Inhibition by fluoxetine of voltage-activated ion channels in rat PC12 cells

The effects of fluoxetine (Prozac) on voltage-activated K⁺, Ca²⁺ and Na⁺ channels were examined using the whole-cell configuration of the patch clamp technique in rat pheochromocytoma (PC12) cells. When applied to the external bath solution, fluoxetine (1, 10, 100 μM) decreased the peak amplitude of K⁺ currents. The K⁺ current inhibition by fluoxetine (10 μM) was voltage-independent and the fraction of current inhibition was 39.7-51.3% at all voltages tested (0 to +50 mV). Neither the activation and inactivation curves nor the reversal potential for K⁺ currents was significantly changed by fluoxetine. The inhibition by fluoxetine of K⁺ currents was use- and concentration-dependent with an IC₅₀ of 16.0 μM. The inhibition was partially reversible upon washout of fluoxetine. The action of fluoxetine was independent of the protein kinases, because the protein kinase C or A inhibitors (H-7, staurosporine, Rp-cAMPS) did not prevent the inhibition by fluoxetine. Intracellular infusion with GDPβS or pretreatment with pertussis toxin did not block the inhibitory effects of fluoxetine. The inhibitory action of fluoxetine was not specific to K⁺ currents because it also inhibited both Ca²⁺ (IC₅₀ = 13.4 μM) and Na⁺ (IC₅₀ = 25.6 μM) currents in a concentration-dependent manner. Our data indicate that when applied to the external side of cells, fluoxetine inhibited voltage-activated K⁺, Ca²⁺ and Na⁺ currents in PC12 cells and its action on K⁺ currents does not appear to be mediated through protein kinases or G proteins.