Intracellular Potassium Stabilizes Human<i>Ether-à-go-go</i>-Related Gene Channels for Export from Endoplasmic Reticulum

Wang, Lu; Dennis, Adrienne T.; Trieu, Phan; Charron, François; Ethier, Natalie; Hébert, Terence E.; Wan, Xiaoping; Ficker, Eckhard

doi:10.1124/mol.108.053793

Cited by 32 publications

(28 citation statements)

References 43 publications

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“…Novel approaches include potassium supplementation for LQT2 patients. In vitro experiments have showed that proper intracellular K + concentration is a requirement for normal HERG channel trafficking to the membrane, and that extracellular potassium modulates HERG current (Guo et al, 2009;Wang et al, 2009). These findings correlate with earlier studies that focused on HERG current density, showing that I Kr current paradoxically increased when extracellular K + concentration was increased (Sanguinetti & Jurkiewicz, 1992).…”

Section: Therapeutic Approachessupporting

confidence: 80%

Phenotypic Correlation of Genetic Mutations with Ventricular Arrhythmias

Krishnan¹,

Chen²,

McDonald³

2012

Cardiac Arrhythmias - New Considerations

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Section: Therapeutic Approachessupporting

confidence: 80%

Phenotypic Correlation of Genetic Mutations with Ventricular Arrhythmias

Krishnan¹,

Chen²,

McDonald³

2012

Cardiac Arrhythmias - New Considerations

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“…Figure 6 shows a Western analysis of brefeldin A-treated hERG gradient fractions, illustrating the distribution of hERG in two prominent protein peaks, P1 and P2, with the majority of hERG protein present in P2. Using Blue Native-PAGE, we have previously determined that hERG is present as monomer or dimer in peak P1, whereas it forms channel tetramers in P2 (Wang et al, 2009). It is noteworthy that we could detect no quantitative differences in the distribution of hERG on sucrose gradients as a consequence of pentamidine exposure.…”

Section: Drug-induced Trafficking Inhibition 201mentioning

confidence: 45%

“…Soluble material (400-800 g of total protein) was layered onto 15 to 45% sucrose gradients (150 mM NaCl, 10 mM Tris, pH 7.4, and 0.1% digitonin). Gradients were made using BIOCOMP Gradient Mate (BIOCOMP, Fredericton, NB, Canada) as described previously (Wang et al, 2009). After centrifugation, 275-l fractions were collected manually from the top of each gradient.…”

Section: Drug-induced Trafficking Inhibitionmentioning

confidence: 99%

“…S1). HERG F627Y was selected for analysis because it rendered channels less sensitive toward cardiac glycosides, another well characterized class of hERG trafficking inhibitors (Wang et al, , 2009). Because F627Y promotes channel inactivation (Gang and Zhang, 2006), we extended our analysis to hERG S641A, a mutation in the S6 transmembrane helix with accelerated inactivation ( Fig.…”

Section: Drug-induced Trafficking Inhibition 201mentioning

confidence: 99%

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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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“…Additionally, some drugs disrupt HERG forward trafficking, thereby causing LQTS (13,33,34). Recently, Wang et al found that inhibition of Na + /K + ATPase disrupted HERG forward trafficking (34,35). However, the 0 mM K + -induced reduction of 155-kDa HERG expression levels is most likely due to the increased membrane instability and degradation of HERG channels, not to the impaired forward trafficking.…”

Section: Discussionmentioning

confidence: 95%

Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines

Guo¹,

Massaeli²,

Xu³

et al. 2009

J. Clin. Invest.

138

190

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Although the modulation of ion channel gating by hormones and drugs has been extensively studied, much less is known about how cell surface ion channel expression levels are regulated. Here, we demonstrate that the cell surface density of both the heterologously expressed K + channel encoded by the human ether-a-gogo-related gene (HERG) and its native counterpart, the rapidly activating delayed rectifier K + channel (I Kr IntroductionThe amplitude of ion channel currents is determined by a combination of channel gating (open versus closed times) and channel density in the plasma membrane. Whereas ion channel gating is known to be modulated by various means, such as hormones and drugs, much less is known about how the density of WT ion channels in the plasma membrane is regulated.The human ether-a-go-go-related gene (HERG) encodes the pore-forming subunits of the rapidly activating delayed rectifier K + channel (I Kr ) in the heart (1, 2). Mutations in HERG reduce I Kr and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to life-threatening arrhythmias (3). In addition, the HERG channel is a common target for diverse classes of drugs that induce acquired long QT syndrome (LQTS; ref. 4). Whereas drugs usually reduce HERG channel current (I HERG ) by blocking the channel, LQTS-causing HERG mutations often decrease I HERG by disrupting forward trafficking of the channel, thereby reducing expression levels of HERG at the plasma membrane (5). However, little is presently known about how the plasma membrane density of WT HERG channels is regulated under either physiological or pathophysiological conditions. Disorders of extracellular K + concentration ([K + ] o ) are the most common electrolyte abnormality found in clinical practice and can be life threatening. For example, abrupt, insulin-induced shifts of K + from the extracellular compartment into cells, abnormal K + losses caused by digestive or kidney disorders, and the use of certain diuretics are common causes of low [K + ] o (hypokalemia). It is also

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

Cited by 32 publications

References 43 publications

Phenotypic Correlation of Genetic Mutations with Ventricular Arrhythmias

Phenotypic Correlation of Genetic Mutations with Ventricular Arrhythmias

Molecular Determinants of Pentamidine-Induced hERG Trafficking Inhibition

Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines

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