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.
Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes.
Kobayashi T
,
Ikeda K
,
Kumanishi T
.
???displayArticle.abstract???
To investigate the effects of various chemical classes of antipsychotic drugs: haloperidol, thioridazine, pimozide and clozapine, on the G-protein-activated inwardly rectifying K(+) (GIRK) channels, we carried out Xenopus oocyte functional assays with GIRK1 and GIRK2 mRNAs or GIRK1 and GIRK4 mRNAs. In oocytes co-injected with GIRK1 and GIRK2 mRNAs, application of each of the various antipsychotic drugs immediately caused a reduction of inward currents through the basally active GIRK channels. These responses were not observed in the presence of 3 mM Ba(2+), which blocks the GIRK channels. In addition, in uninjected oocytes, none of the drugs tested produced any significant current response. These results indicate that all the antipsychotic drugs tested inhibited the brain-type GIRK1/2 heteromultimeric channels. Furthermore, similar results were obtained in oocytes co-injected with GIRK1 and GIRK4 mRNAs, indicating that the antipsychotic drugs also inhibited the cardiac-type GIRK1/4 heteromultimeric channels. All the drugs tested inhibited, in a concentration-dependent manner, both types of GIRK channels with varying degrees of potency and effectiveness at micromolar concentrations. Only pimozide caused slight inhibition of these channels at nanomolar concentrations. We conclude that the various antipsychotic drugs acted as inhibitors at the brain-type and cardiac-type GIRK channels. Our results suggest that inhibition of both types of GIRK channels by these drugs underlies some of the side effects, in particular seizures and sinus tachycardia, observed in clinical practice.
Ayd,
Haloperidol: twenty years' clinical experience.
1978,
Pubmed
Baldessarini,
Tissue concentrations of clozapine and its metabolites in the rat.
1993,
Pubmed
Brown,
Ionic channels and their regulation by G protein subunits.
1990,
Pubmed
Buckley,
Cardiotoxicity more common in thioridazine overdose than with other neuroleptics.
1995,
Pubmed
Doupnik,
The inward rectifier potassium channel family.
1995,
Pubmed
Duprat,
Heterologous multimeric assembly is essential for K+ channel activity of neuronal and cardiac G-protein-activated inward rectifiers.
1995,
Pubmed
,
Xenbase
Fulop,
ECG changes during haloperidol and pimozide treatment of Tourette's disorder.
1987,
Pubmed
Gerlach,
Long-term experience with clozapine in Denmark: research and clinical practice.
1989,
Pubmed
Gould,
Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists.
1983,
Pubmed
Haffner,
Opposing anticholinergic and cardio-depressive effects of promazine and thioridazine in isolated rat atria.
1972,
Pubmed
Hedin,
Cloning of a Xenopus laevis inwardly rectifying K+ channel subunit that permits GIRK1 expression of IKACh currents in oocytes.
1996,
Pubmed
,
Xenbase
Ikeda,
Functional coupling of the nociceptin/orphanin FQ receptor with the G-protein-activated K+ (GIRK) channel.
1997,
Pubmed
,
Xenbase
Ikeda,
Functional couplings of the delta- and the kappa-opioid receptors with the G-protein-activated K+ channel.
1995,
Pubmed
,
Xenbase
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
Ilyin,
Subtype-selective inhibition of N-methyl-D-aspartate receptors by haloperidol.
1996,
Pubmed
,
Xenbase
Janssen,
Pimozide, a chemically novel, highly potent and orally long-acting neuroleptic drug. I. The comparative pharmacology of pimozide, haloperidol, and chlorpromazine.
1968,
Pubmed
Janssen,
Pimozide, a chemically novel, highly potent and orally long-acting neuroleptic drug. II. Kinetic study of the distribution of pimozide and metabolites in brain, liver, and blood of the Wistar rat.
1968,
Pubmed
Karschin,
IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain.
1996,
Pubmed
Kilts,
Effects of thioridazine and its metabolites on dopaminergic function: drug metabolism as a determinant of the antidopaminergic actions of thioridazine.
1984,
Pubmed
Kobayashi,
Effects of clozapine on the delta- and kappa-opioid receptors and the G-protein-activated K+ (GIRK) channel expressed in Xenopus oocytes.
1998,
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
Krapivinsky,
The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins.
1995,
Pubmed
,
Xenbase
Lesage,
Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels.
1995,
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
Marks,
Antipsychotic medications and seizures.
1991,
Pubmed
McCreadie,
Plasma pimozide profiles in chronic schizophrenics.
1979,
Pubmed
Miller,
Anti-muscarinic properties of neuroleptics and drug-induced Parkinsonism.
1974,
Pubmed
North,
Twelfth Gaddum memorial lecture. Drug receptors and the inhibition of nerve cells.
1989,
Pubmed
Ogata,
Psychotropic drugs block voltage-gated ion channels in neuroblastoma cells.
1989,
Pubmed
Patil,
A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation.
1995,
Pubmed
Perry,
Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients.
1991,
Pubmed
Pinder,
Pimozide: a review of its pharmacological properties and therapeutic uses in psychiatry.
1976,
Pubmed
Reuveny,
Activation of the cloned muscarinic potassium channel by G protein beta gamma subunits.
1994,
Pubmed
,
Xenbase
Reynolds,
Developments in the drug treatment of schizophrenia.
1992,
Pubmed
Seeman,
Dopamine receptor pharmacology.
1994,
Pubmed
Signorini,
Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2.
1997,
Pubmed
Sunderland,
Blood to brain distribution of neuroleptics.
1987,
Pubmed
Tune,
Neuroleptic serum levels measured by radioreceptor assay and clinical response in schizophrenic patients.
1981,
Pubmed
Vanderheeren,
Plasma levels and half lives of thioridazine and some of its metabolites. I. High doses in young acute schizophrenics.
1977,
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
Zarifian,
High doses of haloperidol in schizophrenia. A clinical, biochemical, and pharmacokinetic study.
1982,
Pubmed
