Y2 receptors for neuropeptide Y are coupled to three intracellular signal transduction pathways in a human neuroblastoma cell line.
Neuropeptide Y (NPY) attenuated angiotensin II (AII)-or bradykinin (BK)-induced Ca2+ release from intracellular stores and inhibited forskolin-stimulated cAMP accumulation and omega-conotoxin-sensitive high K(+)-induced Ca2+ influx in the human neuroblastoma cell line SMS-KAN. All three NPY actions were mediated via Y2 receptors. Pretreatment with pertussis toxin completely abolished all of the NPY actions. Activation or down-regulation of protein kinase C had no effect on any NPY-mediated effect; herbimycin A, a tyrosine kinase inhibitor, only abolished the inhibitory effect of NPY on AII- or BK-induced Ca2+ mobilization. Herbimycin A also blocked platelet-derived growth factor-induced Ca2+ mobilization, which involves tyrosine kinase activation, and there was a good correlation in the concentration dependency between the two effects of herbimycin A, strongly suggesting that its ability to cancel the NPY effect is due to inhibition of tyrosine kinase activity. NPY attenuated AII- or BK-induced inositol 1,4,5-trisphosphate production, and herbimycin A reversed this NPY effect. These results provide the first evidence that Y2 receptors negatively couple to AII- or BK-induced phosphoinositide turnover leading to Ca2+ mobilization through pertussis toxin-sensitive GTP-binding protein(s). Inhibition of phospholipase C-beta activity by NPY seems to be mediated by activation of protein-tyrosine kinase or phosphotyrosine-containing protein(s).
Shigeri
Y
Y
Shionogi Research Laboratories, Shionogi and Company, Ltd., Osaka, Japan.
Fujimoto
M
M
D000804:Angiotensin II / Q000494:pharmacology; D016227:Benzoquinones; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D047029:Lactams, Macrocyclic; D009447:Neuroblastoma; D009478:Neuropeptide Y / Q000502:physiology*; D037342:Pertussis Toxin; D011188:Potassium / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D017476:Receptors, Neuropeptide Y / Q000502:physiology*; D017828:Rifabutin / Q000031:analogs & derivatives; D015290:Second Messenger Systems; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D009478:Neuropeptide Y; D011809:Quinones; D017476:Receptors, Neuropeptide Y; D010566:Virulence Factors, Bordetella; D000804:Angiotensin II; D017828:Rifabutin; C020754:herbimycin; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D037342:Pertussis Toxin; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium; D001920:Bradykinin; D002118:Calcium