title: Tyrosine kinase inhibitors suppress N-type and T-type Ca2+ channel currents in NG108-15 cells.
abstract: Modulation of Ca2+ channel activity by protein kinases constitutes one of the major mechanisms regulating neuronal functions. Here, we explored the possible modulation of neuronal Ca2+ channels by protein tyrosine kinases (PTKs). To this end, the effects of PTK inhibitors on whole-cell Ba2+ currents (IBa) through voltage-gated Ca2+ channels were analysed in differentiated NG108-15 neuroblastoma x glioma hybrid cells. Genistein suppressed IBa in a concentration-dependent fashion (IC50 = 22 microM). Although daidzein, an analogue of genistein that is devoid of PTK inhibitory activity, also suppressed IBa, we estimated that specific PTK inhibition by genistein reduced IBa amplitude by 30%. In addition, lavendustin A (20 microM) and herbimycin A (20 microM), two other distinct PTK inhibitors, depressed IBa by 22% and 20%, respectively. Genistein suppressed N-type and T-type currents, sparing L-type current, and its effect was independent of G protein activation. The results suggest that the activity of neuronal Ca2+ channels can be modulated by PTKs, opening the possibility that some of the functions of PTKs in the nervous system are mediated by Ca2+ channel modulation.
authors.affiliation: Department of Anesthesia, Kyoto University Hospital, Shogoin, Sakyo-ku, Kyoto 606-01, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Morikawa
authors.forename: K
authors.initials: K
authors.lastname: Fukuda
authors.forename: H
authors.initials: H
authors.lastname: Mima
authors.forename: T
authors.initials: T
authors.lastname: Shoda
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: K
authors.initials: K
authors.lastname: Mori
mesh_terms: D000818:Animals; D016227:Benzoquinones; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000502:physiology; D019833:Genistein / Q000494:pharmacology; D005910:Glioma; D006822:Hybrid Cells; D007529:Isoflavones / Q000494:pharmacology; D007700:Kinetics; D047029:Lactams, Macrocyclic; D009447:Neuroblastoma; D009543:Nifedipine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D020866:omega-Conotoxin GVIA
chemical_list: D016227:Benzoquinones; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D010455:Peptides; D010636:Phenols; D011809:Quinones; D017828:Rifabutin; C062898:lavendustin A; C004742:daidzein; C020754:herbimycin; D020866:omega-Conotoxin GVIA; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; D009543:Nifedipine