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Heart Rhythm. 2020 Jan 2. pii: S1547-5271(19)31174-9. doi: 10.1016/j.hrthm.2019.12.019. [Epub ahead of print]

Distinct Calcium/CAlmodulin-dependent Serine protein Kinase domains control cardiac sodium channel membrane expression and focal adhesion anchoring.

Author information

1
INSERM UMRS1166, ICAN - Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France.
2
INSERM UMRS1166, ICAN - Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France; Institut de Cardiologie, Hôpital Pitié-Salpêtrière, Paris, France.
3
INSERM UMRS1166, ICAN - Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France. Electronic address: elise.balse@upmc.fr.

Abstract

BACKGROUND:

Membrane-associated guanylate kinase (MAGUK) proteins function as adaptor proteins to mediate the recruitment and scaffolding of ion channels in the plasma membrane in various cell types. In the heart, the protein CASK (Calcium/CAlmodulin-dependent Serine protein Kinase) negatively regulates the main cardiac sodium channel, NaV1.5, which carries the sodium current (INa) by preventing its anterograde trafficking. CASK is also a new member of the dystrophin-glycoprotein complex, and like syntrophin, binds to the C-terminal domain of the channel.

OBJECTIVE:

To unravel the mechanisms of CASK-mediated negative INa regulation, and interaction with the dystrophin-glycoprotein complex in cardiac myocytes.

METHODS:

CASK adenoviral truncated constructs with sequential single functional domain deletions were designed for overexpression in cardiac myocytes: CASKΔCAMKII, CASKΔL27A, CASKΔL27B, CASKΔPDZ, CASKΔSH3, CASKΔHOOK, and CASKΔGUK. Combination of whole-cell patch-clamp recording, total internal reflection fluorescence microscopy (TIRFm) and biochemistry experiments were conducted in cardiac myocytes to study the functional consequences of domain deletions.

RESULTS:

We show that both L27B and GUK domains are required for the negative regulatory effect of CASK on INa and NaV1.5 surface expression and that the HOOK domain is essential for interaction with the cell adhesion dystrophin-glycoprotein complex.

CONCLUSIONS:

This study demonstrates that the multi-modular structure of CASK confers an ability to simultaneously interact with several targets within cardiomyocytes. Through its L27B, GUK, and HOOK domains, CASK potentially provides the ability to control channel delivery at adhesion points in cardiomyocyte.

KEYWORDS:

CASK; MAGUK; cardiomyocyte; dystrophin; sodium channel

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