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Circulation. 2014 Jul 8;130(2):147-60. doi: 10.1161/CIRCULATIONAHA.113.007852. Epub 2014 Jun 3.

PDZ domain-binding motif regulates cardiomyocyte compartment-specific NaV1.5 channel expression and function.

Author information

1
From the Department of Clinical Research, University of Bern, Bern, Switzerland (D.S., L.G., J.O., M.A., J.-S.R., M.C.E., N.S., H.A.); Department of Anatomy, Embryology and Physiology (A.O.V.) and Department of Clinical and Experimental Cardiology (R.W., J.B., R.F.M., C.R.B., C.A.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.B.); Center for Human and Clinical Genetics, Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands (A.M.v.M.); Institute of Pathology, University of Lausanne, Lausanne, Switzerland (S.R.); Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 1087, L'Institut du Thorax, Nantes, France (R.R.); Centre National de la Recherche Scientifique Unité Mixte de Recherche 6291, Nantes, France (R.R.); Université de Nantes, Nantes, France (R.R.); and Centre Hospitalier Universitaire Nantes, L'Institut du Thorax, Service de Cardiologie, Nantes, France (R.R.).
2
From the Department of Clinical Research, University of Bern, Bern, Switzerland (D.S., L.G., J.O., M.A., J.-S.R., M.C.E., N.S., H.A.); Department of Anatomy, Embryology and Physiology (A.O.V.) and Department of Clinical and Experimental Cardiology (R.W., J.B., R.F.M., C.R.B., C.A.R.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.B.); Center for Human and Clinical Genetics, Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands (A.M.v.M.); Institute of Pathology, University of Lausanne, Lausanne, Switzerland (S.R.); Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche 1087, L'Institut du Thorax, Nantes, France (R.R.); Centre National de la Recherche Scientifique Unité Mixte de Recherche 6291, Nantes, France (R.R.); Université de Nantes, Nantes, France (R.R.); and Centre Hospitalier Universitaire Nantes, L'Institut du Thorax, Service de Cardiologie, Nantes, France (R.R.). Hugues.Abriel@dkf.unibe.ch.

Abstract

BACKGROUND:

Sodium channel NaV1.5 underlies cardiac excitability and conduction. The last 3 residues of NaV1.5 (Ser-Ile-Val) constitute a PDZ domain-binding motif that interacts with PDZ proteins such as syntrophins and SAP97 at different locations within the cardiomyocyte, thus defining distinct pools of NaV1.5 multiprotein complexes. Here, we explored the in vivo and clinical impact of this motif through characterization of mutant mice and genetic screening of patients.

METHODS AND RESULTS:

To investigate in vivo the regulatory role of this motif, we generated knock-in mice lacking the SIV domain (ΔSIV). ΔSIV mice displayed reduced NaV1.5 expression and sodium current (INa), specifically at the lateral myocyte membrane, whereas NaV1.5 expression and INa at the intercalated disks were unaffected. Optical mapping of ΔSIV hearts revealed that ventricular conduction velocity was preferentially decreased in the transversal direction to myocardial fiber orientation, leading to increased anisotropy of ventricular conduction. Internalization of wild-type and ΔSIV channels was unchanged in HEK293 cells. However, the proteasome inhibitor MG132 rescued ΔSIV INa, suggesting that the SIV motif is important for regulation of NaV1.5 degradation. A missense mutation within the SIV motif (p.V2016M) was identified in a patient with Brugada syndrome. The mutation decreased NaV1.5 cell surface expression and INa when expressed in HEK293 cells.

CONCLUSIONS:

Our results demonstrate the in vivo significance of the PDZ domain-binding motif in the correct expression of NaV1.5 at the lateral cardiomyocyte membrane and underline the functional role of lateral NaV1.5 in ventricular conduction. Furthermore, we reveal a clinical relevance of the SIV motif in cardiac disease.

KEYWORDS:

dystrophin; sodium channels; syntrophin

[Indexed for MEDLINE]

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