Cardiac hERG K+ Channel as Safety and Pharmacological Target

Su, Shi; Sun, Jinglei; Wang, Yi; Xu, Yancheng

doi:10.1007/164_2021_455

Cited by 10 publications

(9 citation statements)

References 179 publications

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“…On the other hand, there are also some studies showing no negative effect on QT interval (37,38). Mechanism of prolonging the QT interval has been suggested to be associated with direct blocking of cardiac potassium channels encoded by the human ether related gene (hERG) (39) and blocking of α L-type calcium channels (40)(41)(42). LQTS may be congenital or acquired abnormality and risk factors for acquired have been identified.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Citalopram levels on QTc Interval in Rats using with Radio-telemetry

HARMANCI¹,

TOPRAK²,

KALTUŞ³

et al. 2022

Osmangazi̇ Journal of Medicine

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Long QT syndrome is an arrhythmogenic disease characterized by prolonged QT interval. Citalopram (CIT) was reported to prolong QT interval dose-dependently. Omeprazole (OMP), inhibits CIT metabolizing enzyme CYP2C19, thereby increases serum concentrations which may increase the risk of QT prolongation. These are commonly co-prescribed and recent studies have raised the safety concerns about. We aimed to investigate the dose dependent effects of citalopram alone and in combination with OMP. Forty male, Sprague Dawley rats were divided into 5 groups (n=8). CIT (10 mg/kg or 30 mg/kg) was given for 2 weeks alone or in combination with OMP (100 mg/kg) starting from the 2nd week. ECG recordings and blood samples were collected. QT interval significantly increased in all groups compared to control. The plasma level of CIT in the CIT30 group was significantly higher than CIT10 group (p<0.01) and was significantly higher in the CIT10+OMP group than that of the CIT10 group (p<0.01). In treatment groups, the increase in plasma citalopram level correlated positively with the increase in QT (r=0.844, r2=0.713). It was determined that CIT caused prolongation of QT interval, the addition of OMP increased QT interval more, and these increases correlated positively with CIT plasma concentration. Therefore, it would be appropriate to routinely measure CIT plasma levels in addition to ECG, particularly in patients with additional risk factors for QT prolongation.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the Citalopram levels on QTc Interval in Rats using with Radio-telemetry

HARMANCI¹,

TOPRAK²,

KALTUŞ³

et al. 2022

Osmangazi̇ Journal of Medicine

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Section: Discussionmentioning

confidence: 99%

“…Because Kv11.1/hERG channel is impaired in inherited or drug-induced acquired long QT syndrome, many hERG activators have been developed and some of those effectively exert antiarrhythmic action ( Su et al, 2021 ). However, the potential proarrhythmic risk of hERG channel activators still exists ( Su et al, 2021 ). Our synthetic PY peptide competitively inhibits the degradation of the Kv11.1 channel, which is over-activated because of higher expression of Nedd4-2 under pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological suppression of Nedd4-2 rescues the reduction of Kv11.1 channels in pathological cardiac hypertrophy

et al. 2022

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The human ether-á-go-go-related gene (hERG) encodes the pore-forming subunit (Kv11.1), conducting a rapidly delayed rectifier K+ current (IKr). Reduction of IKr in pathological cardiac hypertrophy (pCH) contributes to increased susceptibility to arrhythmias. However, practical approaches to prevent IKr deficiency are lacking. Our study investigated the involvement of ubiquitin ligase Nedd4-2-dependent ubiquitination in IKr reduction and sought an intervening approach in pCH. Angiotensin II (Ang II) induced a pCH phenotype in guinea pig, accompanied by increased incidences of sudden death and higher susceptibility to arrhythmias. Patch-clamp recordings revealed a significant IKr reduction in pCH cardiomyocytes. Kv11.1 protein expression was decreased whereas its mRNA level did not change. In addition, Nedd4-2 protein expression was increased in pCH, accompanied by an enhanced Nedd4-2 and Kv11.1 binding detected by immunoprecipitation analysis. Cardiac-specific overexpression of inactive form of Nedd4-2 shortened the prolonged QT interval, reversed IKr reduction, and decreased susceptibility to arrhythmias. A synthesized peptide containing the PY motif in Kv11.1 C-terminus binding to Nedd4-2 and a cell-penetrating sequence antagonized Nedd4-2-dependent degradation of the channel and increased the surface abundance and function of hERG channel in HEK cells. In addition, in vivo administration of the PY peptide shortened QT interval and action potential duration, and enhanced IKr in pCH. We conclude that Nedd4-2-dependent ubiquitination is critically involved in IKr deficiency in pCH. Pharmacological suppression of Nedd4-2 represents a novel approach for antiarrhythmic therapy in pCH.

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“…Several compounds have been identified as hERG activators that can be grouped into four classes depending on the action mechanism: class 1, slowed rate of channel deactivation; class 2, attenuation of inactivation; class 3, negative shift of the voltage dependence of activation; class 4, increase in channel open probability. However, in vivo tests showed that activators of class 2 and 3 have a proarrhythmic risk because they determine a too rapid repolarization of the cardiac action potential thus promoting short QT syndromes …”

Section: Introductionmentioning

confidence: 99%

“…However, in vivo tests showed that activators of class 2 and 3 have a proarrhythmic risk because they determine a too rapid repolarization of the cardiac action potential thus promoting short QT syndromes. 14 In this context, RPR260243 [(3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)prop-2-ynyl]-piperidine-3-carboxylic acid], hereafter RPR (Figure 1b), is the first compound that has been designed to enhance hERG activity without excessive abbreviation of the cardiac action potential. 15 It is an activator of class 1 because it significantly slows the rate of deactivation and slightly attenuates the inactivation (Figure 2).…”

Section: ■ Introductionmentioning

confidence: 99%

Integrated Approach Including Docking, MD Simulations, and Network Analysis Highlights the Action Mechanism of the Cardiac hERG Activator RPR260243

Costa

Ocello

Guardiani

et al. 2023

J. Chem. Inf. Model.

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hERG is a voltage-gated potassium channel involved in the heart contraction whose defections are associated with the cardiac arrhythmia Long QT Syndrome type 2. The activator RPR260243 (RPR) represents a possible candidate to pharmacologically treat LQTS2 because it enhances the opening of the channel. However, the molecular detail of its action mechanism remains quite elusive. Here, we address the problem using a combination of docking, molecular dynamics simulations, and network analysis. We show that the drug preferably binds at the interface between the voltage sensor and the pore, enhancing the canonical activation path and determining a whole-structure rearrangement of the channel that slightly impairs inactivation.

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Cardiac hERG K+ Channel as Safety and Pharmacological Target

Cited by 10 publications

References 179 publications

Evaluation of the Citalopram levels on QTc Interval in Rats using with Radio-telemetry

Evaluation of the Citalopram levels on QTc Interval in Rats using with Radio-telemetry

Pharmacological suppression of Nedd4-2 rescues the reduction of Kv11.1 channels in pathological cardiac hypertrophy

Integrated Approach Including Docking, MD Simulations, and Network Analysis Highlights the Action Mechanism of the Cardiac hERG Activator RPR260243

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