NDLI: The protease inhibitor atazanavir blocks hERG $K^{+}$ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Han, Sheng-na Sun, Xiao-yan Zhang, Zhao Zhang, Li-rong
Description	Country affiliation: China Author Affiliation: Han SN ( Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou 450001, China.); Sun XY ( Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China.); Zhang Z ( Jiangsu Key Laboratory for Molecular & Medical Biotechnology, College of Life Science in Nanjing Normal University, Nanjing 210046, China.); Zhang LR ( Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou 450001, China.)
Abstract	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.
File Format	HTM / HTML
ISSN	16714083
e-ISSN	17457254
DOI	10.1038/aps.2014.165
Journal	Acta Pharmacologica Sinica
Issue Number	4
Volume Number	36
Language	English
Publisher	Macmillan Publishers Limited
Publisher Date	2015-04-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Pharmacology Ether-a-go-go Potassium Channels Antagonists & Inhibitors Hek293 Cells Drug Effects Oligopeptides Pharmacology Protease Inhibitors Pyridines Atazanavir Sulfate Cell Membrane Metabolism Genetics Gene Expression Point Mutation Protein Transport Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Pharmacology Pharmacology (medical)

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

L539 fs/47, a truncated mutation of human ether-a-go-go-related gene (hERG), decreases hERG ion channel currents in HEK 293 cells.

hERG subunit composition determines differential drug sensitivity

The calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide directly blocks human ether à-go-go-related gene potassium channels stably expressed in human embryonic kidney 293 cells

State-dependent blockade of human ether-a-go-go-related gene (hERG) $K^{+}$ channels by changrolin in stably transfected HEK293 cells

H(1) antihistamine drug promethazine directly blocks hERG K(+) channel.

Novel roles for hERG $K^{+}$ channels in cell proliferation and apoptosis

Rab11-dependent Recycling of the Human Ether-a-go-go-related Gene (hERG) Channel

Mechanism of hERG $K^{+}$ channel blockade by the fluoroquinolone antibiotic moxifloxacin

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

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

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The calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide directly blocks human ether à-go-go-related gene potassium channels stably expressed in human embryonic kidney 293 cells

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