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Inhibition by fluoxetine of voltage-activated ion channels in rat PC12 cells
1Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. sjhahn@cmc.cuk.ac.kr
Abstract:
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 microM) decreased the peak amplitude of K+ currents. The K+ current inhibition by fluoxetine (10 microM) 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 microM. 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 GDPbetaS 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 microM) and Na+ (IC50 = 25.6 microM) 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.
Insights
Fluoxetine (Prozac) inhibits voltage-activated potassium (K+), calcium (Ca2+), and sodium (Na+) channels in rat PC12 cells. This effect on K+ channels is concentration-dependent and not mediated by protein kinases or G proteins.
Area of Science:
- Neuropharmacology
- Ion Channel Physiology
- Cellular Electrophysiology
Background:
- Fluoxetine (Prozac) is a widely used antidepressant.
- Its effects on ion channels, crucial for neuronal function, are not fully understood.
- Understanding these interactions is key to elucidating its therapeutic and potential side effects.
Purpose of the Study:
- To investigate the effects of fluoxetine on voltage-activated ion currents in rat pheochromocytoma (PC12) cells.
- To determine the specific ion channels affected and the mechanisms underlying fluoxetine's action.
Main Methods:
- Whole-cell patch clamp technique was employed to record ion currents.
- PC12 cells were treated with varying concentrations of fluoxetine.
- Inhibitors of protein kinases and G proteins were used to explore signaling pathways.
Main Results:
- Fluoxetine significantly inhibited peak amplitude of voltage-activated K+ currents in a concentration-dependent manner (IC50 = 16.0 microM).
- The inhibition of K+ currents was voltage-independent and partially reversible.
- Fluoxetine also inhibited Ca2+ (IC50 = 13.4 microM) and Na+ (IC50 = 25.6 microM) currents.
- These effects were independent of protein kinase C/A or G protein signaling.
Conclusions:
- Fluoxetine inhibits voltage-activated K+, Ca2+, and Na+ currents in PC12 cells when applied extracellularly.
- The mechanism of K+ current inhibition by fluoxetine does not involve protein kinases or G proteins.
- These findings suggest direct interactions of fluoxetine with ion channel pore or gating machinery.