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.
Naunyn Schmiedebergs Arch Pharmacol
2010 May 01;3815:385-400. doi: 10.1007/s00210-010-0496-7.
Show Gene links
Show Anatomy links
Multiple mechanisms of hERG liability: K+ current inhibition, disruption of protein trafficking, and apoptosis induced by amoxapine.
Obers S
,
Staudacher I
,
Ficker E
,
Dennis A
,
Koschny R
,
Erdal H
,
Bloehs R
,
Kisselbach J
,
Karle CA
,
Schweizer PA
,
Katus HA
,
Thomas D
.
???displayArticle.abstract???
The antidepressant amoxapine has been linked to cases of QT prolongation, acute heart failure, and sudden death. Inhibition of cardiac hERG (Kv11.1) potassium channels causes prolonged repolarization and is implicated in apoptosis. Apoptosis in association with amoxapine has not yet been reported. This study was designed to investigate amoxapine effects on hERG currents, hERG protein trafficking, and hERG-associated apoptosis in order to elucidate molecular mechanisms underlying cardiac side effects of the drug. hERG channels were expressed in Xenopus laevis oocytes and HEK 293 cells, and potassium currents were recorded using patch clamp and two-electrode voltage clamp electrophysiology. Protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and cell viability was assessed in HEK cells by immunocytochemistry and colorimetric MTT assay. Amoxapine caused acute hERG blockade in oocytes (IC(50) = 21.6 microM) and in HEK 293 cells (IC(50) = 5.1 microM). Mutation of residues Y652 and F656 attenuated hERG blockade, suggesting drug binding to a receptor inside the channel pore. Channels were mainly blocked in open and inactivated states, and voltage dependence was observed with reduced inhibition at positive potentials. Amoxapine block was reverse frequency-dependent and caused accelerated and leftward-shifted inactivation. Furthermore, amoxapine application resulted in chronic reduction of hERG trafficking into the cell surface membrane (IC(50) = 15.3 microM). Finally, the antidepressant drug triggered apoptosis in cells expressing hERG channels. We provide evidence for triple mechanisms of hERG liability associated with amoxapine: (1) direct hERG current inhibition, (2) disruption of hERG protein trafficking, and (3) induction of apoptosis. Further experiments are required to validate a specific pro-apoptotic effect mediated through blockade of hERG channels.
Becchetti,
A comment on ion channels as pharmacological targets in oncology.
2008, Pubmed
Becchetti,
A comment on ion channels as pharmacological targets in oncology.
2008,
Pubmed
Coccaro,
Second generation antidepressants: a comparative review.
1985,
Pubmed
Delgado,
Electrophysiological effects of amoxapine in untreated and in amoxapine-pretreated rat atria.
1986,
Pubmed
Dennis,
hERG channel trafficking: novel targets in drug-induced long QT syndrome.
2007,
Pubmed
Dorian,
Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization: an overview.
2000,
Pubmed
Duncan,
Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin.
2007,
Pubmed
Ficker,
Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG.
2003,
Pubmed
Ficker,
Mechanisms of arsenic-induced prolongation of cardiac repolarization.
2004,
Pubmed
González-Juanatey,
Doxazosin induces apoptosis in cardiomyocytes cultured in vitro by a mechanism that is independent of alpha1-adrenergic blockade.
2003,
Pubmed
Guo,
Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines.
2009,
Pubmed
Guo,
Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes.
2007,
Pubmed
Hondeghem,
Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence.
1990,
Pubmed
Jo,
Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652.
2008,
Pubmed
,
Xenbase
Kiehn,
Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels.
1999,
Pubmed
,
Xenbase
Kiesecker,
Atypical tetracyclic antidepressant maprotiline is an antagonist at cardiac hERG potassium channels.
2006,
Pubmed
,
Xenbase
Kinugawa,
Inhibitory actions of amoxapine, a tricyclic antidepressant agent, on electrophysiological properties of mammalian isolated cardiac preparations.
1988,
Pubmed
Kudo,
A fatal case of amoxapine poisoning under the influence of chronic use of psychotropic drugs.
2007,
Pubmed
Mahapatra,
Cardiovascular effects of polycyclic antidepressants.
1986,
Pubmed
Milnes,
Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652.
2003,
Pubmed
Mitcheson,
Drug binding to HERG channels: evidence for a 'non-aromatic' binding site for fluvoxamine.
2003,
Pubmed
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Mosmann,
Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.
1983,
Pubmed
Munger,
Amoxapine cardiotoxicity.
1988,
Pubmed
Napolitano,
Torsade de pointes. Mechanisms and management.
1994,
Pubmed
NULL,
Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group.
2000,
Pubmed
Ortiz,
Premature atrial contractions and amoxapine therapy: a case report.
1983,
Pubmed
Paul,
Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine.
2002,
Pubmed
Rajamani,
Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine.
2006,
Pubmed
Redfern,
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
2003,
Pubmed
Robertson,
Endocytic control of ion channel density as a target for cardiovascular disease.
2009,
Pubmed
Roden,
Repolarization reserve: a moving target.
2008,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Satoh,
Role of poly(ADP-ribose) formation in DNA repair.
1992,
Pubmed
Scherer,
Inhibition of cardiac hERG potassium channels by tetracyclic antidepressant mianserin.
2008,
Pubmed
,
Xenbase
Schumacher,
Antiarrhythmic drug-induced internalization of the atrial-specific k+ channel kv1.5.
2009,
Pubmed
Smith,
Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells.
2002,
Pubmed
Sørensen,
Acute myocardial failure following amoxapine intoxication.
1988,
Pubmed
Spector,
Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides.
1996,
Pubmed
,
Xenbase
Staudacher,
hERG: protein trafficking and potential for therapy and drug side effects.
2010,
Pubmed
Takemasa,
Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome.
2008,
Pubmed
Teschemacher,
Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline.
1999,
Pubmed
Thomas,
The antipsychotic drug chlorpromazine inhibits HERG potassium channels.
2003,
Pubmed
,
Xenbase
Thomas,
Doxazosin induces apoptosis of cells expressing hERG K+ channels.
2008,
Pubmed
Thomas,
Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing.
2003,
Pubmed
Thomas,
The cardiac hERG/IKr potassium channel as pharmacological target: structure, function, regulation, and clinical applications.
2006,
Pubmed
Thomas,
High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872.
2001,
Pubmed
,
Xenbase
Thomas,
The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels.
2002,
Pubmed
,
Xenbase
Thomas,
Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A.
1999,
Pubmed
,
Xenbase
van der Heyden,
Drugs and trafficking of ion channels: a new pro-arrhythmic threat on the horizon?
2008,
Pubmed
Viskin,
Long QT syndromes and torsade de pointes.
1999,
Pubmed
Walker,
Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states.
1999,
Pubmed
Wang,
HERG K+ channel, a regulator of tumor cell apoptosis and proliferation.
2002,
Pubmed
Wang,
Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking.
2007,
Pubmed
Warmke,
A family of potassium channel genes related to eag in Drosophila and mammals.
1994,
Pubmed
Wedin,
Relative toxicity of cyclic antidepressants.
1986,
Pubmed
Witchel,
The low-potency, voltage-dependent HERG blocker propafenone--molecular determinants and drug trapping.
2004,
Pubmed
,
Xenbase
Witchel,
Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents.
2002,
Pubmed
Witchel,
Psychotropic drugs, cardiac arrhythmia, and sudden death.
2003,
Pubmed
Yeung,
Inhibition of hERG channel trafficking: an under-explored mechanism for drug-induced QT prolongation.
2008,
Pubmed
Zitron,
Inhibition of cardiac HERG potassium channels by the atypical antidepressant trazodone.
2004,
Pubmed
,
Xenbase
