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The natural beta-carbolines facilitate inositol phosphate accumulation by activating small G-proteins in human neuroblastoma cells (SH-SY5Y).

Abstract
The naturally occurring beta-carbolines exert psychotropic actions in humans and have numerous behavioral effects in animals. The known in vitro activities of these substances do not provide a satisfactory explanation for their in vivo effects. The present study was undertaken to explore the possibility of a specific signal transduction pathway. The human neuroblastoma cell line SH-SY5Y was used as a model system. High-affinity binding sites for [3H]norharman (synonymous: beta-carboline) were detected. Pharmacological characterization revealed displacement of the ligand by beta-carbolines, to a weaker extent by indoleamines, but not by opioids, muscarinic receptor agonists, metabotropic glutamate receptor agonists or several peptide neurotransmitters. Inositol phosphate accumulation was only slightly affected by the beta-carbolines. However, the action of carbachol was clearly facilitated in a dose-dependent and pertussis toxin-insensitive manner. Pretreatment of the cells with Clostridium difficile toxin B blocked the facilitating effect of the beta-carbolines by concentrations which did not affect the action of carbachol alone. This suggests that low molecular weight GTP-binding proteins are involved in the facilitating action of the beta-carbolines. This mechanism was further supported by experiments measuring the concentrations of phosphatidylinositol phosphates after various activating compounds. In conclusion, the facilitating effect of beta-carbolines on inositol phosphate accumulation could play a part in the actions of beta-carbolines and may be produced by stimulating the generation of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), the key component in the activation of phosphoinositide-phospholipase C.
AuthorsB Lichtenberg-Kraag, J F Klinker, E Mühlbauer, H Rommelspacher
JournalNeuropharmacology (Neuropharmacology) 1997 Nov-Dec Vol. 36 Issue 11-12 Pg. 1771-8 ISSN: 0028-3908 [Print] England
PMID9517450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carbolines
  • Inositol Phosphates
  • Botulinum Toxins
  • GTP-Binding Proteins
Topics
  • Binding Sites (drug effects)
  • Biotransformation (drug effects)
  • Botulinum Toxins (pharmacology)
  • Brain Neoplasms (metabolism)
  • Carbolines (pharmacology)
  • GTP-Binding Proteins (metabolism)
  • Humans
  • Inositol Phosphates (metabolism)
  • Neuroblastoma (metabolism)
  • Tumor Cells, Cultured

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