hERG potassium channels and cardiac arrhythmia

Sanguinetti, Michael C.; Tristani‐Firouzi, Martin

doi:10.1038/nature04710

Cited by 1,398 publications

(1,270 citation statements)

References 86 publications

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“…Key aromatic residues in the S6 helix (Tyr 652 , Phe 656 ) and the pore helix (Thr 623 , Ser 624 , Val 625 ) of the K v 11.1 channel have been identified as the detrimental target of a broad spectrum of compounds (Perry, 2005) that impair K + ion flux through the pore and therefore reduce I Kr . This generates a prolongation of the QT interval of the electrocardiogram (ECG), with the potential occurrence of a polymorphic form of ventricular tachycardia known as torsades de pointes (TdP), which can cause sudden death (Sanguinetti and Tristani‐Firouzi, 2006). …”

Section: Cardiotoxicity Caused By Electrical Disruptionmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Cardiotoxicity Caused By Electrical Disruptionmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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“…The disease is linked to mutations in the human ether a go-go-related gene 1 (HERG1/KCNH2), which encodes the ␣-subunit of the hERG/Kv11.1 channel that conducts the rapid component of the delayed rectifier K ϩ current (I Kr ) in the heart (1,2).…”

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confidence: 99%

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

Hantouche

Williamson

Valinsky

et al. 2017

Journal of Biological Chemistry

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Edited by George N. DeMartinoCardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go-related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity. Dissociation of hERG complexes containing Hsp70 and the E3 ubiquitin ligase CHIP requires the interaction of Bag1 with Hsp70, but this does not involve the Bag1 ubiquitin-like domain. The interaction with Bag1 then shifts hERG degradation to the membrane-anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening. TRC8 interacts through the transmembrane region with hERG and decreases hERG functional expression. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, but pharmacological stabilization of the mutant structure prevents degradation. Our results identify TRC8 as a previously unknown Hsp70-independent quality control E3 ligase for hERG.

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“…The risk of inhibition of human ether-a-go-go-related (hERG) gene was varied from low to medium. Inhibition of the hERG gene has been linked to long QT syndrome (Sanguinetti et al, 2006). The results have been in summarized in Table 5.…”

Section: Toxicological Studymentioning

confidence: 99%

The natural anti-tubercular agents: In silico study of physicochemical, pharmacokinetic and toxicological properties

2017

J App Pharm Sci

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The purpose of the present study is to explore the physicochemical, pharmacokinetic and toxicological properties and to correlate the calculated physicochemical properties with the absorption and distribution profile of seven natural anti-tubercular agents such as 6a,7-dehydro-N-formylnornantenine (DNF), Aristololactam (AL), Isoambreinolide (IA), Andrographolide (AGD), 8,8'-Biplumbagin (BPG), Plumericin (PC) and Tiliacorine (TC). The physicochemical properties such as intrinsic solubility (solubility of unionized form) in water (logS), partition coefficient (logP), H bond donor and acceptor count were calculated using MarvinSketch software. The pharmacokinetic and toxicological properties were calculated using online server PreADMET. The calculated aqueous solubility demonstrated that all the seven compounds possess limited solubility which ranged from very slightly soluble to practically insoluble. The calculation of partition coefficient suggested that all the compounds are lipophilic in nature and have higher affinity to reside in n-octanol than in water. The human intestinal absorption (HIA), Caco-2 cell penetrability, plasma protein binding (PPB) and Cbrain/Cblood of the seven compounds were ranged from 94.89% -100.00%, 20.18 -54.75 nm/s, 73.52% -100.00% and 0.353 -2.331, respectively. The computed metabolism demonstrated that DNF, AL, IA, PC and TC are substrate for cytochrome P450 3A4. However, all the compounds displayed inhibitory characteristics against cytochrome P450 3A4. The virtual screening also demonstrated that AL, PG and BPG are 2C19 inhibitors and all the natural agents except DNF are 2C9 inhibitors. In phase II reaction, IA, PG and DNF, AL, PG, BPG are the substrates for UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT), respectively. In the in silico mutagenicity and carcinogenicity investigations, all the compounds except TC exhibited mutagenicity. Among all the natural anti-tubercular agents only DNF and TC demonstrated carcinogenicity in both mouse and rat models. The AL and PG were carcinogenic only in mouse but in rat model they were noncarcinogenic. On the other hand, IA, BPG and PC were noncarcinogenic in both mouse and rat model. In addition, the risk of inhibition of human ether-a-go-go-related (hERG) gene was varied from low to medium risk. Our computed properties may be assistance for the development of promising candidates to combat M. tuberculosis with better pharmacokinetic and toxicological profile.

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hERG potassium channels and cardiac arrhythmia

Cited by 1,398 publications

References 86 publications

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

The natural anti-tubercular agents: In silico study of physicochemical, pharmacokinetic and toxicological properties

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