Reinforcement of signal generation at B2 bradykinin receptors by insulin, epidermal growth factors, and other growth factors.
Insulin and various growth factors (epidermal growth factor (EGF), insulin-like growth factor, fibroblast growth factor, and transforming growth factor alpha), which fail to modify the resting [Ca2+]i in PC12 rat pheochromocytoma and SKNBE human neuroblastoma cells when administered alone, became capable of inducing [Ca2+]i increases when administered a few (4-20) min after another agent, bradykinin. The latter peptide, working through a B2 receptor, caused hydrolysis of polyphosphoinositides and a large, biphasic [Ca2+]i transient (an initial (1-2 min) spike, originated primarily from intracellular stores, followed by a steady-state elevation dependent on Ca2+ influx). Priming by bradykinin of the growth factor effects was quickly dissipated by the addition of a B2 blocker. Activation of other receptors coupled to polyphosphoinositide hydrolysis: muscarinic and purinergic (in PC12 and SKNBE cells); bombesin and vasopressin receptors (in Swiss 3T3 cells), was without effect in priming. Bradykinin-primed, growth factor-induced [Ca2+]i rises in PC12 cells appeared after a 20-30-s delay; they were relatively small, but persistent; their concentration dependence was similar to that of other effects of the factors; and they included both release of Ca2+ from intracellular stores and stimulation of Ca2+ influx, preceded (in PC12 cells) by a transient increase of polyphosphoinositide hydrolysis. Thus the effect of growth factors (possibly dependent on the tyrosine kinase activity of their receptors) consisted in the reinforcement of the transmembrane signaling at B2 receptors. This is the first direct demonstration of a [Ca2+]i rise induced by insulin and insulin-like growth factor-I, and of such an effect of EGF in cell types endowed with a small number of specific EGF receptors.
Pandiella
A
A
Department of Pharmacology, Consiglio Nazionale della Ricerche Center of Cytopharmacology, Milano, Italy.
Meldolesi
J
J
D000310:Adrenal Gland Neoplasms; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D004533:Egtazic Acid / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007700:Kinetics; D009447:Neuroblastoma; D010673:Pheochromocytoma; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D015291:Transforming Growth Factors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D015220:Calcium Channels; D006133:Growth Substances; D007295:Inositol Phosphates; D007328:Insulin; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter; D004533:Egtazic Acid; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D015291:Transforming Growth Factors; D015544:Inositol 1,4,5-Trisphosphate; D066246:ErbB Receptors; D001920:Bradykinin; D002118:Calcium