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Cardiovascular Research 2004 64(3):477-487; doi:10.1016/j.cardiores.2004.07.014
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Divergent action potential morphologies reveal nonequilibrium properties of human cardiac Na channels

János Magyara, Carmen E. Kipera, Robert Dumaineb, Don E. Burgessa, Tamás Bányászc and Jonathan Satina,*

aDepartment of Physiology, MS 508, University of Kentucky College of Medicine, Lexington, KY 40536-0298, USA
bThe Masonic Medical Research Institute, Utica, NY, USA
cDepartment of Physiology, University Medical School of Debrecen, Hungary

* Corresponding author. Tel.: +1 859 323 5356; fax: +1 859 323 1070. Email address: jsatin1{at}uky.edu

Objective: Fast inward Na current (INa) carried by the voltage-gated Na channel (NaV1.5) is critical for action potential (AP) propagation and the rapid upstroke of the cardiac AP. In addition, a small fraction of NaV1.5 channels remains open throughout the plateau of the AP, and this current is termed as late INa. In patients with mutant NaV1.5-based congenital long Q–T (LQT) syndrome, mutant channels pass more late INa compared to wild-type channels in unaffected patients. Although LQT mutant NaV1.5 channels are well studied, there is no careful evaluation of the effects of cardiac APs on early and late current. This is important with the recent documentation of nonequilibrium INa.

Methods: We measured AP-stimulated INa through NaV1.5 wild-type and two LQT mutant channels ({Delta}KPQ and N1325S). Three distinct AP morphologies were used: human embryonic stem cell-derived cardiac myocyte (hES-CM) APs with a relatively slow upstroke and canine endocardial and epicardial ventricular myocytes with rapid upstrokes.

Results: All three APs elicited both early and late INa. For wild-type NaV1.5, the hES-CM AP elicits more early and late INa than either the endocardial or epicardial AP. The mechanism for this difference is that the hES-CM has a relative slow dV/dtmax that causes a maximal open channel probability. Slower upstroke stimulation also allows greater Na flux through wild-type and N1325S channels, but not the {Delta}KPQ mutant.

Conclusions: The inherent gating properties of NaV1.5 provide natural tuning of optimal INa density. Slower upstroke velocities can yield more INa and Na flux in some NaV1.5 variants.

KEYWORDS Na channel; Human stem cell; Gene expression; Long Q–T syndrome

Time for primary review 18 days


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