Late INa in the Heart

In this issue of Circulation , Glynn and colleagues1 make an important contribution to our understanding of the physiological and pathophysiological roles of late sodium current ( I Na) in the heart, with a focus on a key pathways regulating late I Na amplitude. They conducted well-designed and detailed studies with 2 new genetically engineered mouse lines: an S571A mouse that ablates phosphorylation by Ca2+/calmodulin-dependent kinase II (CaMKII)2 selectively at serine 571 (S571) in the cardiac Na channel pore-forming protein Scn5a and an S571E mouse that mimics phosphorylation at S571. S571 was shown previously to be a target for phosphorylation by CaMKII, and this phosphorylation enhanced late I Na.2 The present studies in “knock-in” mice expressing either S571A or S571E have distinct advantages over earlier studies in heterologous expression systems, including cultured myocyte models, because they allow the study of whole-animal and organ phenotypes and cellular and molecular biophysical properties in a more native environment. These new in vivo studies reveal that, despite the extensive network of CaMKII targets, phosphorylation of S571 selectively regulates late I Na and, in particular, enhanced late I Na in failing heart. Article see p 567 Peak I Na is the large inward current flowing mainly through the cardiac Na+ channel pore formed by Scn5a, which is part of a larger sodium channel macromolecular complex. Members of this macromolecular complex act to localize the complex and to regulate I Na.3 With the onset of the action potential (AP) in the myocardium, the peak I Na rapidly rises and decays to nearly zero over several milliseconds. This I Na spike underlies excitability and conduction in working myocardium and the Purkinje conduction system. In contrast to peak I Na, late I Na is a small inward current, usually …