Open Channel Block of Kv3.1 Currents by Fluoxetine

Abstract

The action of fluoxetine, a serotonin reuptake inhibitor, on the cloned neuronal rat Kv3.1 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Fluoxetine reduced Kv3.1 whole-cell currents in a reversible, concentration-dependent manner, with an IC50value and a Hill coefficient of 13.4 μ M and 1.4, respectively. Fluoxetine accelerated the decay rate of inactivation of Kv3.1 currents without modifying the kinetics of current activation. The inhibition increased steeply between 0 and +30 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to +30 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance δ of 0.38. The binding (k+1) and dissociation (k−1) rate constants for fluoxetine-induced block of Kv3.1 were 5.7 μ M−1s−1and 53.5 s−1, respectively. The theoretical KDvalue derived by k− 1/k+1yielded 9.3 μ M. Fluoxetine did not affect the ion selectivity of Kv3.1. Fluoxetine slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of fluoxetine, were superimposed. Inhibition of Kv3.1 by fluoxetine was use-dependent. The present results suggest that fluoxetine acts on Kv3.1 currents as an open-channel blocker. Keywords:: fluoxetine, serotonin reuptake inhibitor, Kv3.1, Shaw-type K+channel, open channel block