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Divergent action potential morphologies reveal nonequilibrium properties of human cardiac Na channels
János Magyar1, Carmen E Kiper, Robert Dumaine
1Department of Physiology, MS 508, University of Kentucky College of Medicine, Lexington, KY 40536-0298, USA.
Objective:
Fast inward Na current (I(Na)) carried by the voltage-gated Na channel (Na(V)1.5) is critical for action potential (AP) propagation and the rapid upstroke of the cardiac AP. In addition, a small fraction of Na(V)1.5 channels remains open throughout the plateau of the AP, and this current is termed as late I(Na). In patients with mutant Na(V)1.5-based congenital long Q-T (LQT) syndrome, mutant channels pass more late I(Na) compared to wild-type channels in unaffected patients. Although LQT mutant Na(V)1.5 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 I(Na).
Methods:
We measured AP-stimulated I(Na) through Na(V)1.5 wild-type and two LQT mutant channels (DeltaKPQ 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 I(Na). For wild-type Na(V)1.5, the hES-CM AP elicits more early and late I(Na) than either the endocardial or epicardial AP. The mechanism for this difference is that the hES-CM has a relative slow dV/dt(max) that causes a maximal open channel probability. Slower upstroke stimulation also allows greater Na flux through wild-type and N1325S channels, but not the DeltaKPQ mutant.
Conclusions:
The inherent gating properties of Na(V)1.5 provide natural tuning of optimal I(Na) density. Slower upstroke velocities can yield more I(Na) and Na flux in some Na(V)1.5 variants.
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