Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2003 Mar 01;1386:1119-28. doi: 10.1038/sj.bjp.0705172.
Show Gene links
Show Anatomy links
Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac).
Kobayashi T
,
Washiyama K
,
Ikeda K
.
???displayArticle.abstract???
1. The effects of fluoxetine, a commonly used antidepressant drug, on G protein-activated inwardly rectifying K(+) channels (GIRK, Kir3) were investigated using Xenopus oocyte expression assays. 2. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, fluoxetine reversibly reduced inward currents through the basal GIRK activity. The inhibition by fluoxetine showed a concentration-dependence, a weak voltage-dependence and a slight time-dependence with a predominant effect on the instantaneous current elicited by voltage pulses and followed by slight further inhibition. Furthermore, in oocytes expressing GIRK1/2 channels and the cloned Xenopus A(1) adenosine receptor, GIRK current responses activated by the receptor were inhibited by fluoxetine. In contrast, ROMK1 and IRK1 channels in other Kir channel subfamilies were insensitive to fluoxetine. 3. The inhibitory effect on GIRK channels was not obtained by intracellularly applied fluoxetine, and not affected by extracellular pH, which changed the proportion of the uncharged to protonated fluoxetine, suggesting that fluoxetine inhibits GIRK channels from the extracellular side. 4. The GIRK currents induced by ethanol were also attenuated in the presence of fluoxetine. 5. We demonstrate that fluoxetine, at low micromolar concentrations, inhibits GIRK channels that play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate through activation of various G-protein-coupled receptors. The present results suggest that inhibition of GIRK channels by fluoxetine may contribute to some of its therapeutic effects and adverse side effects, particularly seizures in overdose, observed in clinical practice.
Barbey,
SSRI safety in overdose.
1998,
Pubmed
Blednov,
Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice.
2001,
Pubmed
Bolo,
Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy.
2000,
Pubmed
Brown,
Ionic channels and their regulation by G protein subunits.
1990,
Pubmed
Choi,
Effects of norfluoxetine, the major metabolite of fluoxetine, on the cloned neuronal potassium channel Kv3.1.
2001,
Pubmed
Choi,
Mechanism of fluoxetine block of cloned voltage-activated potassium channel Kv1.3.
1999,
Pubmed
Dascal,
Signalling via the G protein-activated K+ channels.
1997,
Pubmed
Deák,
Inhibition of voltage-gated calcium channels by fluoxetine in rat hippocampal pyramidal cells.
2000,
Pubmed
Doupnik,
The inward rectifier potassium channel family.
1995,
Pubmed
Fan,
Effects of antidepressants on the inward current mediated by 5-HT3 receptors in rat nodose ganglion neurones.
1994,
Pubmed
Galeotti,
Involvement of potassium channels in amitriptyline and clomipramine analgesia.
2001,
Pubmed
García-Colunga,
Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac).
1997,
Pubmed
,
Xenbase
Ho,
Cloning and expression of an inwardly rectifying ATP-regulated potassium channel.
1993,
Pubmed
,
Xenbase
Ikeda,
Functional couplings of the delta- and the kappa-opioid receptors with the G-protein-activated K+ channel.
1995,
Pubmed
,
Xenbase
Ikeda,
Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys?
2002,
Pubmed
Ikeda,
Functional coupling of the nociceptin/orphanin FQ receptor with the G-protein-activated K+ (GIRK) channel.
1997,
Pubmed
,
Xenbase
Ikeda,
Involvement of G-protein-activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia.
2000,
Pubmed
Ikeda,
Comparison of the three mouse G-protein-activated K+ (GIRK) channels and functional couplings of the opioid receptors with the GIRK1 channel.
1996,
Pubmed
Inanobe,
Characterization of G-protein-gated K+ channels composed of Kir3.2 subunits in dopaminergic neurons of the substantia nigra.
1999,
Pubmed
,
Xenbase
Karschin,
IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain.
1996,
Pubmed
Karson,
Human brain fluoxetine concentrations.
1993,
Pubmed
Kobayashi,
Ethanol opens G-protein-activated inwardly rectifying K+ channels.
1999,
Pubmed
,
Xenbase
Kobayashi,
Molecular cloning of a mouse G-protein-activated K+ channel (mGIRK1) and distinct distributions of three GIRK (GIRK1, 2 and 3) mRNAs in mouse brain.
1995,
Pubmed
Kobayashi,
Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes.
2000,
Pubmed
,
Xenbase
Kobayashi,
Functional characterization of an endogenous Xenopus oocyte adenosine receptor.
2002,
Pubmed
,
Xenbase
Korzeniewska-Rybicka,
Supraspinally mediated analgesic effect of antidepressant drugs.
2000,
Pubmed
Krapivinsky,
The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins.
1995,
Pubmed
,
Xenbase
Kubo,
Primary structure and functional expression of a mouse inward rectifier potassium channel.
1993,
Pubmed
,
Xenbase
Kubo,
Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel.
1993,
Pubmed
,
Xenbase
Lesage,
Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels.
1995,
Pubmed
,
Xenbase
Lewohl,
G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action.
1999,
Pubmed
,
Xenbase
Liao,
Heteromultimerization of G-protein-gated inwardly rectifying K+ channel proteins GIRK1 and GIRK2 and their altered expression in weaver brain.
1996,
Pubmed
Lin,
Effects of increasing serotonergic receptor activity in brain on analgesic activity in rats.
1980,
Pubmed
Mackay,
A comparison of fluvoxamine, fluoxetine, sertraline and paroxetine examined by observational cohort studies.
1997,
Pubmed
Maertens,
Block by fluoxetine of volume-regulated anion channels.
1999,
Pubmed
Maggi,
Effects of fluoxetine on wild and mutant neuronal alpha 7 nicotinic receptors.
1998,
Pubmed
,
Xenbase
Manji,
The cellular neurobiology of depression.
2001,
Pubmed
Messing,
Analgesic effect of fluoxetine hydrochloride (Lilly 110140), a specific inhibitor of serotonin uptake.
1975,
Pubmed
Naranjo,
The role of selective serotonin reuptake inhibitors in reducing alcohol consumption.
2001,
Pubmed
Navarro,
Nonselective and G betagamma-insensitive weaver K+ channels.
1996,
Pubmed
Neely,
Tonic clonic seizures and tachycardia induced by fluoxetine (Prozac) overdose.
1998,
Pubmed
Ni,
Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac).
1997,
Pubmed
,
Xenbase
North,
Twelfth Gaddum memorial lecture. Drug receptors and the inhibition of nerve cells.
1989,
Pubmed
Pancrazio,
Inhibition of neuronal Na+ channels by antidepressant drugs.
1998,
Pubmed
Patil,
A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation.
1995,
Pubmed
Perchenet,
Effects of anorexinogen agents on cloned voltage-gated K(+) channel hKv1.5.
2001,
Pubmed
Rapaport,
A comparison of fluvoxamine and fluoxetine in the treatment of major depression.
1996,
Pubmed
Reimann,
Inwardly rectifying potassium channels.
1999,
Pubmed
Reuveny,
Activation of the cloned muscarinic potassium channel by G protein beta gamma subunits.
1994,
Pubmed
,
Xenbase
Rockman,
An investigation of the mechanisms of action of 5-hydroxytryptamine in the suppression of ethanol intake.
1982,
Pubmed
Saxena,
Cardiovascular effects of serotonin agonists and antagonists.
1990,
Pubmed
Schreiber,
The antinociceptive effect of fluvoxamine.
1996,
Pubmed
Signorini,
Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2.
1997,
Pubmed
Slesinger,
Defective gamma-aminobutyric acid type B receptor-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from weaver and Girk2 null mutant mice.
1997,
Pubmed
,
Xenbase
Stanton,
Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics.
1993,
Pubmed
Sternbach,
The serotonin syndrome.
1991,
Pubmed
Thomas,
The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels.
2002,
Pubmed
,
Xenbase
Tura,
The analgesic effect of tricyclic antidepressants.
1990,
Pubmed
Wickman,
Partial structure, chromosome localization, and expression of the mouse Girk4 gene.
1997,
Pubmed
Wickman,
Abnormal heart rate regulation in GIRK4 knockout mice.
1998,
Pubmed
Wong,
Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication.
1995,
Pubmed
Yeung,
Inhibition of neuronal KV potassium currents by the antidepressant drug, fluoxetine.
1999,
Pubmed
,
Xenbase
Zhou,
Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels.
2001,
Pubmed
,
Xenbase
