A role in the control of excitability has been attributed to insulin via modulation of potassium (K+) currents. To investigate insulin modulatory effects on voltage-activated potassium currents in a neuronal cell line with origin in the sympathetic system, we performed whole-cell voltage-clamp recordings in differentiated N1E-115 neuroblastoma cells. Two main voltage-activated K+ currents were identified: (a) a relatively fast inactivating current (I-fast - time constant 50-300 ms); (b) a slow delayed rectifying K+ current (I-slow - time constant 1-4 s). The kinetics of inactivation of I-fast, rather than I-slow, showed clear voltage dependence. I-fast and I-slow exhibited different activation and inactivation dependence for voltage, and have different but nevertheless high sensitivities to tetraethylammonium, 4-aminopyridine and quinidine. In differentiated cells - rather than in non-differentiated cells - application of up to 300 nM insulin reduced I-slow only (IC50 = 6.7 nM), whereas at higher concentrations I-fast was also affected (IC50 = 7.7 mu M). The insulin inhibitory effect is not due to a change in the activation or inactivation current-voltage profiles, and the time-dependent inactivation is also not altered; this is not likely to be a result of activation of the insulin-growth-factor-1 (IGF1) receptors, as application of IGF1 did not result in significant current alteration. Results suggest that the current sensitive to low concentrations of insulin is mediated by erg-like channels. Similar observations concerning the insulin inhibitory effect on slow voltage-activated K+ currents were also made in isolated rat hippocampal pyramidal neurons, suggesting a widespread neuromodulator role of insulin on K+ channels.