Skip to main content
PMC 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
. 1980 Aug;77(8):4688–4691. doi: 10.1073/pnas.77.8.4688

Activation of brain tryptophan hydroxylase by ATP-MG2+: dependence on calmodulin.

D M Kuhn, J P O'Callaghan, J Juskevich, W Lovenberg
PMCID: PMC349911  PMID: 6107909

Abstract

Tryptophan hydroxylase [tryptophan 5-monooxygenase, L-tryptophan,tetrahydropterin:oxygen oxidoreductase (5-hydroxylating), EC 1.14.16.4] is activated by phosphorylating conditions (ATP-Mg2+) in a calcium-dependent, cyclic AMP-independent manner. Addition to the phosphorylation reaction of certain antipsychotic drugs that bind to calmodulin, the heat-stable calcium-binding protein, prevents the activation of tryptophan hydroxylase by ATP-Mg2+ in a concentration-dependent fashion. External addition of purified calmodulin protects the enzyme from the drug-induced effects. Calmodulin-free tryptophan hydroxylase prepared by affinity chromatography on fluphenazine-Sepharose is not activated by ATP-Mg2+ whereas addition of calmodulin to calmodulin-free enzyme restores the responsiveness of the hydroxylase to ATP-MG2+ only in the presence of Ca2+. These results indicate that the activation of tryptophan hydroxylase by phosphorylating conditions is dependent on both calcium and calmodulin.

Full text

PDF
4690

Images in this article

4690Image
on p.4690

Selected References

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

  1. Baumgarten H. G., Victor S. J., Lovenberg W. Effect of intraventricular injection of 5,7-dihydroxytryptamine on regional tryptophan hydroxylase of rat brain. J Neurochem. 1973 Jul;21(1):251–253. doi: 10.1111/j.1471-4159.1973.tb04246.x. [DOI] [PubMed] [Google Scholar]
  2. 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: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  3. Charbonneau H., Cormier M. J. Purification of plant calmodulin by fluphenazine-Sepharose affinity chromatography. Biochem Biophys Res Commun. 1979 Oct 12;90(3):1039–1047. doi: 10.1016/0006-291x(79)91931-4. [DOI] [PubMed] [Google Scholar]
  4. Cheung W. Y. Calmodulin plays a pivotal role in cellular regulation. Science. 1980 Jan 4;207(4426):19–27. doi: 10.1126/science.6243188. [DOI] [PubMed] [Google Scholar]
  5. Cheung W. Y. Cyclic 3',5'-nucleotide phosphodiesterase. Evidence for and properties of a protein activator. J Biol Chem. 1971 May 10;246(9):2859–2869. [PubMed] [Google Scholar]
  6. Friedman P. A., Kappelman A. H., Kaufman S. Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain. J Biol Chem. 1972 Jul 10;247(13):4165–4173. [PubMed] [Google Scholar]
  7. Hamon M., Bourgoin S., Artaud F., Héry F. Rat brain stem tryptophan hydroxylase: mechanism of activation by calcium. J Neurochem. 1977 Apr;28(4):811–818. doi: 10.1111/j.1471-4159.1977.tb10632.x. [DOI] [PubMed] [Google Scholar]
  8. Hamon M., Bourgoin S., Héry F., Simonnet G. Activation of tryptophan hydroxylase by adenosine triphosphate, magnesium, and calcium. Mol Pharmacol. 1978 Jan;14(1):99–110. [PubMed] [Google Scholar]
  9. Jéquier E., Lovenberg W., Sjoerdsma A. Tryptophan hydroxylase inhibition: the mechanism by which p-chlorophenylalanine depletes rat brain serotonin. Mol Pharmacol. 1967 May;3(3):274–278. [PubMed] [Google Scholar]
  10. Klee C. B. Conformational transition accompanying the binding of Ca2+ to the protein activator of 3',5'-cyclic adenosine monophosphate phosphodiesterase. Biochemistry. 1977 Mar 8;16(5):1017–1024. doi: 10.1021/bi00624a033. [DOI] [PubMed] [Google Scholar]
  11. Kuhn D. M., Vogel R. L., Lovenberg W. Calcium-dependent activation of tryptophan hydroxylase by ATP and magnesium. Biochem Biophys Res Commun. 1978 May 30;82(2):759–766. doi: 10.1016/0006-291x(78)90940-3. [DOI] [PubMed] [Google Scholar]
  12. Levin R. M., Weiss B. Binding of trifluoperazine to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. Mol Pharmacol. 1977 Jul;13(4):690–697. [PubMed] [Google Scholar]
  13. Levin R. M., Weiss B. Mechanism by which psychotropic drugs inhibit adenosine cyclic 3',5'-monophosphate phosphodiesterase of brain. Mol Pharmacol. 1976 Jul;12(4):581–589. [PubMed] [Google Scholar]
  14. Levin R. M., Weiss B. Selective binding of antipsychotics and other psychoactive agents to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. J Pharmacol Exp Ther. 1979 Mar;208(3):454–459. [PubMed] [Google Scholar]
  15. Lovenberg W., Bruckwick E. A., Hanbauer I. ATP, cyclic AMP, and magnesium increase the affinity of rat striatal tyrosine hydroxylase for its cofactor. Proc Natl Acad Sci U S A. 1975 Aug;72(8):2955–2958. doi: 10.1073/pnas.72.8.2955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lysz T. W., Sze P. Y. Activation of brain tryptophan hydroxylase by a phosphorylating system. J Neurosci Res. 1978;3(5-6):411–418. doi: 10.1002/jnr.490030512. [DOI] [PubMed] [Google Scholar]
  17. O'Farrell P. H. High resolution two-dimensional electrophoresis of proteins. J Biol Chem. 1975 May 25;250(10):4007–4021. [PMC free article] [PubMed] [Google Scholar]
  18. Post R. M., Jimerson D. C., Bunney W. E., Jr, Goodwin F. K. Dopamine and mania: behavioral and biochemical effects of the dopamine receptor blocker pimozide. Psychopharmacology (Berl) 1980;67(3):297–305. doi: 10.1007/BF00431272. [DOI] [PubMed] [Google Scholar]
  19. Schulman H., Greengard P. Ca2+-dependent protein phosphorylation system in membranes from various tissues, and its activation by "calcium-dependent regulator". Proc Natl Acad Sci U S A. 1978 Nov;75(11):5432–5436. doi: 10.1073/pnas.75.11.5432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Shiman R., Akino M., Kaufman S. Solubilization and partial purification of tyrosine hydroxylase from bovine adrenal medulla. J Biol Chem. 1971 Mar 10;246(5):1330–1340. [PubMed] [Google Scholar]
  21. Uzunov P., Weiss B. Effects of phenothiazine tranquilizers on the cyclic 3',5'-adenosine monophosphate system of rat brain. Neuropharmacology. 1971 Nov;10(6):697–708. doi: 10.1016/0028-3908(71)90084-0. [DOI] [PubMed] [Google Scholar]
  22. Uzunov P., Weiss B. Psychopharmacological agents and the cyclic AMP system of rat brain. Adv Cyclic Nucleotide Res. 1972;1:435–453. [PubMed] [Google Scholar]
  23. Yamauchi T., Fujisawa H. Activation of tryptophan 5-monooxygenase by calcium-dependent regulator protein. Biochem Biophys Res Commun. 1979 Sep 12;90(1):28–35. doi: 10.1016/0006-291x(79)91585-7. [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