The natural beta-carbolines facilitate inositol phosphate accumulation by activating small G-proteins in human neuroblastoma cells (SH-SY5Y).
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.
Lichtenberg-Kraag
B
B
Department of Clinical Neurobiology, Free University, Berlin, Germany.
Klinker
J F
JF
Mühlbauer
E
E
Rommelspacher
H
H
D001665:Binding Sites / Q000187:drug effects; D001711:Biotransformation / Q000187:drug effects; D001905:Botulinum Toxins / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002243:Carbolines; D007295:Inositol Phosphates; D001905:Botulinum Toxins; D019204:GTP-Binding Proteins