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(Circulation Research. 2006;99:407.)
© 2006 American Heart Association, Inc.

Cellular Biology

Cardiac Sodium Channel Na_v1.5 Is Regulated by a Multiprotein Complex Composed of Syntrophins and Dystrophin

Bruno Gavillet, Jean-Sébastien Rougier, Andrea A. Domenighetti, Romina Behar, Christophe Boixel, Patrick Ruchat, Hans-Anton Lehr, Thierry Pedrazzini, Hugues Abriel

From the Department of Pharmacology and Toxicology (B.G., J.-S.R., R.B., C.B., H.A.), University of Lausanne, Switzerland; Service of Cardiology (H.A.), CHUV, Lausanne, Switzerland; Department for Cardiovascular Surgery (P.R.), CHUV, Lausanne, Switzerland; Institute of Pathology (H.-A.L.), CHUV, Lausanne, Switzerland; Deparment of Medicine (A.A.D., T.P.), CHUV, Lausanne, Switzerland.

Correspondence to H. Abriel, MD, PhD, SNF-Professor, Department of Pharmacology and Toxicology, Service of Cardiology, University of Lausanne, Bugnon, 27, 1005 Lausanne, Switzerland. E-mail Hugues.Abriel{at}unil.ch

The cardiac sodium channel Na_v1.5 plays a key role in cardiac excitability and conduction. The purpose of this study was to elucidate the role of the PDZ domain-binding motif formed by the last three residues (Ser-Ile-Val) of the Na_v1.5 C-terminus. Pull-down experiments were performed using Na_v1.5 C-terminus fusion proteins and human or mouse heart protein extracts, combined with mass spectrometry analysis. These experiments revealed that the C-terminus associates with dystrophin, and that this interaction was mediated by alpha- and beta-syntrophin proteins. Truncation of the PDZ domain-binding motif abolished the interaction. We used dystrophin-deficient mdx^5cv mice to study the role of this protein complex in Na_v1.5 function. Western blot experiments revealed a 50% decrease in the Na_v1.5 protein levels in mdx^5cv hearts, whereas Na_v1.5 mRNA levels were unchanged. Patch-clamp experiments showed a 29% decrease of sodium current in isolated mdx^5cv cardiomyocytes. Finally, ECG measurements of the mdx^5cv mice exhibited a 19% reduction in the P wave amplitude, and an 18% increase of the QRS complex duration, compared with controls. These results indicate that the dystrophin protein complex is required for the proper expression and function of Na_v1.5. In the absence of dystrophin, decreased sodium current may explain the alterations in cardiac conduction observed in patients with dystrophinopathies.

Key Words: Duchenne dystrophy • dystrophin • ECG • mouse • sodium channels • syntrophin

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