Transcriptional and post-transcriptional regulation of Tyrosine Hydroxylase messenger RNA in PC12 cells during persistent stimulation by VIP and PACAP38: Differential regulation by protein kinase A and protein kinase C-dependent pathways

J. Corbitt, T. Hagerty, E. Fernandez, W. W. Morgan, R. Strong

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

VIP and PACAP38 are closely related peptides that are released in the adrenal gland and sympathetic ganglia and regulate catecholamine synthesis and release. We used PC12 cells as a model system to examine receptor and second messenger pathways by which each peptide stimulates transcriptional and post-transcriptional mechanisms that regulate the level of the mRNA for tyrosine hydroxylase (TH), the rate-limiting enzymatic step in catecholamine synthesis. Concentration-response studies revealed that PACAP38 had both greater efficacy and potency than VIP. The specific PAC1 receptor antagonist PACAP[6-38] blocked the effects of each peptide on TH mRNA content while the PACAP/VIP type II receptor antagonist (N-AC-Tyr1-D-Phe2)-GRF-(1-29)-NH2 was without effect. At equipotent concentrations, each peptide stimulated a transient increase in TH gene transcription lasting less than 3 h. Continuous VIP treatment stimulated a transient increase in TH mRNA lasting less than 24 h. In contrast, continuous exposure to PACAP38 stimulated a stable increase in TH mRNA that persisted for 2 days in the absence of elevated transcription, pointing to different post-transcriptional effects of the two peptides. PACAP38 alone had no effect on the magnitude of TH gene transcription or TH mRNA in A126-1B2 PKA-deficient PC12 cells. However, when combined with dexamethasone, PACAP38 produced a synergistic increase in TH mRNA in the absence of PACAP38-stimulated TH gene transcription. In contrast, VIP had no effect on either TH mRNA content or TH gene transcription in this model. PACAP38, but not VIP, stimulated PKC activity. Calphostin C antagonized the effect of PACAP38 on the persistent post-transcriptional elevation in TH mRNA. Thus, the results support the conclusion that VIP and PACAP38 each stimulate PAC1 receptors to increase TH gene transcription through a PKA-controlled pathway, but their divergent post-transcriptional effects result at least partly from differing abilities to stimulate PKC.

Original languageEnglish (US)
Pages (from-to)34-45
Number of pages12
JournalNeuropeptides
Volume36
Issue number1
DOIs
StatePublished - Feb 2002

ASJC Scopus subject areas

  • Endocrinology
  • Neurology
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience

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