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 mu M) decreased the peak amplitude of K+ currents. The K+ current inhibition by fluoxetine (10 mu M) 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 mu M 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 GDP beta S 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 mu M) and Na+ (IC50 = 25.6 mu M) 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. (C) 1999 Elsevier Science B.V. All rights reserved.