Effect of fluoxetine on a neuronal, voltage-dependent potassium channel (Kv1.1).
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 beneficial psychotropic effects 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 effect of fluoxetine on a neuronal, voltage-dependent potassium (K+) channel (RCK1; Kv1.1), expressed in p6nopus 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 fluoxetine was found to be use- and dose-dependent. Wash-out of this compound could not be achieved. Fluoxetine did not affect 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 fluoxetine was observed, including tail current crossover upon repolarization. 5. Hodgkin-Huxley type of models and more generalized Markov chain models were used to fit the kinetics of the data. Based upon a Markov kinetic scheme, our data can be interpreted to mean that blockade of fluoxetine 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 first biophysical working model for the mechanism of action of fluoxetine on a neuronal, voltage-dependent K+ channel, RCK1. Although this channel is not very potently blocked by fluoxetine when expressed in oocytes, this study may help us to understand some of the clinical symptoms seen with elevated serum concentrations of this SSRI.
Tytgat
J
J
Laboratory of Toxicology, University of Leuven, Belgium.
Maertens
C
C
Daenens
P
P
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009865:Oocytes / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects*; D014982:Xenopus laevis
D018687:Antidepressive Agents, Second-Generation; D015221:Potassium Channels; D005473:Fluoxetine