Insulin increases excitability via a dose‐dependent dual inhibition of voltage‐activated K⁺ currents in differentiated N1E‐115 neuroblastoma cells

Abstract

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 (IC(50) = 6.7 nm), whereas at higher concentrations I(fast) was also affected (IC(50) = 7.7 microm). 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.

Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy

“…We hypothesize that disruption of neuronal membrane integrity by insertion of (proto-)fibrillar A␤ before plaque formation yields robust changes to V R . Subsequent disruption of, for instance, voltagedependent channel functions (Talley et al, 2003;Ye et al, 2003;Misonou et al, 2005;Plant et al, 2006;Lima et al, 2008) pertinent to maintain a stable, hyperpolarized plasmalemmal membrane potential may underscore sustained membrane depolarization. This notion is also consistent with the observations of lowered seizure thresholds after systemic challenge with pentylentetrazol not only in plaque-bearing APP transgenic mice (Palop et al, 2007) but also in those with elevated levels of soluble A␤ aggregates but no plaques (Del Vecchio et al, 2004;Palop et al, 2007).…”

Feeding cycle alters the biophysics and molecular expression of voltage‐gated Na+ currents in rat hippocampal CA1 neurones

“…Still, the effect of feeding cycle on neuronal activities is scarcely understood, especially in the hippocampus. There is a single work showing that the effect of insulin on the excitability of rat hippocampal CA1 neurones (Lima, Vicente, Alves, Dionísio, & Costa, ) is only detectable in fed animals, contrasting with the lack of response in fasted ones (Lima et al., ). This clearly suggests a marked impact of feeding cycle periods over the activity of central nervous system neurones, particularly in protein ion channels involved in excitability.…”