Late I(Na) in the Heart: Physiology, Pathology, and Pathways.

1 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 Ca 2+ /calmod-ulin-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 phosphoryla-tion 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 myo-cyte 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. 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 excit-ability 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 <0.5% of peak I Na , that flows throughout the AP plateau. Although the amplitude of late I Na is small, it plays a role in maintaining the AP plateau because competing repolarizing potassium currents are also small. Increased late I Na can directly affect cardiac electrophysiology by prolonging refractoriness and predisposing to triggered activity as early afterdepolarizations, observed clinically as long-QT arrhyth-mia. Because late I Na flows for much longer time than peak I Na (≈300–400 milliseconds for late I Na), it is predicted to play a greater role in Na + loading than peak I Na. 4 Increased Na + loading increases intracellular Ca 2+ levels through effects on Na +-Ca …