Intracellular Uptake of Agents That Block the hERG Channel Can Confound Assessment of QT Prolongation and Arrhythmic Risk

Heart Rhythm ◽  
2021 ◽  
Author(s):  
Alexander Burashnikov ◽  
Hector Barajas-Martinez ◽  
Robert Cox ◽  
Mark A. Demitrack ◽  
Michael J. Fossler ◽  
...  
Keyword(s):  
Qt Prolongation ◽  
Herg Channel ◽  
Intracellular Uptake

scholarly journals High Glucose Represses hERG K+ Channel Expression through Trafficking Inhibition

2015 ◽  
Vol 37 (1) ◽  
pp. 284-296 ◽  
Author(s):  
Yuan-Qi Shi ◽  
Meng Yan ◽  
Li-Rong Liu ◽  
Xiao Zhang ◽  
Xue Wang ◽  
...  
Keyword(s):  
Western Blot ◽  
High Glucose ◽  
Qt Prolongation ◽  
Herg Channel ◽  
K Channel ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Down Regulation ◽  
Channel Trafficking ◽  
Herg Current

Background/Aims: Abnormal QT prolongation is the most prominent cardiac electrical disturbance in patients with diabetes mellitus (DM). It is well known that the human ether-ago-go-related gene (hERG) controls the rapid delayed rectifier K+ current (IKr) in cardiac cells. The expression of the hERG channel is severely down-regulated in diabetic hearts, and this down-regulation is a critical contributor to the slowing of repolarization and QT prolongation. However, the intracellular mechanisms underlying the diabetes-induced hERG deficiency remain unknown. Methods: The expression of the hERG channel was assessed via western blot analysis, and the hERG current was detected with a patch-clamp technique. Results: The results of our study revealed that the expression of the hERG protein and the hERG current were substantially decreased in high-glucose-treated hERG-HEK cells. Moreover, we demonstrated that the high-glucose-mediated damage to the hERG channel depended on the down-regulation of protein levels but not the alteration of channel kinetics. These discoveries indicated that high glucose likely disrupted hERG channel trafficking. From the western blot and immunoprecipitation analyses, we found that high glucose induced trafficking inhibition through an effect on the expression of Hsp90 and its interaction with hERG. Furthermore, the high-glucose-induced inhibition of hERG channel trafficking could activate the unfolded protein response (UPR) by up-regulating the expression levels of activating transcription factor-6 (ATF-6) and the ER chaperone protein calnexin. In addition, we demonstrated that 100 nM insulin up-regulated the expression of the hERG channel and rescued the hERG channel repression caused by high glucose. Conclusion: The results of our study provide the first evidence of a high-glucose-induced hERG channel deficiency resulting from the inhibition of channel trafficking. Furthermore, insulin promotes the expression of the hERG channel and ameliorates the high-glucose-induced inhibition of the hERG channel.

scholarly journals Synthetic cannabinoid, JWH-030, induces QT prolongation through hERG channel inhibition

2016 ◽  
Vol 5 (6) ◽  
pp. 1663-1671 ◽  
Author(s):  
Jaesuk Yun ◽  
Kyung Sik Yoon ◽  
Tac-Hyung Lee ◽  
Hyunjin Lee ◽  
Sun Mi Gu ◽  
...  
Keyword(s):  
Synthetic Cannabinoids ◽  
Qt Prolongation ◽  
Synthetic Cannabinoid ◽  
Herg Channel ◽  
Psychoactive Substance ◽  
New Psychoactive Substance ◽  
Channel Inhibition

The problem of new psychoactive substance (NPS) abuse, which includes synthetic cannabinoids, is emerging globally, and the cardiotoxicity of these synthetic cannabinoids has not yet been evaluated extensively.

scholarly journals Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Yan Liu ◽  
Xueqi Xu ◽  
Yuhao Zhang ◽  
Mingzhu Li ◽  
Jiamengyi Guo ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Calcium Channels ◽  
Er Stress ◽  
Calcium Channel ◽  
Qt Prolongation ◽  
Herg Channel ◽  
Ros Production ◽  
Oxygen Species ◽  
Channel Activation ◽  
Intracellular Ca

Thioridazine (THIO) is a phenothiazine derivative that is mainly used for the treatment of psychotic disorders. However, cardiac arrhythmias especially QT interval prolongation associated with the application of this compound have received serious attention after its introduction into clinical practice, and the mechanisms underlying the cardiotoxicity induced by THIO have not been well defined. The present study was aimed at exploring the long-term effects of THIO on the hERG and L-type calcium channels, both of which are relevant to the development of QT prolongation. The hERG current (IhERG) and the calcium current (ICa‐L) were measured by patch clamp techniques. Protein levels were analyzed by Western blot, and channel-chaperone interactions were determined by coimmunoprecipitation. Reactive oxygen species (ROS) were determined by flow cytometry and laser scanning confocal microscopy. Our results demonstrated that THIO induced hERG channel deficiency but did not alter channel kinetics. THIO promoted ROS production and stimulated endoplasmic reticulum (ER) stress and the related proteins. The ROS scavenger N-acetyl cysteine (NAC) significantly attenuated hERG reduction induced by THIO and abolished the upregulation of ER stress marker proteins. Meanwhile, THIO increased the degradation of hERG channels via disrupting hERG-Hsp70 interactions. The disordered hERG proteins were degraded in proteasomes after ubiquitin modification. On the other hand, THIO increased ICa‐L density and intracellular Ca2+ ([Ca2+]i) in neonatal rat ventricular cardiomyocytes (NRVMs). The specific CaMKII inhibitor KN-93 attenuated the intracellular Ca2+ overload, indicating that ROS-mediated CaMKII activation promoted calcium channel activation induced by THIO. Optical mapping analysis demonstrated the slowing effects of THIO on cardiac repolarization in mouse hearts. THIO significantly prolonged APD50 and APD90 and increased the incidence of early afterdepolarizations (EADs). In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), THIO also resulted in APD prolongation. In conclusion, dysfunction of hERG channel proteins and activation of L-type calcium channels via ROS production might be the ionic mechanisms for QT prolongation induced by THIO.

scholarly journals The Effect of a Synthetic Estrogen, Ethinylestradiol, on the hERG Block by E-4031

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1385
Author(s):  
Fumiya Tamura ◽  
Shintaro Sugimoto ◽  
Mana Sugimoto ◽  
Kazuho Sakamoto ◽  
Masahiko Yamaguchi ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Qt Prolongation ◽  
Drug Binding ◽  
Herg Channel ◽  
Drug Binding Site ◽  
Synthetic Estrogen ◽  
Synthetic Estrogens ◽  
Herg Current ◽  
Channel Currents ◽  
Kinetics Of

Inhibition of K+-conductance through the human ether-a-go-go related gene (hERG) channel leads to QT prolongation and is associated with cardiac arrhythmias. We previously reported that physiological concentrations of some estrogens partially suppress the hERG channel currents by interacting with the S6 residue F656 and increase the sensitivity of hERG blockade by E-4031. Although these studies suggested that clinically used synthetic estrogens with similar structures have the marked potential to alter hERG functions, the hERG interactions with synthetic estrogens have not been assessed. We therefore examined whether ethinylestradiol (EE2), a synthetic estrogen used in oral contraceptives, affects hERG function and blockade by drugs. Supratherapeutic concentrations of EE2 did not alter amplitudes or kinetics of the hERG currents elicited by train pulses at 20 mV (0.1 Hz). On the other hand, EE2 at therapeutic concentrations reduced the degree of hERG current suppression by E-4031. The administration of EE2 followed by E-4031 blockade reversed the current suppression, suggesting that the interaction of EE2 and E-4031 alters hERG at the drug-binding site. The effects of EE2 on hERG blockade raised the possibility that other estrogens, including synthetic estrogens, can alter hERG blockade by drugs that cause QT prolongation and ventricular arrhythmias.

HERG channel inhibiting activity of Rauvolfia nukuhivensis alkaloid content

Planta Medica ◽  
2014 ◽  
Vol 80 (16) ◽  
Author(s):  
NJ Martin ◽  
EA López ◽  
G Lecellier ◽  
M Nicolas ◽  
C Paetz ◽  
...  
Keyword(s):  
Alkaloid Content ◽  
Herg Channel ◽  
Inhibiting Activity
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