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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2014
Author Shy Diana, Gillet Ludovic, Ogrodnik Jakob, Albesa Maxime, Verkerk Arie O, Wolswinkel Rianne, Rougier Jean-Sébastien, Barc Julien, Essers Maria C, Syam Ninda, Marsman Roos F, van Mil Anneke M, Rotman Samuel, Redon Richard, Bezzina Connie R, Remme Carol Ann, Abriel Hugues,
Project In vivo relevance of the PY and PDZ-domain binding motifs of the cardiac sodium channel Nav1.5
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Original article (peer-reviewed)

Journal Circulation
Volume (Issue) 130(2)
Page(s) 147 - 60
Title of proceedings Circulation
DOI 10.1161/CIRCULATIONAHA.113.007852


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. 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. 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.