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

Details

Serval ID
serval:BIB_E2B37847F5D4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PDZ domain-binding motif regulates cardiomyocyte compartment-specific NaV1.5 channel expression and function.
Journal
Circulation
Author(s)
Shy D., Gillet L., Ogrodnik J., Albesa M., Verkerk A.O., Wolswinkel R., Rougier J.S., Barc J., Essers M.C., Syam N., Marsman R.F., van Mil A.M., Rotman S., Redon R., Bezzina C.R., Remme C.A., Abriel H.
ISSN
1524-4539 (Electronic)
ISSN-L
0009-7322
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
130
Number
2
Pages
147-160
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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
Animals, Gene Expression Regulation, Gene Knock-In Techniques, HEK293 Cells, Humans, Mice, Myocytes, Cardiac/metabolism, NAV1.5 Voltage-Gated Sodium Channel/biosynthesis, NAV1.5 Voltage-Gated Sodium Channel/physiology, PDZ Domains/physiology, Protein Interaction Domains and Motifs/physiology
Pubmed
Web of science
Open Access
Yes
Create date
08/08/2014 18:01
Last modification date
20/08/2019 16:06
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