Effect of fluoxetine on a neuronal, voltage‐dependent potassium channel (Kv1.1)

Abstract

1 Fluoxetine (Prozac) is widely used as an antidepressant drug and is assumed to be a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI). Claims that its bene®cial psychotropic e ects extend beyond those in treatment of depression have drawn clinical and popular attention to this compound, raising the question of whether there is anything exceptional about the supposed selective actions. 2 We have used the voltage clamp technique to study the e ect of¯uoxetine on a neuronal, voltagedependent potassium (K + ) channel (RCK1; Kv1.1), expressed in Xenopus laevis oocytes. This channel subunit is abundantly expressed in the central nervous system and K + channels containing this subunit are involved in the repolarization process of many types of neurones. 3 Blockade of the K + currents by¯uoxetine was found to be use-and dose-dependent. Wash-out of this compound could not be achieved. Fluoxetine did not a ect the ion selectivity of this K + channel, as the reversal potential was unaltered. 4 Slowing of both activation and deactivation kinetics of the channel by¯uoxetine was observed, including tail current crossover upon repolarization. 5 Hodgkin-Huxley type of models and more generalized Markov chain models were used to ®t the kinetics of the data. Based upon a Markov kinetic scheme, our data can be interpreted to mean that blockade of¯uoxetine consists of two components: a voltage-independent occurring in the last closed, but available state of the channel, and a voltage-dependent occurring in the open state. 6 This study describes the ®rst biophysical working model for the mechanism of action of¯uoxetine on a neuronal, voltage-dependent K + channel, RCK1. Although this channel is not very potently blocked by¯uoxetine when expressed in oocytes, this study may help us to understand some of the clinical symptoms seen with elevated serum concentrations of this SSRI.

Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter

“…Although SERT blockade occurs within minutes of administration, antidepressant efficacy arises only after many weeks of treatment (6), leading some to question whether SERT inhibition is responsible for the beneficial actions of SSRIs. Indeed, despite their high affinity for SERT, SSRIs have been found to interact with many other proteins, including ion channels (7,8), receptors (9), signaling proteins (10)(11)(12)(13)(14), and transcription factors (15)(16)(17), conceivably accounting for dose-limiting side effects and/or therapeutic actions (18). Finally, many patients treated with SSRIs have a poor treatment course outcome or do not show a response and may abandon treatment, with potentially life-threatening consequences (5).…”

Inhibition of K+ currents of outer hair cells in guinea pig cochlea by fluoxetine

“…Fluoxetine is known to block a variety of voltagedependent K + channels in other preparations Farrugia, 1996;Hahn et al, 1999;Rae et al, 1995;Thomas et al, 2002;Tytgat et al, 1997;Yeung et al, 1999). Fluoxetine block has been reported variably to be useindependent (Thomas et al, 2002;Yeung et al, 1999; the present study), use-dependent Tytgat et al, 1997), voltage-independent Thomas et al, 2002;Tytgat et al, 1997;Yeung et al, 1999; the present study for the leak current inhibition), or voltagedependent Tytgat et al, 1997; the present study for the voltage-activated current inhibition).…”

“…Fluoxetine block has been reported variably to be useindependent (Thomas et al, 2002;Yeung et al, 1999; the present study), use-dependent Tytgat et al, 1997), voltage-independent Thomas et al, 2002;Tytgat et al, 1997;Yeung et al, 1999; the present study for the leak current inhibition), or voltagedependent Tytgat et al, 1997; the present study for the voltage-activated current inhibition). Depending on the types of K + channels, the IC 50 values of fluoxetine vary from a few to several hundred micromolars.…”

“…Fluoxetine block of K V 1.1 channel expressed in Xenopus oocytes was use-and voltage-dependent (Tytgat et al, 1997). They postulated that fluoxetine exerted two types of block: voltage-independent block and voltage-dependent block.…”

“…Fluoxetine inhibits delayed rectifier K + currents in rabbit corneal epithelial cells and in cultured human lens epithelium (Rae et al, 1995), in isolated canine and human jejunal circular smooth muscle cells (Farrugia, 1996), and in cerebellar granule neurons (Yeung et al, 1999). This compound also inhibits voltage-gated K V 1.1 channels expressed in Xenopus oocytes (Tytgat et al, 1997), K V 1.1 channels (Yeung et al, 1999) and K V 1.3 channels expressed in the Chinese hamster ovary cell line, and voltage-activated K + currents in PC12 cells , as well as HERG K + currents, a rapid component of the delayed rectifier K + currents of cardiac ventricular myocytes (Thomas et al, 2002). However, the effect of fluoxetine on K + channel of outer hair cells is unclear.…”