Copyright © 2006, European Society of Cardiology
Functional modulation of the transient outward current Ito by KCNE β-subunits and regional distribution in human non-failing and failing hearts
aMedical Faculty, Dresden University of Technology, Fetscherstr. 74, Dresden, 01307 Germany
bDivision of Cardiovascular Pharmacology, Hungarian Academy of Sciences, 6701 Hungary
cDepartment of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, Dom ter 12, Szeged, 6701 Hungary
dVirginia Commonwealth University, Department of Physiology-Box 980551, Richmond, Virginia 23298-055, USA
* Corresponding author. Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Fetscherstr. 74, Dresden, 01307 Germany. Tel.: +49 351 458 6278; fax: 49 351 458 6315. Email address: erich.wettwer{at}tu-dresden.de
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; Ventricular function; K-channel; Membrane currents
Time for primary review 21 days
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