Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Dec 1;90(23):11277–11281. doi: 10.1073/pnas.90.23.11277

Regulation by the neuropeptide cholecystokinin (CCK-8S) of protein phosphorylation in the neostriatum.

G L Snyder 1, G Fisone 1, P Morino 1, V Gundersen 1, O P Ottersen 1, T Hökfelt 1, P Greengard 1
PMCID: PMC47965  PMID: 8248241

Abstract

Despite physiological evidence that cholecystokinin (CCK) is an excitatory neurotransmitter in the brain, little is known about its mechanism of action. CCK immunoreactivity in the brain, including projections to the striatum, is primarily attributable to the sulfated octapeptide CCK-8S. We report here that CCK-8S abolishes cAMP-dependent phosphorylation of a dopamine- and cAMP-regulated 32-kDa phosphoprotein (DARPP-32) in striatal neurons. The effect of CCK-8S is prevented by antagonists of CCKB and N-methyl-D-aspartate receptors. Our results support a model in which CCK-8S, originating from CCK or CCK/glutamate corticostriatal neurons, promotes the release of an excitatory neurotransmitter that causes the dephosphorylation and inactivation of DARPP-32, a potent protein phosphatase inhibitor, thereby modulating neuronal excitability.

Full text

PDF
11277

Images in this article

11278Fig. 1
on p.11278
11279Fig. 2
on p.11279
11280Fig. 3
on p.11280

Selected References

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

  1. Altar C. A., Boyar W. C. Brain CCK-B receptors mediate the suppression of dopamine release by cholecystokinin. Brain Res. 1989 Apr 3;483(2):321–326. doi: 10.1016/0006-8993(89)90176-5. [DOI] [PubMed] [Google Scholar]
  2. Barnes S., Whistler H. L., Hughes J., Woodruff G. N., Hunter J. C. Effect of cholecystokinin octapeptide on endogenous amino acid release from the rat ventromedial nucleus of the hypothalamus and striatum. J Neurochem. 1991 Apr;56(4):1409–1416. doi: 10.1111/j.1471-4159.1991.tb11439.x. [DOI] [PubMed] [Google Scholar]
  3. Beinfeld M. C., Meyer D. K., Eskay R. L., Jensen R. T., Brownstein M. J. The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay. Brain Res. 1981 May 11;212(1):51–57. doi: 10.1016/0006-8993(81)90031-7. [DOI] [PubMed] [Google Scholar]
  4. Beresford I. J., Hall M. D., Clark C. R., Hill R. G., Hughes J., Sirinathsinghji D. J. Striatal lesions and transplants demonstrate that cholecystokinin receptors are localized on intrinsic striatal neurones: a quantitative autoradiographic study. Neuropeptides. 1987 Aug-Sep;10(2):109–136. doi: 10.1016/0143-4179(87)90014-x. [DOI] [PubMed] [Google Scholar]
  5. Bertorello A. M., Aperia A., Walaas S. I., Nairn A. C., Greengard P. Phosphorylation of the catalytic subunit of Na+,K(+)-ATPase inhibits the activity of the enzyme. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11359–11362. doi: 10.1073/pnas.88.24.11359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blackstad T. W., Karagülle T., Ottersen O. P. MORFOREL, a computer program for two-dimensional analysis of micrographs of biological specimens, with emphasis on immunogold preparations. Comput Biol Med. 1990;20(1):15–34. doi: 10.1016/0010-4825(90)90041-m. [DOI] [PubMed] [Google Scholar]
  7. Burgunder J. M., Young W. S., 3rd Cortical neurons expressing the cholecystokinin gene in the rat: distribution in the adult brain, ontogeny, and some of their projections. J Comp Neurol. 1990 Oct 1;300(1):26–46. doi: 10.1002/cne.903000104. [DOI] [PubMed] [Google Scholar]
  8. Calabresi P., Mercuri N., Stanzione P., Stefani A., Bernardi G. Intracellular studies on the dopamine-induced firing inhibition of neostriatal neurons in vitro: evidence for D1 receptor involvement. Neuroscience. 1987 Mar;20(3):757–771. doi: 10.1016/0306-4522(87)90239-9. [DOI] [PubMed] [Google Scholar]
  9. Chiodo L. A., Berger T. W. Interactions between dopamine and amino acid-induced excitation and inhibition in the striatum. Brain Res. 1986 Jun 4;375(1):198–203. doi: 10.1016/0006-8993(86)90976-5. [DOI] [PubMed] [Google Scholar]
  10. Dockray G. J. Immunochemical evidence of cholecystokinin-like peptides in brain. Nature. 1976 Dec 9;264(5586):568–570. doi: 10.1038/264568a0. [DOI] [PubMed] [Google Scholar]
  11. Dodd J., Kelly J. S. The actions of cholecystokinin and related peptides on pyramidal neurones of the mammalian hippocampus. Brain Res. 1981 Feb 2;205(2):337–350. doi: 10.1016/0006-8993(81)90344-9. [DOI] [PubMed] [Google Scholar]
  12. Halpain S., Girault J. A., Greengard P. Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices. Nature. 1990 Jan 25;343(6256):369–372. doi: 10.1038/343369a0. [DOI] [PubMed] [Google Scholar]
  13. Hassler R., Chung J. W., Rinne U., Wagner A. Selective degeneration of two out of the nine types of synapses in cat caudate nucleus after cortical lesions. Exp Brain Res. 1978 Jan 18;31(1):67–80. doi: 10.1007/BF00235805. [DOI] [PubMed] [Google Scholar]
  14. Hemmings H. C., Jr, Greengard P. DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein: regional, tissue, and phylogenetic distribution. J Neurosci. 1986 May;6(5):1469–1481. doi: 10.1523/JNEUROSCI.06-05-01469.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hemmings H. C., Jr, Greengard P., Tung H. Y., Cohen P. DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. Nature. 1984 Aug 9;310(5977):503–505. doi: 10.1038/310503a0. [DOI] [PubMed] [Google Scholar]
  16. Hepler J. R., Toomim C. S., McCarthy K. D., Conti F., Battaglia G., Rustioni A., Petrusz P. Characterization of antisera to glutamate and aspartate. J Histochem Cytochem. 1988 Jan;36(1):13–22. doi: 10.1177/36.1.2891743. [DOI] [PubMed] [Google Scholar]
  17. Hughes J., Boden P., Costall B., Domeney A., Kelly E., Horwell D. C., Hunter J. C., Pinnock R. D., Woodruff G. N. Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6728–6732. doi: 10.1073/pnas.87.17.6728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hökfelt T., Johansson O., Ljungdahl A., Lundberg J. M., Schultzberg M. Peptidergic neurones. Nature. 1980 Apr 10;284(5756):515–521. doi: 10.1038/284515a0. [DOI] [PubMed] [Google Scholar]
  19. Ingram S. M., Krause R. G., 2nd, Baldino F., Jr, Skeen L. C., Lewis M. E. Neuronal localization of cholecystokinin mRNA in the rat brain by using in situ hybridization histochemistry. J Comp Neurol. 1989 Sep 8;287(2):260–272. doi: 10.1002/cne.902870209. [DOI] [PubMed] [Google Scholar]
  20. Innis R. B., Snyder S. H. Distinct cholecystokinin receptors in brain and pancreas. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6917–6921. doi: 10.1073/pnas.77.11.6917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ji Z. Q., Aas J. E., Laake J., Walberg F., Ottersen O. P. An electron microscopic, immunogold analysis of glutamate and glutamine in terminals of rat spinocerebellar fibers. J Comp Neurol. 1991 May 8;307(2):296–310. doi: 10.1002/cne.903070210. [DOI] [PubMed] [Google Scholar]
  22. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  23. 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]
  24. Magistretti P. J., Morrison J. H., Shoemaker W. J., Sapin V., Bloom F. E. Vasoactive intestinal polypeptide induces glycogenolysis in mouse cortical slices: a possible regulatory mechanism for the local control of energy metabolism. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6535–6539. doi: 10.1073/pnas.78.10.6535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Marshall F. H., Barnes S., Hughes J., Woodruff G. N., Hunter J. C. Cholecystokinin modulates the release of dopamine from the anterior and posterior nucleus accumbens by two different mechanisms. J Neurochem. 1991 Mar;56(3):917–922. doi: 10.1111/j.1471-4159.1991.tb02009.x. [DOI] [PubMed] [Google Scholar]
  26. Meyer D. K., Beinfeld M. C., Oertel W. H., Brownstein M. J. Origin of the cholecystokinin-containing fibers in the rat caudatoputamen. Science. 1982 Jan 8;215(4529):187–188. doi: 10.1126/science.7053570. [DOI] [PubMed] [Google Scholar]
  27. Meyer D. K., Protopapas Z. Studies on cholecystokinin-containing neuronal pathways in rat cerebral cortex and striatum. Ann N Y Acad Sci. 1985;448:133–143. doi: 10.1111/j.1749-6632.1985.tb29913.x. [DOI] [PubMed] [Google Scholar]
  28. Morino P., Herrera-Marschitz M., Meana J. J., Ungerstedt U., Hökfelt T. Immunohistochemical evidence for a crossed cholecystokinin corticostriatal pathway in the rat. Neurosci Lett. 1992 Dec 14;148(1-2):133–136. doi: 10.1016/0304-3940(92)90822-o. [DOI] [PubMed] [Google Scholar]
  29. Nicklas W. J., Duvoisin R. C., Berl S. Amino acids in rat neostriatum: alteration by kainic acid lesion. Brain Res. 1979 May 5;167(1):107–117. doi: 10.1016/0006-8993(79)90266-x. [DOI] [PubMed] [Google Scholar]
  30. Ottersen O. P. Quantitative electron microscopic immunocytochemistry of neuroactive amino acids. Anat Embryol (Berl) 1989;180(1):1–15. doi: 10.1007/BF00321895. [DOI] [PubMed] [Google Scholar]
  31. Ouimet C. C., Miller P. E., Hemmings H. C., Jr, Walaas S. I., Greengard P. DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J Neurosci. 1984 Jan;4(1):111–124. doi: 10.1523/JNEUROSCI.04-01-00111.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Snyder G. L., Girault J. A., Chen J. Y., Czernik A. J., Kebabian J. W., Nathanson J. A., Greengard P. Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: regulation by factors other than dopamine. J Neurosci. 1992 Aug;12(8):3071–3083. doi: 10.1523/JNEUROSCI.12-08-03071.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Snyder S. H. Brain peptides as neurotransmitters. Science. 1980 Aug 29;209(4460):976–983. doi: 10.1126/science.6157191. [DOI] [PubMed] [Google Scholar]
  34. Storm-Mathisen J., Ottersen O. P., Fu-Long T., Gundersen V., Laake J. H., Nordbø G. Metabolism and transport of amino acids studied by immunocytochemistry. Med Biol. 1986;64(2-3):127–132. [PubMed] [Google Scholar]
  35. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Vanderhaeghen J. J., Lotstra F., Vierendeels G., Gilles C., Deschepper C., Verbanck P. Cholecystokinins in the central nervous system and neurohypophysis. Peptides. 1981;2 (Suppl 2):81–88. doi: 10.1016/0196-9781(81)90016-4. [DOI] [PubMed] [Google Scholar]
  37. Vanderhaeghen J. J., Signeau J. C., Gepts W. New peptide in the vertebrate CNS reacting with antigastrin antibodies. Nature. 1975 Oct 16;257(5527):604–605. doi: 10.1038/257604a0. [DOI] [PubMed] [Google Scholar]
  38. Vickroy T. W., Bianchi B. R., Kerwin J. F., Jr, Kopecka H., Nadzan A. M. Evidence that type A CCK receptors facilitate dopamine efflux in rat brain. Eur J Pharmacol. 1988 Aug 2;152(3):371–372. doi: 10.1016/0014-2999(88)90735-2. [DOI] [PubMed] [Google Scholar]
  39. Wagner J. J., Terman G. W., Chavkin C. Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus. Nature. 1993 Jun 3;363(6428):451–454. doi: 10.1038/363451a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Walaas S. I., Aswad D. W., Greengard P. A dopamine- and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions. Nature. 1983 Jan 6;301(5895):69–71. doi: 10.1038/301069a0. [DOI] [PubMed] [Google Scholar]
  41. Walaas S. I., Greengard P. DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Regional and cellular distribution in the rat brain. J Neurosci. 1984 Jan;4(1):84–98. doi: 10.1523/JNEUROSCI.04-01-00084.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Weisskopf M. G., Zalutsky R. A., Nicoll R. A. The opioid peptide dynorphin mediates heterosynaptic depression of hippocampal mossy fibre synapses and modulates long-term potentiation. Nature. 1993 Apr 1;362(6419):423–427. doi: 10.1038/362423a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES