Protein kinase C ε mediates up-regulation of N-type calcium channels by ethanol

Thomas Mcmahon, Reid Andersen, Pamela Metten, John C. Crabbe, Robert O. Messing

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Brief exposure to ethanol inhibits L-type and N-type voltage-gated calcium channels in neural cells. Although chronic ethanol exposure up- regulates the density and function of L-type channels via a protein kinase C (PKC) δ-dependent mechanism, the effect of prolonged ethanol exposure on N- type channels is not known. Using PC12 cells, we found that exposure to 25 to 150 mM ethanol for 0 to 8 days produced a time- and concentration-dependent increase in the density of binding sites for the N-type channel antagonist 125I-ω-conotoxin GVIA. This was associated with an increase in ω- conotoxin GVIA-sensitive, depolarization-evoked rises in [Ca2+](i). Increases in 125I-ω-conotoxin GVIA binding also were observed in the frontal cortex and the hippocampus, but not in the thalamus of mice exposed to ethanol vapor for 3 days. In PC12 cells, increases in 125I-ω-conotoxin GVIA binding were blocked by the PKC inhibitor bisindolylmaleimide I and by expression of a selective peptide inhibitor of PKCE. Expression of a selective inhibitor of PKCδ did not alter ethanol-induced increases in 125I-ω-conotoxin GVIA binding. These findings indicate that PKCε mediates upregulation of N-type channels by ethanol. Because N-type channels modulate calcium-dependent neurotransmitter release, these findings suggest a mechanism that may contribute to neuronal hyperexcitability observed during alcohol withdrawal.

Original languageEnglish (US)
Pages (from-to)53-58
Number of pages6
JournalMolecular pharmacology
Volume57
Issue number1
StatePublished - 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Mcmahon, T., Andersen, R., Metten, P., Crabbe, J. C., & Messing, R. O. (2000). Protein kinase C ε mediates up-regulation of N-type calcium channels by ethanol. Molecular pharmacology, 57(1), 53-58.