Expression of the IKr components KCNH2 (rERG) and KCNE2 (rMiRP1) during late rat heart development

Chun, K.R. Julian; Koenen, Michael; Katus, HA; Zehelein, Joerg

doi:10.1038/emm.2004.48

Cited by 30 publications

(11 citation statements)

References 15 publications

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“…Throughout rat heart development MiRP1 strongly co-localizes with rERG (Chun et al, 2004), consistent with our data here suggesting formation of MiRP1-rERG complexes in rat heart (Figure 1F). Further, in a canine model of cardiac disease, MiRP1 upregulation was recently shown to reduce I Kr (Jiang et al, 2004), as would be expected if the two co-assemble in canine heart, because MiRP1 lowers the unitary conductance of ERG (Abbott et al, 1999).…”

Section: Discussionsupporting

confidence: 91%

Regulation of the Kv2.1 Potassium Channel by MinK and MiRP1

et al. 2009

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Kv2.1 is a voltage-gated potassium (Kv) channel α subunit expressed in mammalian heart and brain. MinK-related peptides (MiRPs), encoded by KCNE genes, are single transmembrane domain ancillary subunits that form complexes with Kv channel α subunits to modify their function. Mutations in human MinK (KCNE1) and MiRP1 (KCNE2) are associated with inherited and acquired forms of long QT syndrome (LQTS). Here, co-immunoprecipitations from rat heart tissue suggested that both MinK and MiRP1 form native cardiac complexes with Kv2.1. In whole-cell voltage clamp studies of subunits expressed in CHO cells, rat MinK and MiRP1 reduced Kv2.1 current density 3- and 2-fold respectively, slowed Kv2.1 activation (at +60 mV) 2- and 3-fold respectively, and each slowed Kv2.1 deactivation <2-fold. Human MinK slowed Kv2.1 activation 25%, while human MiRP1 slowed Kv2.1 activation and deactivation 2-fold. Inherited mutations in human MinK and MiRP1, previously associated with LQTS, were also evaluated. D76N-MinK and S74L-MinK reduced Kv2.1 current density (3-fold and 40%, respectively) and slowed deactivation (60 and 80%, respectively). Compared to wild-type human MiRP1-Kv2.1 complexes, channels formed with M54T- or I57T-MiRP1 showed greatly slowed activation (10-fold and 5-fold, respectively). The data broaden the potential roles of MinK and MiRP1 in cardiac physiology and support the possibility that inherited mutations in either subunit could contribute to cardiac arrhythmia by multiple mechanisms.

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Section: Discussionsupporting

confidence: 91%

Regulation of the Kv2.1 Potassium Channel by MinK and MiRP1

et al. 2009

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“…In accordance with various in vivo and in vitro experimental data in fetal guinea pigs [20] rats [29,30], and mice [31], I Kr maximal conductance was greater than in the adult CMs and it decreased during maturation, we chose the specific expression ratios in order to mimick maximum diastolic potential (MDP) and the APD at the different developmental stages:…”

Section: Methodsmentioning

confidence: 99%

Mathematical modelling of the action potential of human embryonic stem cell derived cardiomyocytes

et al. 2012

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BackgroundHuman embryonic stem cell derived cardiomyocytes (hESC-CMs) hold high potential for basic and applied cardiovascular research. The development of a reliable simulation platform able to mimic the functional properties of hESC-CMs would be of considerable value to perform preliminary test complementing in vitro experimentations.MethodsWe developed the first computational model of hESC-CM action potential by integrating our original electrophysiological recordings of transient-outward, funny, and sodium-calcium exchanger currents and data derived from literature on sodium, calcium and potassium currents in hESC-CMs.ResultsThe model is able to reproduce basal electrophysiological properties of hESC-CMs at 15 40 days of differentiation (Early stage). Moreover, the model reproduces the modifications occurring through the transition from Early to Late developmental stage (50-110, days of differentiation). After simulated blockade of ionic channels and pumps of the sarcoplasmic reticulum, Ca2+ transient amplitude was decreased by 12% and 33% in Early and Late stage, respectively, suggesting a growing contribution of a functional reticulum during maturation. Finally, as a proof of concept, we tested the effects induced by prototypical channel blockers, namely E4031 and nickel, and their qualitative reproduction by the model.ConclusionsThis study provides a novel modelling tool that may serve useful to investigate physiological properties of hESC-CMs.

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“…In addition, in rat embryos, a and b subunits for the I Kr /hERG channel have been identified throughout the myocardium of the developing heart from GD 14.5 to 18.5, earlier stages were not examined (Chun et al, 2004).…”

Section: Potassium Channelsmentioning

confidence: 99%

The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

Abela

Ritchie

Ababneh

et al. 2010

Birth Defects Research Pt B

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This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.

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Expression of the IKr components KCNH2 (rERG) and KCNE2 (rMiRP1) during late rat heart development

Abstract: Abbreviations: cNBD, cyclic nucleotide binding domain; cTnI, cardiac specific troponin I; dpc, dies post conceptionem; ERG, ether a go-go-related gene; hERG, human ERG; IKr, rapidly activating component of the delayed rectifier K + current; IKs, slowly

Cited by 30 publications

References 15 publications

Regulation of the Kv2.1 Potassium Channel by MinK and MiRP1

Regulation of the Kv2.1 Potassium Channel by MinK and MiRP1

Mathematical modelling of the action potential of human embryonic stem cell derived cardiomyocytes

The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

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