Functional modulation of the transient outward current Ito by KCNE β-subunits and regional distribution in human non-failing and failing hearts

Susanne Radicke, Diego Cotella, Eva Maria Graf, Ulrich Banse, N. Jost, A. Varró, Gea Ny Tseng, Ursula Ravens, Erich Wettwer

Research output: Article

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Abstract

Objectives: The function of Kv4.3 (KCND3) channels, which underlie the transient outward current Ito in human heart, can be modulated by several accessory subunits such as KChIP2 and KCNE1-KCNE5. Here we aimed to determine the regional expression of Kv4.3, KChIP2, and KCNE mRNAs in non-failing and failing human hearts and to investigate the functional consequences of subunit coexpression in heterologous expression systems. Methods: We quantified mRNA levels for two Kv4.3 isoforms, Kv4.3-S and Kv4.3-L, and for KChIP2 as well as KCNE1-KCNE5 with real-time RT-PCR. We also studied the effects of KCNEs on Kv4.3 + KChIP2 current characteristics in CHO cells with the whole-cell voltage-clamp method. Results: In non-failing hearts, low expression was found for KCNE1, KCNE3, and KCNE5, three times higher expression for KCNE2, and 60 times higher for KCNE4. Transmural gradients were detected only for KChIP2 in left and right ventricles. Compared to non-failing tissue, failing hearts showed higher expression of Kv4.3-L and KCNE1 and lower of Kv4.3-S, KChIP2, KCNE4, and KCNE5. In CHO cells, Kv4.3 + KChIP2 currents were differentially modified by co-expressed KCNEs: time constants of inactivation were shorter with KCNE1 and KCNE3-5 while time-to-peak was decreased, and V0.5 of steady-state inactivation was shifted to more negative potentials by all KCNE subunits. Importantly, KCNE2 induced a unique and prominent 'overshoot' of peak current during recovery from inactivation similar to that described for human Ito while other KCNE subunits induced little (KCNE4,5) or no overshoot. Conclusions: All KCNEs are expressed in the human heart at the transcript level. Compared to Ito in native human myocytes, none of the combination of KChIP2 and KCNE produced an ideal congruency in current characteristics, suggesting that additional factors contribute to the regulation of the native Ito channel.

Original languageEnglish
Pages (from-to)695-703
Number of pages9
JournalCardiovascular Research
Volume71
Issue number4
DOIs
Publication statusPublished - szept. 1 2006

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CHO Cells
Heart Ventricles
Messenger RNA
Population Groups
Muscle Cells
Real-Time Polymerase Chain Reaction
Protein Isoforms

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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Functional modulation of the transient outward current Ito by KCNE β-subunits and regional distribution in human non-failing and failing hearts. / Radicke, Susanne; Cotella, Diego; Graf, Eva Maria; Banse, Ulrich; Jost, N.; Varró, A.; Tseng, Gea Ny; Ravens, Ursula; Wettwer, Erich.

In: Cardiovascular Research, Vol. 71, No. 4, 01.09.2006, p. 695-703.

Research output: Article

Radicke, Susanne ; Cotella, Diego ; Graf, Eva Maria ; Banse, Ulrich ; Jost, N. ; Varró, A. ; Tseng, Gea Ny ; Ravens, Ursula ; Wettwer, Erich. / Functional modulation of the transient outward current Ito by KCNE β-subunits and regional distribution in human non-failing and failing hearts. In: Cardiovascular Research. 2006 ; Vol. 71, No. 4. pp. 695-703.
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abstract = "Objectives: The function of Kv4.3 (KCND3) channels, which underlie the transient outward current Ito in human heart, can be modulated by several accessory subunits such as KChIP2 and KCNE1-KCNE5. Here we aimed to determine the regional expression of Kv4.3, KChIP2, and KCNE mRNAs in non-failing and failing human hearts and to investigate the functional consequences of subunit coexpression in heterologous expression systems. Methods: We quantified mRNA levels for two Kv4.3 isoforms, Kv4.3-S and Kv4.3-L, and for KChIP2 as well as KCNE1-KCNE5 with real-time RT-PCR. We also studied the effects of KCNEs on Kv4.3 + KChIP2 current characteristics in CHO cells with the whole-cell voltage-clamp method. Results: In non-failing hearts, low expression was found for KCNE1, KCNE3, and KCNE5, three times higher expression for KCNE2, and 60 times higher for KCNE4. Transmural gradients were detected only for KChIP2 in left and right ventricles. Compared to non-failing tissue, failing hearts showed higher expression of Kv4.3-L and KCNE1 and lower of Kv4.3-S, KChIP2, KCNE4, and KCNE5. In CHO cells, Kv4.3 + KChIP2 currents were differentially modified by co-expressed KCNEs: time constants of inactivation were shorter with KCNE1 and KCNE3-5 while time-to-peak was decreased, and V0.5 of steady-state inactivation was shifted to more negative potentials by all KCNE subunits. Importantly, KCNE2 induced a unique and prominent 'overshoot' of peak current during recovery from inactivation similar to that described for human Ito while other KCNE subunits induced little (KCNE4,5) or no overshoot. Conclusions: All KCNEs are expressed in the human heart at the transcript level. Compared to Ito in native human myocytes, none of the combination of KChIP2 and KCNE produced an ideal congruency in current characteristics, suggesting that additional factors contribute to the regulation of the native Ito channel.",
keywords = "Gene expression, Heart failure, K-channel, Membrane currents, Ventricular function",
author = "Susanne Radicke and Diego Cotella and Graf, {Eva Maria} and Ulrich Banse and N. Jost and A. Varr{\'o} and Tseng, {Gea Ny} and Ursula Ravens and Erich Wettwer",
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T1 - Functional modulation of the transient outward current Ito by KCNE β-subunits and regional distribution in human non-failing and failing hearts

AU - Radicke, Susanne

AU - Cotella, Diego

AU - Graf, Eva Maria

AU - Banse, Ulrich

AU - Jost, N.

AU - Varró, A.

AU - Tseng, Gea Ny

AU - Ravens, Ursula

AU - Wettwer, Erich

PY - 2006/9/1

Y1 - 2006/9/1

N2 - Objectives: The function of Kv4.3 (KCND3) channels, which underlie the transient outward current Ito in human heart, can be modulated by several accessory subunits such as KChIP2 and KCNE1-KCNE5. Here we aimed to determine the regional expression of Kv4.3, KChIP2, and KCNE mRNAs in non-failing and failing human hearts and to investigate the functional consequences of subunit coexpression in heterologous expression systems. Methods: We quantified mRNA levels for two Kv4.3 isoforms, Kv4.3-S and Kv4.3-L, and for KChIP2 as well as KCNE1-KCNE5 with real-time RT-PCR. We also studied the effects of KCNEs on Kv4.3 + KChIP2 current characteristics in CHO cells with the whole-cell voltage-clamp method. Results: In non-failing hearts, low expression was found for KCNE1, KCNE3, and KCNE5, three times higher expression for KCNE2, and 60 times higher for KCNE4. Transmural gradients were detected only for KChIP2 in left and right ventricles. Compared to non-failing tissue, failing hearts showed higher expression of Kv4.3-L and KCNE1 and lower of Kv4.3-S, KChIP2, KCNE4, and KCNE5. In CHO cells, Kv4.3 + KChIP2 currents were differentially modified by co-expressed KCNEs: time constants of inactivation were shorter with KCNE1 and KCNE3-5 while time-to-peak was decreased, and V0.5 of steady-state inactivation was shifted to more negative potentials by all KCNE subunits. Importantly, KCNE2 induced a unique and prominent 'overshoot' of peak current during recovery from inactivation similar to that described for human Ito while other KCNE subunits induced little (KCNE4,5) or no overshoot. Conclusions: All KCNEs are expressed in the human heart at the transcript level. Compared to Ito in native human myocytes, none of the combination of KChIP2 and KCNE produced an ideal congruency in current characteristics, suggesting that additional factors contribute to the regulation of the native Ito channel.

AB - Objectives: The function of Kv4.3 (KCND3) channels, which underlie the transient outward current Ito in human heart, can be modulated by several accessory subunits such as KChIP2 and KCNE1-KCNE5. Here we aimed to determine the regional expression of Kv4.3, KChIP2, and KCNE mRNAs in non-failing and failing human hearts and to investigate the functional consequences of subunit coexpression in heterologous expression systems. Methods: We quantified mRNA levels for two Kv4.3 isoforms, Kv4.3-S and Kv4.3-L, and for KChIP2 as well as KCNE1-KCNE5 with real-time RT-PCR. We also studied the effects of KCNEs on Kv4.3 + KChIP2 current characteristics in CHO cells with the whole-cell voltage-clamp method. Results: In non-failing hearts, low expression was found for KCNE1, KCNE3, and KCNE5, three times higher expression for KCNE2, and 60 times higher for KCNE4. Transmural gradients were detected only for KChIP2 in left and right ventricles. Compared to non-failing tissue, failing hearts showed higher expression of Kv4.3-L and KCNE1 and lower of Kv4.3-S, KChIP2, KCNE4, and KCNE5. In CHO cells, Kv4.3 + KChIP2 currents were differentially modified by co-expressed KCNEs: time constants of inactivation were shorter with KCNE1 and KCNE3-5 while time-to-peak was decreased, and V0.5 of steady-state inactivation was shifted to more negative potentials by all KCNE subunits. Importantly, KCNE2 induced a unique and prominent 'overshoot' of peak current during recovery from inactivation similar to that described for human Ito while other KCNE subunits induced little (KCNE4,5) or no overshoot. Conclusions: All KCNEs are expressed in the human heart at the transcript level. Compared to Ito in native human myocytes, none of the combination of KChIP2 and KCNE produced an ideal congruency in current characteristics, suggesting that additional factors contribute to the regulation of the native Ito channel.

KW - Gene expression

KW - Heart failure

KW - K-channel

KW - Membrane currents

KW - Ventricular function

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