Vasoactive intestinal peptide induces both tyrosine hydroxylase activity and tetrahydrobiopterin biosynthesis in PC12 cells

Panagiotis Z Anastasiadis, L. Bezin, L. J. Gordon, B. Imerman, J. Blitz, R. A. Levine

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Vasoactive intestinal peptide plays an important role in the trans- synaptic activation of tyrosine hydroxylase in sympathoadrenal tissues in response to physiological stress. Since tyrosine hydroxylase is thought to be subsaturated with its cofactor, tetrahydrobiopterin, we tested the hypothesis that up-regulation of tyrosine hydroxylase gene expression following vasoactive intestinal peptide treatment is accompanied by a concomitant elevation of intracellular tetrahydrobiopterin biosynthesis. We also investigated the second messenger systems involved in vasoactive intestinal peptide's effects on tetrahydrobiopterin metabolism. Our results demonstrate that treatment of PC12 cells for 24 h with vasoactive intestinal peptide induced intracellular tetrahydrobiopterin levels 3.5-fold. This increase was due to increased expression of the gene encoding GTP cyclohydrolase, the initial and rate-limiting enzyme in tetrahydrobiopterin biosynthesis, which was blocked by the transcriptional inhibitor, actinomycin D. Activation of tyrosine hydroxylase and GTP cyclohydrolase by vasoactive intestinal peptide was mediated by cyclic-AMP. Furthermore, stimulation of cyclic-AMP-mediated responses or protein kinase C activity induced the maximal in vitro activities of both tyrosine hydroxylase and GTP cyclohydrolase; the responses were additive when both treatments were combined. Induction of sphingolipid metabolism had no effect on the activation of tyrosine hydroxylase, while it induced GTP cyclohydrolase in a protein kinase C-independent manner. Our results support the hypothesis that intracellular tetrahydrobiopterin levels are tightly linked to tyrosine hydroxylation and that tetrahydrobiopterin bioavailability modulates catecholamine synthesis.

Original languageEnglish (US)
Pages (from-to)179-189
Number of pages11
JournalNeuroscience
Volume86
Issue number1
DOIs
StatePublished - May 21 1998
Externally publishedYes

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Vasoactive Intestinal Peptide
PC12 Cells
Tyrosine 3-Monooxygenase
GTP Cyclohydrolase
Cyclic AMP
Protein Kinase C
Gene Expression
Sphingolipids
Physiological Stress
Dactinomycin
Second Messenger Systems
Hydroxylation
sapropterin
Biological Availability
Catecholamines
Tyrosine
Up-Regulation
Enzymes

Keywords

  • Adrenal medulla
  • cAMP
  • Catecholamines
  • GTP cyclohydrolase
  • Protein kinase C
  • Sphingosine

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Vasoactive intestinal peptide induces both tyrosine hydroxylase activity and tetrahydrobiopterin biosynthesis in PC12 cells. / Anastasiadis, Panagiotis Z; Bezin, L.; Gordon, L. J.; Imerman, B.; Blitz, J.; Levine, R. A.

In: Neuroscience, Vol. 86, No. 1, 21.05.1998, p. 179-189.

Research output: Contribution to journalArticle

Anastasiadis, Panagiotis Z ; Bezin, L. ; Gordon, L. J. ; Imerman, B. ; Blitz, J. ; Levine, R. A. / Vasoactive intestinal peptide induces both tyrosine hydroxylase activity and tetrahydrobiopterin biosynthesis in PC12 cells. In: Neuroscience. 1998 ; Vol. 86, No. 1. pp. 179-189.
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