Late INa in the Heart: Physiology, Pathology, and Pathways
In this issue of Circulation, Hund and colleagues1 make an important contribution to understanding the physiological and pathophysiological roles of late sodium current (INa) in the heart, with a focus on a key pathway regulating late INa amplitude. They conducted well designed and detailed studies with two new genetically engineered mouse lines: one a S571A mouse that ablates phosphorylation by Ca2+/calmodulin-dependent kinase II (CaMKII)2 selectively at serine 571 in the cardiac Na channel pore-forming protein Scn5a, and the other a S571E mouse that mimics phosphorylation at serine 571. Serine 571 was shown previously to be a target for phosphorylation by CaMKII and this phosphorylation enhanced late INa2. The present studies in "knock-in" mice expressing either S571A or S571E have distinct advantages over other earlier studies in heterologous expression systems including cultured myocyte models because they allow the study of whole animal and organ phenotypes, as well as the study of cellular and molecular biophysical properties in a more native environment. What these new in vivo studies reveal is that despite the extensive network of CaMKII targets, phosphorylation of S571 selectively regulates late INa and in particular enhanced late INa in failing heart.
- sodium current
- long QT syndrome
- calcium/calmodulin-dependent protein kinase II
- Received July 15, 2015.
- Accepted July 15, 2015.