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

Shy, Diana Amy; Gillet, Ludovic; Ogrodnik, Jakob; Albesa, Maxime; Verkerk, Arie O; Wolswinkel, Rianne; Rougier, Jean-Sébastien; Barc, Julien; Essers, Maria Cristina; Syam, Ninda Ratna Maharani; Marsman, Roos F; van Mil, Anneke M; Rotman, Samuel; Redon, Richard; Bezzina, Connie R; Remme, Carol Ann; Abriel, Hugues (2014). PDZ domain-binding motif regulates cardiomyocyte compartment-specific NaV1.5 channel expression and function. Circulation, 130(2), pp. 147-160. Lippincott Williams & Wilkins 10.1161/CIRCULATIONAHA.113.007852

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Shy, Diana Amy; Gillet, Ludovic; Ogrodnik, Jakob; Albesa, Maxime; Rougier, Jean-Sébastien; Essers, Maria Cristina; Syam, Ninda Ratna Maharani and Abriel, Hugues

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0009-7322

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Verena de Serra Frazao-Bill

Date Deposited:

13 Mar 2015 10:26

Last Modified:

02 Nov 2015 11:02

Publisher DOI:

10.1161/CIRCULATIONAHA.113.007852

PubMed ID:

24895455

Uncontrolled Keywords:

dystrophin sodium channels syntrophin

BORIS DOI:

10.7892/boris.64457

URI:

https://boris.unibe.ch/id/eprint/64457

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