title: Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel.
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 I(Ks) and I(Kr). 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 I(Kr) 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.
authors: Department of Neuroscience, High Throughput Biology Center, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Hongkang
authors: H
authors: Zhang
authors: Beiyan
authors: B
authors: Zou
authors: Haibo
authors: H
authors: Yu
authors: Alessandra
authors: A
authors: Moretti
authors: Xiaoying
authors: X
authors: Wang
authors: Wei
authors: W
authors: Yan
authors: Joseph J
authors: JJ
authors: Babcock
authors: Milena
authors: M
authors: Bellin
authors: Owen B
authors: OB
authors: McManus
authors: Gordon
authors: G
authors: Tomaselli
authors: Fajun
authors: F
authors: Nan
authors: Karl-Ludwig
authors: KL
authors: Laugwitz
authors: Min
authors: M
authors: Li
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers / Q000235:genetics; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D051656:KCNQ Potassium Channels / Q000378:metabolism* / Q000502:physiology; D008133:Long QT Syndrome / Q000235:genetics* / Q000473:pathology; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000502:physiology; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D026941:Sodium Channel Blockers / Q000494:pharmacology
chemical_list: C000610702:2-(4-benzoylphenoxy)-N-(pyridin-3-yl)acetamide; D000081:Acetamides; D017931:DNA Primers; D051638:Ether-A-Go-Go Potassium Channels; D051656:KCNQ Potassium Channels; D011725:Pyridines; D026941:Sodium Channel Blockers