PDZ Domain–Binding Motif Regulates Cardiomyocyte Compartment-Specific Na V 1.5 Channel Expression and Function

作者：Diana Shy, Ludovic Gillet, Jakob Ogrodnik, Maxime Albesa, Arie O. Verkerk, Rianne Wolswinkel, Jean‐Sébastien Rougier, Julien Barc, Maria C. Essers, Ninda Syam, Roos F. Marsman, Anneke M. van Mil, Samuel Rotman, Richard Redon, Connie R. Bezzina, Carol Ann Remme, Hugues Abriel · 发表于：Circulation · 年份：2014 · DOI：10.1161/circulationaha.113.007852 · 被引用次数：122 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、Ion Channels and Receptors

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 s...