Fast inward Na current (I Na) carried by the voltage-gated Na channel (Na V1.5) is critical for action potential (AP) propagation and the rapid upstroke of the cardiac AP. In addition, a small fraction of Na V1.5 channels remains open throughout the plateau of the AP, and this current is termed as late I Na. In patients with mutant Na V1.5-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 V1.5 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. We measured AP-stimulated I Na through Na V1.5 wild-type and two LQT mutant channels (ΔKPQ 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. All three APs elicited both early and late I Na. For wild-type Na V1.5, 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 ΔKPQ mutant. The inherent gating properties of Na V1.5 provide natural tuning of optimal I Na density. Slower upstroke velocities can yield more I Na and Na flux in some Na V1.5 variants.
|Number of pages||11|
|State||Published - Dec 1 2004|
Bibliographical noteFunding Information:
This work was supported by NIH HL-63416, HL07491 (J.S.), and Hungarian Research Fund (OTKA-T043182). J.S. is an established investigator of the American Heart Association. hES work was supported by the Lady Davis Foundation (J.S.).
- Gene expression
- Human stem cell
- Long Q-T syndrome
- Na channel
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)