Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel

Hongkang Zhang, Beiyan Zou, Haibo Yu, Alessandra Moretti, Xiaoying Wang, Wei Yan, Joseph J. Babcock, Milena Bellin, Owen B. McManus, Gordon F. Tomaselli, Fajun Nan, Karl Ludwig Laugwitz, Min Li

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Long QT syndrome (LQTS) is a genetic disease characterized by a prolonged QT interval in an electrocardiogram (ECG), leading to higher risk of sudden cardiac death. Among the 12 identified genes causal to heritable LQTS, ∼90%of affected individuals harbor mutations in either KCNQ1 or human ether-a-go-go related genes (hERG), which encode two repolarizing potassium currents known as IKs and IKr. The ability to quantitatively assess contributions of different current components is therefore important for investigating disease phenotypes and testing effectiveness of pharmacological modulation. Here we report a quantitative analysis by simulating cardiac action potentials of cultured human cardiomyocytes to match the experimental waveforms of both healthy control and LQT syndrome type 1 (LQT1) action potentials. The quantitative evaluation suggests that elevation of I Kr by reducing voltage sensitivity of inactivation, not via slowing of deactivation, could more effectively restore normal QT duration if I Ks is reduced. Using a unique specific chemical activator for I Kr that has a primary effect of causing a right shift of V 1/2 for inactivation, we then examined the duration changes of autonomous action potentials from differentiated human cardiomyocytes. Indeed, this activator causes dose-dependent shortening of the action potential durations and is able to normalize action potentials of cells of patients with LQT1. In contrast, an IKr chemical activator of primary effects in slowing channel deactivation was not effective in modulating action potential durations. Our studies provide both the theoretical basis and experimental support for compensatory normalization of action potential duration by a pharmacological agent.

Original languageEnglish (US)
Pages (from-to)11866-11871
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number29
DOIs
StatePublished - Jul 17 2012
Externally publishedYes

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KCNQ1 Potassium Channel
Potassium Channels
Ether
Action Potentials
Genes
Long QT Syndrome
Cardiac Myocytes
Pharmacology
Inborn Genetic Diseases
Sudden Cardiac Death
Potassium
Electrocardiography
Phenotype
Mutation

Keywords

  • Drugs
  • Stem cells

ASJC Scopus subject areas

  • General

Cite this

Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel. / Zhang, Hongkang; Zou, Beiyan; Yu, Haibo; Moretti, Alessandra; Wang, Xiaoying; Yan, Wei; Babcock, Joseph J.; Bellin, Milena; McManus, Owen B.; Tomaselli, Gordon F.; Nan, Fajun; Laugwitz, Karl Ludwig; Li, Min.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 29, 17.07.2012, p. 11866-11871.

Research output: Contribution to journalArticle

Zhang, Hongkang ; Zou, Beiyan ; Yu, Haibo ; Moretti, Alessandra ; Wang, Xiaoying ; Yan, Wei ; Babcock, Joseph J. ; Bellin, Milena ; McManus, Owen B. ; Tomaselli, Gordon F. ; Nan, Fajun ; Laugwitz, Karl Ludwig ; Li, Min. / Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 29. pp. 11866-11871.
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AU - Zhang, Hongkang

AU - Zou, Beiyan

AU - Yu, Haibo

AU - Moretti, Alessandra

AU - Wang, Xiaoying

AU - Yan, Wei

AU - Babcock, Joseph J.

AU - Bellin, Milena

AU - McManus, Owen B.

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AU - Nan, Fajun

AU - Laugwitz, Karl Ludwig

AU - Li, Min

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AB - Long QT syndrome (LQTS) is a genetic disease characterized by a prolonged QT interval in an electrocardiogram (ECG), leading to higher risk of sudden cardiac death. Among the 12 identified genes causal to heritable LQTS, ∼90%of affected individuals harbor mutations in either KCNQ1 or human ether-a-go-go related genes (hERG), which encode two repolarizing potassium currents known as IKs and IKr. The ability to quantitatively assess contributions of different current components is therefore important for investigating disease phenotypes and testing effectiveness of pharmacological modulation. Here we report a quantitative analysis by simulating cardiac action potentials of cultured human cardiomyocytes to match the experimental waveforms of both healthy control and LQT syndrome type 1 (LQT1) action potentials. The quantitative evaluation suggests that elevation of I Kr by reducing voltage sensitivity of inactivation, not via slowing of deactivation, could more effectively restore normal QT duration if I Ks is reduced. Using a unique specific chemical activator for I Kr that has a primary effect of causing a right shift of V 1/2 for inactivation, we then examined the duration changes of autonomous action potentials from differentiated human cardiomyocytes. Indeed, this activator causes dose-dependent shortening of the action potential durations and is able to normalize action potentials of cells of patients with LQT1. In contrast, an IKr chemical activator of primary effects in slowing channel deactivation was not effective in modulating action potential durations. Our studies provide both the theoretical basis and experimental support for compensatory normalization of action potential duration by a pharmacological agent.

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