Coexistence of hERG current block and disruption of protein trafficking in ketoconazole‐induced long QT syndrome

Takemasa, Hiroko; Nagatomo, Toshihisa; Abe, Haruhiko; Kawakami, Kyojiro; Igarashi, Takashi; Tsurugi, Takuo; Kabashima, Narutoshi; Tamura, M.; Okazaki, Masako; Delisle, Brian P.; January, Craig T.; Otsuji, Yutaka

doi:10.1038/sj.bjp.0707537

Cited by 75 publications

(66 citation statements)

References 33 publications

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“…Both mechanisms converge to create cardiac repolarization abnormalities that are reflected in a high incidence of adverse cardiac events during therapy (Ohnishi et al, 2000(Ohnishi et al, , 2002Barbey et al, 2003). Likewise, a large number of direct hERG blockers provide a double hit on cardiac repolarization in that they combine conventional hERG block with unconventional hERG trafficking inhibition Rajamani et al, 2006;Takemasa et al, 2008;Obers et al, 2010;Staudacher et al, 2011). Unfortunately, few compounds that cause acLQTS by unconventional mechanisms have been fully characterized at the cellular and molecular level.…”

Section: Introductionmentioning

confidence: 99%

Molecular Determinants of Pentamidine-Induced hERG Trafficking Inhibition

Dennis¹,

Wang²,

Wan³

et al. 2011

Mol Pharmacol

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Pentamidine is an antiprotozoal compound that clinically causes acquired long QT syndrome (acLQTS), which is associated with prolonged QT intervals, tachycardias, and sudden cardiac arrest. Pentamidine delays terminal repolarization in human heart by acutely blocking cardiac inward rectifier currents. At the same time, pentamidine reduces surface expression of the cardiac potassium channel I Kr /human ether à -gogo-related gene (hERG). This is unusual in that acLQTS is caused most often by direct block of the cardiac potassium current I Kr /hERG. The present study was designed to provide a more complete picture of how hERG surface expression is disrupted by pentamidine at the cellular and molecular levels. Using biochemical and electrophysiological methods, we found that pentamidine exclusively inhibits hERG export from the endoplasmic reticulum to the cell surface in a heterologous expression system as well as in cardiomyocytes. hERG trafficking inhibition could be rescued in the presence of the pharmacological chaperone astemizole. We used rescue experiments in combination with an extensive mutational analysis to locate an interaction site for pentamidine at phenylalanine 656, a crucial residue in the canonical drug binding site of terminally folded hERG. Our data suggest that pentamidine binding to a folding intermediate of hERG arrests channel maturation in a conformational state that cannot be exported from the endoplasmic reticulum. We propose that pentamidine is the founding member of a novel pharmacological entity whose members act as small molecule antichaperones.

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Section: Introductionmentioning

confidence: 99%

Molecular Determinants of Pentamidine-Induced hERG Trafficking Inhibition

Dennis¹,

Wang²,

Wan³

et al. 2011

Mol Pharmacol

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“…Moreover, up to 40% of all direct hERG-blockers combine conventional hERG block with unconventional hERG trafficking inhibition, i.e. they exert combined hERG activity (7)(8)(9)(10)(11). Few of these compounds have been fully characterized at the cellular level.…”

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confidence: 99%

Antidepressant-induced Ubiquitination and Degradation of the Cardiac Potassium Channel hERG

Dennis

Nassal

Deschênes

et al. 2011

Journal of Biological Chemistry

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Background: Acquired long QT syndrome is usually precipitated by direct hERG block. Results: Tricyclic antidepressants do not only block hERG but inhibit forward trafficking and promote endocytosis via increased channel ubiquitination. Conclusion: Tricyclic antidepressants trigger multiple mechanisms controlling hERG surface expression. Significance: A better mechanistic understanding of acquired long QT syndrome impacts how cardiac safety of therapeutic compounds is assessed.

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“…Similar to direct channel block, disruption of hERG trafficking decreases hERG current but on a much slower time scale by reducing channel numbers at the cell surface. Examples for therapeutic compounds that can cause acLQTS by inhibition of hERG trafficking include arsenic trioxide, which is used in the treatment of acute promyelocytic leukemia (Ficker et al, 2004), the antiprotozoical agent pentamidine (Cordes et al, 2005;Kuryshev et al, 2005), the cholesterol-lowering compound probucol (Guo et al, 2007), the antidepressant fluoxetine (Prozac) as well as the antifungal drug ketoconalzole, both of which belong to a potentially large group of compounds that directly block hERG and inhibit channel trafficking at the same time Rajamani et al, 2006;Takemasa et al, 2007).…”

mentioning

confidence: 99%

Intracellular Potassium Stabilizes HumanEther-à-go-go-Related Gene Channels for Export from Endoplasmic Reticulum

Wang¹,

Dennis²,

Trieu³

et al. 2009

Mol Pharmacol

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Several therapeutic compounds have been identified that prolong the QT interval on the electrocardiogram and cause torsade de pointes arrhythmias not by direct block of the cardiac potassium channel human ether-à -go-go-related gene (hERG) but via disruption of hERG trafficking to the cell surface membrane. One example of a clinically important compound class that potently inhibits hERG trafficking are cardiac glycosides. We have shown previously that inhibition of hERG trafficking by cardiac glycosides is initiated via direct block of Na ϩ /K ϩ pumps and not via off-target interactions with hERG or any other protein. However, it was not known how pump inhibition at the cell surface is coupled to hERG processing in the endoplasmic reticulum. Here, we show that depletion of intracellular K ϩ -either indirectly after long-term exposure to cardiac glycosides or directly after exposure to gramicidin in low sodium media-is sufficient to disrupt hERG trafficking. In K ϩ -depleted cells, hERG trafficking can be restored by permeating K ϩ or Rb ϩ ions, incubation at low temperature, exposure to the pharmacological chaperone astemizole, or specific mutations in the selectivity filter of hERG. Our data suggest a novel mechanism for drug-induced trafficking inhibition in which cardiac glycosides produce a [K ϩ ] i -mediated conformational defect directly in the hERG channel protein.The cardiac potassium channel hERG (KCNH2) encodes the ␣-subunit of the rapid delayed rectifier current I Kr , which plays a central role in terminal repolarization of human ventricular myocytes. Loss of hERG/I Kr function either by inherited mutations or unintentional drug blockade produces long QT syndrome in the clinic and is characterized by a prolongation of the QT interval on the electrocardiogram, an increased propensity for patients to experience syncope and to present with torsades de pointes arrhythmias, or sudden cardiac arrest (Sanguinetti and Tristani-Firouzi, 2006).Although tremendous progress has been made toward a mechanistic understanding of drug-induced or acquired long QT syndrome (acLQTS) as a result of direct hERG block by a diverse set of small organic molecules (Sanguinetti and Mitcheson, 2005), much less is known about inhibition of hERG trafficking by therapeutic compounds, a novel, more recently discovered mechanism that can also result in ABBREVIATIONS: hERG, human ether à -go-go-related gene; I Kr , rapidly activating delayed rectifier K current; acLQTS, acquired long QT syndrome; ER, endoplasmic reticulum; HEK, human embryonic kidney; WT, wild type; HA, hemaggultinin; HA ex , extracellular hemagglutinin tag; DMEM, Dulbecco's modified Eagle's medium; pH i , intracellular pH; MEM, minimal essential medium; sf, serum-free; Ch, choline chloride; NMDG, N-methyl-D-glucamine; AM, acetoxymethyl ester; BCECF, sodium binding benzofuran isophthalate 2Ј,7Ј-bis(carboxyethyl)-5(6Ј)-carboxyfluorescein; PBFI, K ϩ binding benzofuran isophtalate; BN, blue native; PAGE, polyacrylamide gel electrophoresis; ROS, reactive oxygen s...

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Coexistence of hERG current block and disruption of protein trafficking in ketoconazole‐induced long QT syndrome

Cited by 75 publications

References 33 publications

Molecular Determinants of Pentamidine-Induced hERG Trafficking Inhibition

Molecular Determinants of Pentamidine-Induced hERG Trafficking Inhibition

Antidepressant-induced Ubiquitination and Degradation of the Cardiac Potassium Channel hERG

Intracellular Potassium Stabilizes HumanEther-à-go-go-Related Gene Channels for Export from Endoplasmic Reticulum

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