Role of phospholipase D signaling in ethanol-induced inhibition of carbachol-stimulated DNA synthesis of 1321N1 astrocytoma cells

Marina Guizzetti, Brian D. Thompson, Yunie Kim, Kathryn VanDeMark, Lucio G. Costa

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Inhibition of astrocyte proliferation has been suggested to be an important event in the developmental neurotoxicity associated with ethanol. We have previously shown that the acetylcholine analog carbachol induces astroglial cell proliferation through activation of muscarinic M3 receptors, and that ethanol strongly inhibits this effect by inhibiting activation of protein kinase C (PKC) ζ and its down-stream effector 70-kDa ribosomal S6 kinase (p70S6K). In this study, we investigated whether inhibition by ethanol of this signal transduction pathway in 1321N1 human astrocytoma cells may be due, at least in part, to inhibition of the formation of the PKC ζ activator phosphatidic acid (PA), which is formed by hydrolysis of phosphatidylcholine by phospholipase D (PLD). 1-Butanol, which is a substrate for PLD and inhibits PA formation, inhibited carbachol-induced cell proliferation and the underlying intracellular signaling, whereas its analog tert-butanol, which is a poor substrate for PLD, was much less effective. In addition, exogenous PAs were able to increase DNA synthesis and to activate PKC ζ and p70S6K. Furthermore, in carbachol-stimulated cells, ethanol increased the formation of phosphatidylethanol and inhibited the formation of PA. Taken together, these results indicate that PLD activation plays an important role in carbachol-induced astroglial cell proliferation by generating the second messenger PA, which activates PKC ζ. Moreover, the effect of ethanol on carbachol-induced proliferation appears to be mediated, at least in part, by its ability to interact with PLD leading to a decreased synthesis of PA.

Original languageEnglish (US)
Pages (from-to)646-653
Number of pages8
JournalJournal of neurochemistry
Volume90
Issue number3
DOIs
StatePublished - Aug 1 2004

Keywords

  • Astrocytoma cells
  • Cell proliferation
  • Ethanol
  • Muscarinic receptors
  • Phosphatidic acid
  • Phospholipase D

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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