Insulin-like growth factor I modulates voltage-dependent Ca²⁺ channels in neuronal cells

Insulin and insulin-like growth factors are neuroactive peptides. We investigated the effect of insulin-like growth factor I (IGF-I) on Ca²⁺ channel currents in 108CC15 neuroblastoma × glioma (N × G) cells and a possible role of protein kinase C (PKC). Whereas the native IGF-I enhanced the Ca²⁺ channel current density in N × G cells, the boiled IGF-I had no effect. The effect of IGF-I occurred after 1-2 h incubation and reversed within 24 h. Ca²⁺ channel currents recorded in control cells were mainly of a low-threshold fast inactivating type and showed a mean density of 5.9 ± 0.3 pA/pF. Current density in cells incubated with IGF-I (0.2 μg/ml) for 2 h increased to 9.2 ± 0.8 pA/pF. Ca²⁺ channel currents in cells treated with IGF-I showed an enhanced amount of a high-threshold slowly inactivating Ca²⁺ current type sensitive to the dihydropyridine isradipine and the snail toxin ω-conotoxin. The effect of IGF-I was suppressed by coincubation with the PKC inhibitors 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7) and staurosporin which were both without effect on current density in control cells. Whereas the inactive phorbol ester phorbol 12-myristate 13-acetate (PMA) failed to modulate Ca²⁺ channels in N × G cells, stimulation of PKC by the active phorbol ester PMA mimicked the effect of IGF-I. The effects of IGF-I and phorbol ester were not additive. Our data suggest an intracellular mechanism dependent on PKC and we propose a physiological relevance of the observed Ca²⁺ channel modulation by IGF-I in the neuroactivity of the peptide.