Repolarizing currents in ventricular myocytes from young patients with tetralogy of Fallot

Schäffer, Péter; Pelzmann, Brigitte; Bernhart, Eva; Lang, Petra; Mächler, Heinrich; Rigler, B; Koidl, Bernd

doi:10.1016/s0008-6363(99)00118-2

Cited by 15 publications

(24 citation statements)

References 56 publications

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“…Despite the fact that hERG is the predominant channel for human cardiac repolarization and its defects cause LQTS (1,4), an absence of I Kr in ventricular myocytes isolated from human tissues has been reported by Beuckelmann et al (48). Similarly, Schaffer et al (49) reported that I Kr was absent in 32 of 34 ventricular myo-cytes isolated from human tissue. As well, Konarzewska et al (50) reported that the delayed rectifier K ϩ current (I K ) was not measurable, but inward rectifier K ϩ current I K1 and transient outward K ϩ current I to were robust in human ventricular myocytes.…”

Section: Discussionmentioning

confidence: 97%

The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage

Lamothe

Guo

et al. 2016

Journal of Biological Chemistry

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The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Dysfunction of hERG causes long QT syndrome and sudden death, which occur in patients with cardiac ischemia. Cardiac ischemia is also associated with activation, up-regulation, and secretion of various proteolytic enzymes. Here, using whole-cell patch clamp and Western blotting analysis, we demonstrate that the hERG/IKr channel was selectively cleaved by the serine protease, proteinase K (PK). Using molecular biology techniques including making a chimeric channel between protease-sensitive hERG and insensitive human ether-a-go-go (hEAG), as well as application of the scorpion toxin BeKm-1, we identified that the S5-pore linker of hERG is the target domain for proteinase K cleavage. To investigate the physiological relevance of the unique susceptibility of hERG to proteases, we show that cardiac ischemia in a rabbit model was associated with a reduction in mature ERG expression and an increase in the expression of several proteases, including calpain. Using cell biology approaches, we found that calpain-1 was actively released into the extracellular milieu and cleaved hERG at the S5-pore linker. Using protease cleavage-predicting software and site-directed mutagenesis, we identified that calpain-1 cleaves hERG at position Gly-603 in the S5-pore linker of hERG. Clarification of protease-mediated damage of hERG extends our understanding of hERG regulation. Damage of hERG mediated by proteases such as calpain may contribute to ischemia-associated QT prolongation and sudden cardiac death.

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Section: Discussionmentioning

confidence: 97%

The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage

Lamothe

Guo

et al. 2016

Journal of Biological Chemistry

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“…Delayed rectifier K ϩ channel currents in human cardiac myocytes are reported to be of small amplitude and in some cases have not been detected (2,15,21,25,41,(45)(46), and most quantitative data have been obtained from animal and heterologous expression models. In our hiPSC-derived cardiomyocytes, the current density and activation properties for I Kr are close to values reported for human cardiac myocytes (9,20).…”

Section: Discussionmentioning

confidence: 99%

High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents

Guo

Fiene

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

684

771

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Human-induced pluripotent stem cells (hiPSCs) can differentiate into functional cardiomyocytes; however, the electrophysiological properties of hiPSC-derived cardiomyocytes have yet to be fully characterized. We performed detailed electrophysiological characterization of highly pure hiPSC-derived cardiomyocytes. Action potentials (APs) were recorded from spontaneously beating cardiomyocytes using a perforated patch method and had atrial-, nodal-, and ventricular-like properties. Ventricular-like APs were more common and had maximum diastolic potentials close to those of human cardiac myocytes, AP durations were within the range of the normal human electrocardiographic QT interval, and APs showed expected sensitivity to multiple drugs (tetrodotoxin, nifedipine, and E4031). Early afterdepolarizations (EADs) were induced with E4031 and were bradycardia dependent, and EAD peak voltage varied inversely with the EAD take-off potential. Gating properties of seven ionic currents were studied including sodium (I(Na)), L-type calcium (I(Ca)), hyperpolarization-activated pacemaker (I(f)), transient outward potassium (I(to)), inward rectifier potassium (I(K1)), and the rapidly and slowly activating components of delayed rectifier potassium (I(Kr) and I(Ks), respectively) current. The high purity and large cell numbers also enabled automated patch-clamp analysis. We conclude that these hiPSC-derived cardiomyocytes have ionic currents and channel gating properties underlying their APs and EADs that are quantitatively similar to those reported for human cardiac myocytes. These hiPSC-derived cardiomyocytes have the added advantage that they can be used in high-throughput assays, and they have the potential to impact multiple areas of cardiovascular research and therapeutic applications.

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“…There are some contradictory reports, although according to the majority of the previously published papers, it was assumed that the sex, cell location, and measurement temperature do not significantly influence the electric capacitance [16, 17]. Two studies describing age-capacitance correlation were based on the biological material derived from young individuals [18, 19]. Both of them describe non-healthy children diagnosed with the tetralogy of Fallot, which is connected with right ventricular hypertrophy [20, 21].…”

Section: Methodsmentioning

confidence: 99%

Inter-individual Variability in the Pre-clinical Drug Cardiotoxic Safety Assessment—Analysis of the Age–Cardiomyocytes Electric Capacitance Dependence

Polak

Fijorek

2012

J. of Cardiovasc. Trans. Res.

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Electrical phenomena located within the plasma membrane of the mammalian cardiac cells are connected with the cells’ main physiological functions—signals processing and contractility. They were extensively studied and described mathematically in so-called Hodgkin–Huxley paradigm. One of the physiological parameters, namely cell electric capacitance, has not been analyzed in-depth. The aim of the study was to validate the mechanistic model describing the capacitive properties of cells, based on a collected experimental dataset which describes the electric capacitance of human ventricular myocytes. The gathered data was further utilized for developing an empirical correlation between a healthy individual’s age and cardiomyocyte electric capacitance.

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Repolarizing currents in ventricular myocytes from young patients with tetralogy of Fallot

Cited by 15 publications

References 56 publications

The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage

The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage

High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents

Inter-individual Variability in the Pre-clinical Drug Cardiotoxic Safety Assessment—Analysis of the Age–Cardiomyocytes Electric Capacitance Dependence

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