Cardiac Glycosides as Novel Inhibitors of Human Ether-a-go-go-Related Gene Channel Trafficking

Wang, Lu; Wible, Barbara A.; Wan, Xiaoping; Ficker, Eckhard

doi:10.1124/jpet.106.113043

Cited by 91 publications

(64 citation statements)

References 38 publications

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“…Consistently, i.v. administration of the Digibind antibody reverses digitoxin toxicity in humans within the same limited time frame (14)(15)(16). We interpret the latter data to mean that the toxic mechanism for digitoxin action is equally available to an extracellular inhibitory antibody in a cultured cell system, a planar lipid bilayer system, and in vivo in humans.…”

Section: Discussionmentioning

confidence: 76%

“…Digibind is an inactivating Fab fragment antibody against the digitalis pharmacophore, which is widely available in all poison control centers. In fact, the NaKATPase hypothesis for the regulation of positive inotropic effects of cardiac glycosides has been under continuous questioning by investigators for many years without compelling resolution (11)(12)(13)(14)(15)(16). Non-NaKATPase effects also have been observed.…”

mentioning

confidence: 97%

“…As mentioned in the Introduction, an overdose of digitoxin or digoxin in humans treated for heart failure can be quickly reversed over a 15-to 30-min time period by administering specific anti-digitoxin/ digoxin antibodies (14)(15)(16). Therefore, we hypothesized that if digitoxin channel activity contributed to cytotoxic adverse events, anti-digitoxin antibodies might quickly block both channel activity in vitro and digitoxin-dependent calcium uptake into cells.…”

Section: Digitoxin Channel Kinetics Are Influenced By the Phospholipimentioning

confidence: 99%

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Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

Arispe

Díaz

Šimáková

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Digitoxin and other cardiac glycosides are important, centuries-old drugs for treating congestive heart failure. However, the mechanism of action of these compounds is still being elucidated. Calcium is known to potentiate the toxicity of these drugs, and we have hypothesized that digitoxin might mediate calcium entry into cells. We report here that digitoxin molecules mediate calcium entry into intact cells. Multimers of digitoxin molecules also are able to form calcium channels in pure planar phospholipid bilayers. These digitoxin channels are blocked by Al 3؉ and La 3؉ but not by Mg 2؉ or the classical L-type calcium channel blocker, nitrendipine. In bilayers, we find that the chemistry of the lipid affects the kinetics of the digitoxin channel activity, but not the cation selectivity. Antibodies against digitoxin promptly neutralize digitoxin channels in both cells and bilayers. We propose that these digitoxin calcium channels may be part of the mechanism by which digitoxin and other active cardiac glycosides, such as digoxin, exert system-wide actions at and above the therapeutic concentration range.cardiac glycoside ͉ cytotoxicity

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Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 97%

Section: Digitoxin Channel Kinetics Are Influenced By the Phospholipimentioning

confidence: 99%

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Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

Arispe

Díaz

Šimáková

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies reported that some drugs such as fluconazole [15] , cardiac glycosides [20] , and pentamidine [21] are able to reduce hERG surface expression by interrupting protein trafficking to the cell membrane. Therefore, we studied the effect of ATV on hERG channel protein trafficking.…”

Section: Disruption Of Herg Protein Traffickingmentioning

confidence: 99%

The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

et al. 2015

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Aim: Atazanavir (ATV) is a HIV-1 protease inhibitor for the treatment of AIDS patients, which is recently reported to provoke excessive prolongation of the QT interval and torsades de pointes (TdP). In order to elucidate its arrhythmogenic mechanisms, we investigated the effects of ATV on the hERG K + channels expressed in HEK293 cells. Methods: hERG K + currents were detected using whole-cell patch clamp recording in HEK293 cells transfected with EGFP-hERG plasmids. The expression of hERG protein was measured with Western blotting. Two mutants (Y652A and F656C) were constructed in the S6 domain within the inner helices of hERG K + channels that were responsible for binding of various drugs. The trafficking of hERG protein was studied with confocal microscopy. Results: Application of ATV (0.01-30 μmol/L) concentration-dependently decreased hERG K + currents with an IC 50 of 5.7±1.8 μmol/L. ATV (10 μmol/L) did not affect the activation and steady-state inactivation of hERG K + currents. Compared with the wild type hERG K + channels, both Y652A and F656C mutants significantly reduced the inhibition of ATV on hERG K + currents. Overnight treatment with ATV (0.1-30 μmol/L) concentration-dependently reduced the amount of fully glycosylated 155 kDa hERG protein without significantly affecting the core-glycosylated 135 kDa hERG protein in the cells expressing the WT-hERG protein. Confocal microscopy studies confirmed that overnight treatment with ATV obstructed the trafficking of hERG protein to the cell membrane. Conclusion: ATV directly blocks hERG K + channels via binding to the residues Y652 and F656 in the S6 domain, and indirectly obstructs the transport of the hERG protein to the cell membrane.

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“…[8][9][10] However, there are some drugs which have no acute effect on the hERG channel current, but induce QT prolongation and ventricular arrhythmia such as pentamidine, [11][12][13] probucol 14,15) and cardiac glycosides. 16) These drugs have been reported to inhibit the intracellular trafficking of the hERG channel to the cell membrane. Long term application of such drugs can cause a decrease in the density of the hERG channel on the myocardial cell membrane and lead to QT prolongation.…”

mentioning

confidence: 99%

Effect of Terfenadine and Pentamidine on the hERG Channel and Its Intracellular Trafficking: Combined Analysis with Automated Voltage Clamp and Confocal Microscopy

Tanaka

Takahashi

Hamaguchi

et al. 2014

Biological & Pharmaceutical Bulletin

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The effects of terfenadine and pentamidine on the human ether-a-go-go related gene (hERG) channel current and its intracellular trafficking were evaluated. Green fluorescent protein (GFP)-linked hERG channels were expressed in HEK293 cells, and the membrane current was measured by an automated whole cell voltage clamp system. To evaluate drug effects on channel trafficking to the cell membrane, the fraction of channel present on the cell membrane was quantified by current measurement after drug washout and confocal microscopy. Terfenadine directly blocked the hERG channel current but had no effect on trafficking of hERG channels to the cell membrane after application in culture medium for 2 d. In contrast, pentamidine had no direct effect on the hERG channel current but reduced trafficking of hERG channels. The two drugs inhibited hERG channel function through different mechanisms: terfenadine through direct channel blockade and pentamidine through inhibition of channel trafficking to the cell membrane. Combined use of automated voltage clamp and confocal microscopic analyses would provide insights into the mechanisms of drug-induced QT-prolongation and arrhythmogenesis.

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Cardiac Glycosides as Novel Inhibitors of Human Ether-a-go-go-Related Gene Channel Trafficking

Cited by 91 publications

References 38 publications

Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

Effect of Terfenadine and Pentamidine on the hERG Channel and Its Intracellular Trafficking: Combined Analysis with Automated Voltage Clamp and Confocal Microscopy

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