Lateral Membrane-Specific MAGUK CASK Down-Regulates NaV1.5 Channel in Cardiac Myocytes.

Eichel, Catherine A; Beuriot, Adeline; Chevalier, Morgan Yoann Edwin; Rougier, Jean-Sébastien; Louault, Florent; Dilanian, Gilles; Amour, Julien; Coulombe, Alain; Abriel, Hugues; Hatem, Stéphane N; Balse, Elise (2016). Lateral Membrane-Specific MAGUK CASK Down-Regulates NaV1.5 Channel in Cardiac Myocytes. Circulation research, 119(4), pp. 544-556. Lippincott Williams & Wilkins 10.1161/CIRCRESAHA.116.309254

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RATIONALE Mechanisms underlying membrane protein localization are crucial in the proper function of cardiac myocytes. The main cardiac sodium channel, NaV1.5, carries the sodium current (INa) that provides a rapid depolarizing current during the upstroke of the action potential. Although enriched in the intercalated disc, NaV1.5 is present in different membrane domains in myocytes and interacts with several partners. OBJECTIVE To test the hypothesis that the MAGUK (membrane-associated guanylate kinase) protein CASK (calcium/calmodulin-dependent serine protein kinase) interacts with and regulates NaV1.5 in cardiac myocytes. METHODS AND RESULTS Immunostaining experiments showed that CASK localizes at lateral membranes of cardiac myocytes, in association with dystrophin. Whole-cell patch clamp showed that CASK-silencing increases INa in vitro. In vivo CASK knockdown similarly increased INa recorded in freshly isolated myocytes. Pull-down experiments revealed that CASK directly interacts with the C-terminus of NaV1.5. CASK silencing reduces syntrophin expression without affecting NaV1.5 and dystrophin expression levels. Total Internal Reflection Fluorescence microscopy and biotinylation assays showed that CASK silencing increased the surface expression of NaV1.5 without changing mRNA levels. Quantification of NaV1.5 expression at the lateral membrane and intercalated disc revealed that the lateral membrane pool only was increased upon CASK silencing. The protein transport inhibitor brefeldin-A prevented INa increase in CASK-silenced myocytes. During atrial dilation/remodeling, CASK expression was reduced but its localization remained unchanged. CONCLUSION This study constitutes the first description of an unconventional MAGUK protein, CASK, which directly interacts with NaV1.5 channel and controls its surface expression at the lateral membrane by regulating ion channel trafficking.

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

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Chevalier, Morgan Yoann Edwin; Rougier, Jean-Sébastien and Abriel, Hugues

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0009-7330

Publisher:

Lippincott Williams & Wilkins

Funders:

[UNSPECIFIED] Fondation Leducq
[UNSPECIFIED] European Union
[UNSPECIFIED] AFM-Telethon
[UNSPECIFIED] Swiss National Science Foundation

Language:

English

Submitter:

Peggy Kübler

Date Deposited:

18 Apr 2017 08:59

Last Modified:

04 Jun 2018 14:03

Publisher DOI:

10.1161/CIRCRESAHA.116.309254

PubMed ID:

27364017

Uncontrolled Keywords:

calcium/calmodulin-dependent serine protein kinase; cardiac myocytes; dystrophin; ion channels; membrane-associated guanylate kinase; sodium channels; syntrophin

BORIS DOI:

10.7892/boris.94308

URI:

https://boris.unibe.ch/id/eprint/94308

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