Involvement of Caveolin in Probucol-Induced Reduction in hERG Plasma-Membrane Expression

Guo, Jun; Li, Xian; Shallow, Heidi; Xu, Jimmy P.; Yang, Tonghua; Massaeli, Hamid; Li, Wentao; Sun, Tao; Pierce, Grant N.; Zhang, Shetuan

doi:10.1124/mol.110.069419

Cited by 43 publications

(42 citation statements)

References 39 publications

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“…Furthermore, we provide the first example of a therapeutic compound that arrests hERG maturation in a nonexportable form via binding to residues in the canonical drug-binding site of hERG. This is very different from what has been proposed for proarrhythmic compounds such as probucol or progesterone (Guo et al, 2011;Wu et al, 2011), which are thought to mediate changes in hERG surface expression via effects on the composition of lipid rafts surrounding the channel protein. The reliance of pentamidine on hERG-specific amino acid residues may also provide an answer to its specificity and may explain why pentamidine effects are restricted to ER export, because the native conformation of hERG that is present in post-ER compartments binds pentamidine with much lower affinity only.…”

Section: Drug-induced Trafficking Inhibition 207mentioning

confidence: 47%

“…However, channel endocytosis in combination with accelerated degradation has emerged more recently as an alternative mechanism used by proarrhythmic compounds to control hERG surface expression. For example, it has been shown that probucol, a cholesterol-lowering drug causing acLQTS, increased endocytic hERG uptake from the cell surface (Guo et al, 2011). A similar increase in endocytosis has been described upon exposure of hERG to low extracellular potassium concentrations (Guo et al, 2009).…”

Section: Discussionmentioning

confidence: 85%

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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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Section: Drug-induced Trafficking Inhibition 207mentioning

confidence: 47%

Section: Discussionmentioning

confidence: 85%

Molecular Determinants of Pentamidine-Induced hERG Trafficking Inhibition

Dennis¹,

Wang²,

Wan³

et al. 2011

Mol Pharmacol

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“…This could be deleterious to hERG channels that are thought to localize to cholesterol-rich lipid rafts (48). A similar hypothesis has been proposed to explain how probucol, a drug known to deplete cellular cholesterol levels, may induce hERG endocytosis (41). On the other hand, hERG endocytosis cannot be induced by exposure to methyl-␤-cyclodextrin, a chelator often used to extract cholesterol from cell membranes (49).…”

Section: Discussionmentioning

confidence: 90%

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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“…To study the effect of carbachol on hERG degradation, BFA (10 mM) was used to block the conversion of hERG from the immature 135-kDa form to the mature 155-kDa form (Guo et al, 2009(Guo et al, , 2011a. The degradation rate of hERG was monitored by detecting the 155-kDa band expression level at different time points after BFA treatments in control and carbachol-treated cells.…”

Section: Muscarinic Receptor Modulation Of Herg Channelsmentioning

confidence: 99%

Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

Wang¹,

Hogan-Cann²,

Kang³

et al. 2014

Mol Pharmacol

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The human ether-à-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel, which is important for cardiac repolarization. Reduction of hERG current due to genetic mutations or drug interferences causes long QT syndrome, leading to cardiac arrhythmias and sudden death. To date, there is no effective therapeutic method to restore or enhance hERG channel function. Using cell biology and electrophysiological methods, we found that the muscarinic receptor agonist carbachol increased the expression and function of hERG, but not ether-à-go-go or K v 1.5 channels stably expressed in human embryonic kidney cells. The carbachol-mediated increase in hERG expression was abolished by the selective M3 antagonist 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide) but not by the M2 antagonistTreatment of cells with carbachol reduced the hERG-ubiquitin interaction and slowed the rate of hERG degradation. We previously showed that the E3 ubiquitin ligase Nedd4-2 mediates degradation of hERG channels. Here, we found that disrupting the Nedd4-2 binding domain in hERG completely eliminated the effect of carbachol on hERG channels. Carbachol treatment enhanced the phosphorylation level, but not the total level, of Nedd4-2. Blockade of the protein kinase C (PKC) pathway abolished the carbachol-induced enhancement of hERG channels. Our data suggest that muscarinic activation increases hERG channel expression by phosphorylating Nedd4-2 via the PKC pathway.

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Involvement of Caveolin in Probucol-Induced Reduction in hERG Plasma-Membrane Expression

Cited by 43 publications

References 39 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

Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

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