Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

Patel, Chinmay; Antzelevitch, Charles

doi:10.1016/j.hrthm.2008.01.022

Cited by 88 publications

(69 citation statements)

References 24 publications

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“…Hansen et al (2008) also reported that in vivo treatment of guinea pigs with NS3623 produced a reversal of E4031-induced prolongation of the QT interval. In the absence of pharmacologic blockade of hERG1, Patel and Antzelevitch (2008) reported that the hERG1 activator PD118057 abbreviated the QT interval but increased transmural dispersion of repolarization. This leads to polymorphic ventricular tachycardia induction in a canine wedge preparation (Patel and Antzelevitch, 2008).…”

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confidence: 99%

“…In the absence of pharmacologic blockade of hERG1, Patel and Antzelevitch (2008) reported that the hERG1 activator PD118057 abbreviated the QT interval but increased transmural dispersion of repolarization. This leads to polymorphic ventricular tachycardia induction in a canine wedge preparation (Patel and Antzelevitch, 2008). Thus, it is still uncertain whether hERG1 activators will be antiarrhythmic or prodysrhythmic.…”

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confidence: 99%

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Structure-Guided Topographic Mapping and Mutagenesis to Elucidate Binding Sites for the Human Ether-a-Go-Go-Related Gene 1 Potassium Channel (KCNH2) Activator NS1643

Durdağı¹,

Guo²,

Lees‐Miller³

et al. 2012

J Pharmacol Exp Ther

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Loss-of -function mutations in human ether-a-go-go-related gene 1 (hERG1) is associated with life-threatening arrhythmias. hERG1 activators are being developed as treatments for acquired or genetic forms of long QT syndrome. The locations of the putative binding pockets for activators are still being elucidated. In silico docking of the activator 1,3-bis-(2-hydroxy-5-trifluoromethylphenyl)-urea (NS1643) to an S1-S6 transmembrane homology model of hERG1 predicted putative binding sites. The predictions of the in silico docking guided subsequent in vitro mutagenesis and electrophysiological measurements. The novel interacting site for NS1643 is predicted around Asn629 at the outer mouth of the channel. The applied N629H mutation is the sole amino acid replacement in the literature that abrogates the NS1643-induced left shift of the V 1/2 of activation. In contrast, both N629T and N629D showed pharmacologic responses similar to wild type. Another important interacting pocket is predicted at the intracellular surface in the S4 -S5 linker. Mutagenesis of the residues critical to interactions in this pocket had major effects on the pharmacologic response to NS1643. The inward conductance elicited by hyperpolarization of D540K hERG1 was abrogated by NS1643 treatment, suggesting that it alters the inward movement of the S4 segment. The neighboring E544L mutation markedly exaggerated tail-current responses to NS1643. However, an L564A substitution inhibited drug response. Structure-guided mutagenesis identified widespread clusters of amino acids modulating drug-induced shifts in inactivation; such modulation may reflect allosteric changes in tertiary structure. Modelguided mutagenesis led to the discovery of a range of novel interacting residues that modify NS1643-induced pharmacologic responses.

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Section: Downloaded Frommentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

Structure-Guided Topographic Mapping and Mutagenesis to Elucidate Binding Sites for the Human Ether-a-Go-Go-Related Gene 1 Potassium Channel (KCNH2) Activator NS1643

Durdağı¹,

Guo²,

Lees‐Miller³

et al. 2012

J Pharmacol Exp Ther

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“…Augmented TDR as the basis for arrhythmogenesis in SQTS has been demonstrated in experimental models in which repolarization is abbreviated using the I Kr agonist, PD-118057, 28 thus mimicking the cellular conditions created by the genetic defect associated with SQT1. Dispersion of repolarization and refractoriness serve as substrates for reentry by promoting unidirectional block.…”

Section: Mechanism Of Arrhythmia In Sqtsmentioning

confidence: 99%

Management of Ventricular Arrhythmias in Suspected Channelopathies

Obeyesekere

Antzelevitch

Krahn

2015

Circ: Arrhythmia and Electrophysiology

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“…Insight into the effect of [73]. Subsequent use of an I Kr -activating compound (PD-118057) in experiments with the ventricular wedge preparation has shown QT interval shortening, increased TDR and ERP abbreviation and susceptibility to evoked arrhythmia [74].…”

Section: Mechanisms Of Arrhythmogenesismentioning

confidence: 99%

The Short QT Syndrome

Hancox

McPate

Harchi

et al. 2011

Heart Rate and Rhythm

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Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

Abstract: Background-Short QT syndrome (SQT) is a primary electrical disease associated with a high risk of sudden cardiac death. A gain-of-function in I Kr , due to a mutation in KCNH2, underlies SQT1.

Cited by 88 publications

References 24 publications

Structure-Guided Topographic Mapping and Mutagenesis to Elucidate Binding Sites for the Human Ether-a-Go-Go-Related Gene 1 Potassium Channel (KCNH2) Activator NS1643

Structure-Guided Topographic Mapping and Mutagenesis to Elucidate Binding Sites for the Human Ether-a-Go-Go-Related Gene 1 Potassium Channel (KCNH2) Activator NS1643

Management of Ventricular Arrhythmias in Suspected Channelopathies

The Short QT Syndrome

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