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Neuropsychopharmacology
2010 Jun 01;357:1560-9. doi: 10.1038/npp.2010.27.
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Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine.
Kobayashi T
,
Washiyama K
,
Ikeda K
.
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Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K(+) (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A(1) adenosine receptors or by intracellularly applied GTPgammaS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain- and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function.
Ahern,
The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice.
2006, Pubmed
Ahern,
The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice.
2006,
Pubmed
Barker,
Acute oxcarbazepine and atomoxetine overdose with quetiapine.
2004,
Pubmed
Belle,
Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics.
2002,
Pubmed
Bettahi,
Contribution of the Kir3.1 subunit to the muscarinic-gated atrial potassium channel IKACh.
2002,
Pubmed
Blednov,
Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice.
2001,
Pubmed
Boot,
Discovery and structure-activity relationships of novel selective norepinephrine and dual serotonin/norepinephrine reuptake inhibitors.
2005,
Pubmed
Cruz,
Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice.
2008,
Pubmed
Cusack,
Binding of antidepressants to human brain receptors: focus on newer generation compounds.
1994,
Pubmed
Dascal,
Signalling via the G protein-activated K+ channels.
1997,
Pubmed
Garland,
Atomoxetine hydrochloride.
2004,
Pubmed
Garside,
Postmortem tissue distribution of atomoxetine following fatal and nonfatal doses--three case reports.
2006,
Pubmed
Geller,
Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder.
2007,
Pubmed
Hajós,
The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile.
2004,
Pubmed
Hashimoto,
Tertiapin, a selective IKACh blocker, terminates atrial fibrillation with selective atrial effective refractory period prolongation.
2006,
Pubmed
Hill,
Reduced ethanol-induced conditioned taste aversion and conditioned place preference in GIRK2 null mutant mice.
2003,
Pubmed
Ho,
Cloning and expression of an inwardly rectifying ATP-regulated potassium channel.
1993,
Pubmed
,
Xenbase
Ikeda,
Opioid receptor coupling to GIRK channels. In vitro studies using a Xenopus oocyte expression system and in vivo studies on weaver mutant mice.
2003,
Pubmed
,
Xenbase
Inanobe,
Characterization of G-protein-gated K+ channels composed of Kir3.2 subunits in dopaminergic neurons of the substantia nigra.
1999,
Pubmed
,
Xenbase
Kadhe,
Reboxetine: a novel antidepressant.
2003,
Pubmed
Kanegawa,
Synthesis and evaluation of radioiodinated (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter.
2006,
Pubmed
Karschin,
IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain.
1996,
Pubmed
Keller,
Norepinephrine transporter-deficient mice exhibit excessive tachycardia and elevated blood pressure with wakefulness and activity.
2004,
Pubmed
Kiyono,
Evaluation of radioiodinated (R)-N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine as a ligand for brain norepinephrine transporter imaging.
2004,
Pubmed
Kiyono,
Evaluation of radioiodinated (2S,alphaS)-2-(alpha-(2-iodophenoxy)benzyl)morpholine as a radioligand for imaging of norepinephrine transporter in the heart.
2008,
Pubmed
Kobayashi,
Inhibition of G protein-activated inwardly rectifying K+ channels by the antidepressant paroxetine.
2006,
Pubmed
,
Xenbase
Kobayashi,
Ethanol opens G-protein-activated inwardly rectifying K+ channels.
1999,
Pubmed
,
Xenbase
Kobayashi,
Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes.
2000,
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,
Functional characterization of an endogenous Xenopus oocyte adenosine receptor.
2002,
Pubmed
,
Xenbase
Kobayashi,
Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac).
2003,
Pubmed
,
Xenbase
Kobayashi,
G protein-activated inwardly rectifying potassium channels as potential therapeutic targets.
2006,
Pubmed
Kovoor,
Agonist-induced desensitization of the mu opioid receptor-coupled potassium channel (GIRK1).
1995,
Pubmed
,
Xenbase
Kovoor,
Evaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model.
2001,
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
Kuzhikandathil,
Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels.
2002,
Pubmed
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
Lovecchio,
Isolated atomoxetine (Strattera) ingestions commonly result in toxicity.
2006,
Pubmed
Lüscher,
G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons.
1997,
Pubmed
McElroy,
Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial.
2007,
Pubmed
Montgomery,
Antidepressants and seizures: emphasis on newer agents and clinical implications.
2005,
Pubmed
Morgan,
Decreased cocaine self-administration in Kir3 potassium channel subunit knockout mice.
2003,
Pubmed
North,
Twelfth Gaddum memorial lecture. Drug receptors and the inhibition of nerve cells.
1989,
Pubmed
Ohman,
Bioanalysis of racemic reboxetine and its desethylated metabolite in a therapeutic drug monitoring setting using solid phase extraction and HPLC.
2001,
Pubmed
Poggesi,
Pharmacokinetics of reboxetine in elderly patients with depressive disorders.
2000,
Pubmed
Reimann,
Inwardly rectifying potassium channels.
1999,
Pubmed
Sawant,
Seizures and prolonged QTc with atomoxetine overdose.
2004,
Pubmed
Scherer,
Selective noradrenaline reuptake inhibitor atomoxetine directly blocks hERG currents.
2009,
Pubmed
,
Xenbase
Signorini,
Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2.
1997,
Pubmed
Simpson,
Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder.
2004,
Pubmed
Szerman,
Reboxetine for the treatment of patients with Cocaine Dependence Disorder.
2005,
Pubmed
Takahashi,
G protein-activated inwardly rectifying K+ channel inhibition and rescue of weaver mouse motor functions by antidepressants.
2006,
Pubmed
,
Xenbase
Tirado,
Atomoxetine for treatment of marijuana dependence: a report on the efficacy and high incidence of gastrointestinal adverse events in a pilot study.
2008,
Pubmed
Versiani,
Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder.
2002,
Pubmed
Weber,
Ion currents of Xenopus laevis oocytes: state of the art.
1999,
Pubmed
,
Xenbase
Wernicke,
Seizure risk in patients with attention-deficit-hyperactivity disorder treated with atomoxetine.
2007,
Pubmed
Wilens,
Atomoxetine treatment of adults with ADHD and comorbid alcohol use disorders.
2008,
Pubmed
Witcher,
Atomoxetine pharmacokinetics in children and adolescents with attention deficit hyperactivity disorder.
2003,
Pubmed
Wong,
Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor.
2000,
Pubmed
