberts, S. (1971) Catecholamine-sensitive adenyl cyclase in cell-free preparations from rat cerebral cortex. Life Sci. 10, (II) 443–450.Google Scholar
  34. 34.
    Von Hungen, K., andRoberts, S. (1973) Catecholamine and Ca2+ activation of adenylate cyclase systems in synaptosomal fractions from rat cerebral, cortex. Nature, New Biology 242, 58–60.Google Scholar
  35. 35.
    Von Hungen, K., andRoberts, S. (1973) Adenylate cyclase receptor for adrenergic neurotransmitters in rat cerebral cortex. Eur. J. Biochem. 36, 391–401.PubMedGoogle Scholar
  36. 36.
    Kebabian, J.W., Petzold, G.L., andGreengard, P. (1972) Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain and its, similarity to the “dopamine receptor”. Proc. Natl. Acad. Sci. U.S.A. 69, 2145–2149.PubMedGoogle Scholar
  37. 37.
    Maeno, H., Ueda, T., andGreengard, P. (1975) Adenosine 3′,5′-monophosphate-dependent protein phosphatase activity in synaptic membrane fractions. J. Cyclic Nucleotide Res. 1, 37–48.Google Scholar
  38. 38.
    Ueda, T., Maeno, H., andGreengard, P. (1973) Regulation of endogenous phosphorylation of specific proteins in synaptic membrane fractions from rat brain by adenosine 3′,5′-monophosphate. J. Biol. Chem. 248, 8295–8305.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1976

Authors and Affiliations

  • A. Revuelta
    • 1
  • P. Uzunov
    • 1
  • E. Costa
    • 1
  1. 1.Laboratory of Preclinical Pharmacology National Institute of Mental HealthSaint Elizabeths HospitalWashington D.C.

Personalised recommendations