The influence of hERG1a and hERG1b isoforms on drug safety screening in iPSC-CMs

Goversen, Birgit; Jonsson, Malin K.B.; Heuvel, Nikki Hl. van den; Rijken, Rianne; Vos, Marc A.; Veen, Toon A van; Boer, Teun P. de

doi:10.1016/j.pbiomolbio.2019.02.003

Cited by 9 publications

(10 citation statements)

References 84 publications

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“…ERG1a, ERG1b, and ERG1c transcription is initiated from distinct subunit-specific promoter regions making them alternate transcripts of the same gene ( Lees-Miller et al, 1997 ; London et al, 1997 ; Huffaker et al, 2009 ). Conducting ERG1 channels of native tissue can comprise at least three subunits: ERG1a, ERG1b, and ERG1c ( Lees-Miller et al, 1997 ; London et al, 1997 ; Jones et al, 2004 , 2014 ; Huffaker et al, 2009 ; Calcaterra et al, 2016 ; Carr et al, 2016 ; Goversen et al, 2019 ). 15 exons encode the ERG1a transcript, the first five of which encode the long N-terminal domain that contains the channel’s PAS domain.…”

Section: Erg1 Structure and Functionmentioning

confidence: 99%

The ERG1 K+ Channel and Its Role in Neuronal Health and Disease

Sanchez-Conde

Jiménez-Vázquez

Auerbach

et al. 2022

Front. Mol. Neurosci.

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The ERG1 potassium channel, encoded by KCNH2, has long been associated with cardiac electrical excitability. Yet, a growing body of work suggests that ERG1 mediates physiology throughout the human body, including the brain. ERG1 is a regulator of neuronal excitability, ERG1 variants are associated with neuronal diseases (e.g., epilepsy and schizophrenia), and ERG1 serves as a potential therapeutic target for neuronal pathophysiology. This review summarizes the current state-of-the-field regarding the ERG1 channel structure and function, ERG1’s relationship to the mammalian brain and highlights key questions that have yet to be answered.

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Section: Erg1 Structure and Functionmentioning

confidence: 99%

The ERG1 K+ Channel and Its Role in Neuronal Health and Disease

Sanchez-Conde

Jiménez-Vázquez

Auerbach

et al. 2022

Front. Mol. Neurosci.

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“…Many different cardiac drugs (mainly antiarrhythmic drugs) and non-cardiac drugs (including antihistaminic, antipsychotic, anti-depressant, antibiotics, antimalarial, gastrointestinal, and anesthetic agents) have been implicated in the prolongation of the ventricular repolarization and pro-arrhythmias (Locati et al, 2019;Roden, 2016) (Table 5). Virtually all QT prolonging drugs act by blocking the potassium channels, mainly the rapid component of the delayed rectifier potassium channel (I kr ) encoded by the human Ether-à-gogo-Related Gene (hERG) (Antzelevitch and Burashnikov, 2011;Roden, 2016;Goversen et al, 2019;Locati et al, 2019;Roden, 2016). The complete and updated list of specific drugs that prolong the QT interval is available at www.qtdrugs.org.…”

Section: Drug-induced Qt Prolongation and Proarrhythmiasmentioning

confidence: 99%

Role of Pharmacogenetics in Adverse Drug Reactions: An Update towards Personalized Medicine

et al. 2021

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Adverse drug reactions (ADRs) are an important and frequent cause of morbidity and mortality. ADR can be related to a variety of drugs, including anticonvulsants, anaesthetics, antibiotics, antiretroviral, anticancer, and antiarrhythmics, and can involve every organ or apparatus. The causes of ADRs are still poorly understood due to their clinical heterogeneity and complexity. In this scenario, genetic predisposition toward ADRs is an emerging issue, not only in anticancer chemotherapy, but also in many other fields of medicine, including hemolytic anemia due to glucose-6-phosphate dehydrogenase (G6PD) deficiency, aplastic anemia, porphyria, malignant hyperthermia, epidermal tissue necrosis (Lyell’s Syndrome and Stevens-Johnson Syndrome), epilepsy, thyroid diseases, diabetes, Long QT and Brugada Syndromes. The role of genetic mutations in the ADRs pathogenesis has been shown either for dose-dependent or for dose-independent reactions. In this review, we present an update of the genetic background of ADRs, with phenotypic manifestations involving blood, muscles, heart, thyroid, liver, and skin disorders. This review aims to illustrate the growing usefulness of genetics both to prevent ADRs and to optimize the safe therapeutic use of many common drugs. In this prospective, ADRs could become an untoward “stress test,” leading to new diagnosis of genetic-determined diseases. Thus, the wider use of pharmacogenetic testing in the work-up of ADRs will lead to new clinical diagnosis of previously unsuspected diseases and to improved safety and efficacy of therapies. Improving the genotype-phenotype correlation through new lab techniques and implementation of artificial intelligence in the future may lead to personalized medicine, able to predict ADR and consequently to choose the appropriate compound and dosage for each patient.

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“…In the heart, Kv11.1 is key for cardiac repolarization and therefore, its off-target inhibition induces long QT syndrome. Thus, safety pharmacological studies include K V 11.1 channel assays as the primary test, decreasing its practical impact as an anticancer therapy-related target (Goversen et al, 2019). K V 10.1 channel is selectively expressed in brain areas (Table 1).…”

Section: K + -Channels In Cancermentioning

confidence: 99%

Voltage-Gated K+/Na+ Channels and Scorpion Venom Toxins in Cancer

Díaz-García

Varela

2020

Front. Pharmacol.

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Ion channels have recently been recognized as novel therapeutic targets in cancer research since they are overexpressed in different histological tissues, and their activity is linked to proliferation, tumor progression, angiogenesis, metastasis, and apoptosis. Voltage gated-potassium channels (VGKC) are involved in cell proliferation, cancer progression, cell cycle transition, and apoptosis. Moreover, voltage-dependent sodium channels (VGSC) contribute to decreases in extracellular pH, which, in turn, promotes cancer cell migration and invasion. Furthermore, VGSC and VGKC modulate voltagesensitive Ca 2+ channel activity by controlling the membrane potential and regulating Ca 2+ influx, which functions as a second messenger in processes related to proliferation, invasion, migration, and metastasis. The subgroup of these types of channels that have shown a high oncogenic potential have become known as "oncochannels", and the evidence has highlighted them as key potential therapeutic targets. Scorpion venoms contain a high proportion of peptide toxins that act by modulating voltage-gated Na + /K + channel activity. Increasing scientific data have pointed out that scorpion venoms and their toxins can affect the activity of oncochannels, thus showing their potential for anticancer therapy. In this review, we provide an update of the most relevant voltage-gated Na + \K + ion channels as cellular targets and discuss the possibility of using scorpion venom and toxins for anticancer therapy.

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The influence of hERG1a and hERG1b isoforms on drug safety screening in iPSC-CMs

Cited by 9 publications

References 84 publications

The ERG1 K+ Channel and Its Role in Neuronal Health and Disease

The ERG1 K+ Channel and Its Role in Neuronal Health and Disease

Role of Pharmacogenetics in Adverse Drug Reactions: An Update towards Personalized Medicine

Voltage-Gated K+/Na+ Channels and Scorpion Venom Toxins in Cancer

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