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(Circulation Research. 2006;98:1538.)
© 2006 American Heart Association, Inc.

Cellular Biology

14-3-3 Is a Regulator of the Cardiac Voltage-Gated Sodium Channel Nav1.5

Marie Allouis^*, Françoise Le Bouffant^*, Ronald Wilders, David Péroz, Jean-Jacques Schott, Jacques Noireaud, Hervé Le Marec, Jean Mérot, Denis Escande, Isabelle Baró

From Inserm UMR 533 (M.A., F.L.B., D.P., J.-J.S., J.N., H.L.M., J.M., D.E., I.B.), Université de Nantes, Nantes Atlantique Universités, l’institut du thorax, Faculté de Médecine, France; and the Department of Physiology (R.W.), Academic Medical Center, University of Amsterdam, the Netherlands.

Correspondence to Isabelle Baró, Inserm UMR533, l’institut du thorax, Faculté de Médecine, 1, rue G. Veil, 44035 Nantes Cedex, France. E-mail isabelle.baro{at}nantes.inserm.fr

The voltage-sensitive Na⁺ channel Na_v1.5 plays a crucial role in generating and propagating the cardiac action potential and its dysfunction promotes cardiac arrhythmias. The channel takes part into a large molecular complex containing regulatory proteins. Thus, factors that modulate its biosynthesis, localization, activity, and/or degradation are of great interest from both a physiological and pathological standpoint. Using a yeast 2-hybrid screen, we unveiled a novel partner, 14-3-3, interacting with the Na_v1.5 cytoplasmic I interdomain. The interaction was confirmed by coimmunoprecipitation of 14-3-3 and full-length Na_v1.5 both in COS-7 cells expressing recombinant Na_v1.5 and in mouse cardiac myocytes. Using immunocytochemistry, we also found that 14-3-3 and Na_v1.5 colocalized at the intercalated discs. We tested the functional link between Na_v1.5 and 14-3-3 using the whole-cell patch-clamp configuration. Coexpressing Na_v1.5, the ß1 subunit and 14-3-3 induced a negative shift in the inactivation curve of the Na⁺ current, a delayed recovery from inactivation, but no changes in the activation curve or in the current density. The negative shift was reversed, and the recovery from inactivation was normalized by overexpressing the Na_v1.5 cytoplasmic I interdomain interacting with 14-3-3. Reversal was also obtained with the dominant negative R56,60A 14-3-3 mutant, suggesting that dimerization of 14-3-3 is needed for current regulation. Computer simulations suggest that the absence of 14-3-3 could exert proarrhythmic effects on cardiac electrical restitution properties. Based on these findings, we propose that the 14-3-3 protein is a novel component of the cardiac Na⁺ channel acting as a cofactor for the regulation of the cardiac Na⁺ current.

Key Words: Na⁺ channel • auxiliary subunit • congenital heart disease

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