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

Tanaka, Hikaru; Takahashi, Yukiko; Hamaguchi, Satoshi; Iida-Tanaka, Naoko; Oka, Takayuki; Nishio, Masato; Ohtsuki, Atsushi; Namekata, Iyuki

doi:10.1248/bpb.b14-00417

Cited by 13 publications

(7 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It appears that KCNH K + channels should be localized to plasma membrane. However, as previously reported, the staining of KCNH-class channels was not restricted to plasma membrane but rather was diffused throughout cytosol Tanaka et al, 2014;Uhlé n et al, 2015). KCNH6 is also expressed in a cells, and it is surprising that glucagon secretion is unaltered in this study.…”

Section: Discussionsupporting

confidence: 75%

From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

et al. 2018

View full text Add to dashboard Cite

Graphical Abstract Highlights d KCNH6 regulates insulin secretion and glucose hemostasis in humans and mice d KCNH6 dysfunction causes a phenotype from hyper-to hypoinsulinemia and diabetes d KCNH6 dysfunction increases intracellular calcium levels and hyperinsulinemia d Chronic elevation of intracellular calcium causes b cell loss and hypoinsulinemia In Brief Yang et al. show that KCNH6 plays a key role in insulin secretion and glucose hemostasis in humans and mice. Dysfunction of KCNH6 results in a hyperinsulinemia phenotype in the short term and hypoinsulinemia and diabetes in the long term. SUMMARYGlucose-stimulated insulin secretion from islet b cells is mediated by K ATP channels. However, the role of non-K ATP K + channels in insulin secretion is largely unknown. Here, we show that a non-K ATP K + channel, KCNH6, plays a key role in insulin secretion and glucose hemostasis in humans and mice. KCNH6 p.P235L heterozygous mutation co-separated with diabetes in a four-generation pedigree. Kcnh6 knockout (KO) or Kcnh6 p.P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. Islets from the young KO mice had increased intracellular calcium concentration and increased insulin secretion. However, islets from the adult KO mice not only had increased intracellular calcium levels but also had remarkable ER stress and apoptosis, associated with loss of b cell mass and decreased insulin secretion. Therefore, dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and b cell failure in the long term.

show abstract

Section: Discussionsupporting

confidence: 75%

From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In addition to this, we found several other classes of drugs showing activity against hERG in the present assay, such as antihistamine drugs (Astemizole, Terfenadine, Clemastine, Ebastine), prokinetic drugs (Cisapride, Domperidone), and some chemotherapeutic agents (Lapatinib, Bosutinib methanoate). The ability of these non-CV drugs to induce QT interval prolongations or arrhythmias has been established by various studies [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. One of the most well-known chemotherapeutic agents with cardiotoxic effects is 5-fluorouracil, which was tested here, but was inactive, consistent with the hypothesized mechanisms of direct cellular damage and/or ischemia, rather than hERG channel inhibition [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Chemical Screening and Structure-Based Models to Predict hERG Inhibition

Krishna

Borrel

Huang

et al. 2022

Biology

View full text Add to dashboard Cite

Chemical inhibition of the human ether-a -go-go-related gene (hERG) potassium channel leads to a prolonged QT interval that can contribute to severe cardiotoxicity. The adverse effects of hERG inhibition are one of the principal causes of drug attrition in clinical and pre-clinical development. Preliminary studies have demonstrated that a wide range of environmental chemicals and toxicants may also inhibit the hERG channel and contribute to the pathophysiology of cardiovascular (CV) diseases. As part of the US federal Tox21 program, the National Center for Advancing Translational Science (NCATS) applied a quantitative high throughput screening (qHTS) approach to screen the Tox21 library of 10,000 compounds (~7871 unique chemicals) at 14 concentrations in triplicate to identify chemicals perturbing hERG activity in the U2OS cell line thallium flux assay platform. The qHTS cell-based thallium influx assay provided a robust and reliable dataset to evaluate the ability of thousands of drugs and environmental chemicals to inhibit hERG channel protein, and the use of chemical structure-based clustering and chemotype enrichment analysis facilitated the identification of molecular features that are likely responsible for the observed hERG activity. We employed several machine-learning approaches to develop QSAR prediction models for the assessment of hERG liabilities for drug-like and environmental chemicals. The training set was compiled by integrating hERG bioactivity data from the ChEMBL database with the Tox21 qHTS thallium flux assay data. The best results were obtained with the random forest method (~92.6% balanced accuracy). The data and scripts used to generate hERG prediction models are provided in an open-access format as key in vitro and in silico tools that can be applied in a translational toxicology pipeline for drug development and environmental chemical screening.

show abstract

“…Further experiments on compound–protein interactions are required to qualify these drugs as Hsp90-targeted inhibitors. Although a variety of drugs have been shown to interfere with hERG transport to reduce current, direct blockade of drugs without trafficking defects has also been reported ( Borsini et al, 2012 ; Tanaka et al, 2014 ). Recently, a study of the effects of COVID-19 drugs chloroquine and hydroxychloroquine on blocking the hERG potassium channel showed that these drugs acutely and severely inhibited the hERG current, but remdesivir increased the I hERG with promoted hERG maturation when acting alone ( Szendrey et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Chronic Administration of COVID-19 Drugs Fluvoxamine and Lopinavir Shortens Action Potential Duration by Inhibiting the Human Ether‐à‐go‐go–Related Gene and Cav1.2

Zheng

Cai

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Background: Old drugs for new indications in the novel coronavirus disease of 2019 (COVID-19) pandemic have raised concerns regarding cardiotoxicity, especially the development of drug-induced QT prolongation. The acute blocking of the cardiac hERG potassium channel is conventionally thought to be the primary mechanism of QT prolongation induced by COVID-19 drugs fluvoxamine (FLV) and lopinavir (LPV). The chronic impact of these medications on the hERG expression has yet to be determined.Methods: To investigate the effect of long-term incubation of FLV and LPV on the hERG channel, we used electrophysiological assays and molecular experiments, such as Western blot, RT-qPCR, and immunofluorescence, in HEK-293 cells stably expressing hERG and human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs).Results: Compared to the acute effects, chronic incubation for FLV and LPV generated much lower half-maximal inhibitory concentration (IC50) values, along with a left-shifted activation curve and retarded channel activation. Inconsistent with the reduction in current, we unexpectedly found that the chronic effects of drugs promoted the maturation of hERG proteins, accompanied by the high expression of Hsp70 and low expression of Hsp90. Targeting Hsp70 using siRNA was able to reverse the effects of these drugs on hERG proteins. In addition, FLV and LPV resulted in a significant reduction of APD90 and triggered the early after-depolarizations (EADs), as well as inhibited the protein level of the L-type voltage–operated calcium channel (L-VOCC) in hiPSC-CMs.Conclusion: Chronic incubation with FLV and LPV produced more severe channel-blocking effects and contributed to altered channel gating and shortened action potential duration by inhibiting hERG and Cav1.2.

show abstract

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

Cited by 13 publications

References 26 publications

From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion

High-Throughput Chemical Screening and Structure-Based Models to Predict hERG Inhibition

Chronic Administration of COVID-19 Drugs Fluvoxamine and Lopinavir Shortens Action Potential Duration by Inhibiting the Human Ether‐à‐go‐go–Related Gene and Cav1.2

Contact Info

Product

Resources

About