A Distinct Pool of Nav1.5 Channels at the Lateral Membrane of Murine Ventricular Cardiomyocytes

Rougier, Jean-Sébastien; Essers, Maria Cristina; Gillet, Ludovic; Guichard, Sabrina Lucienne Anny; Sonntag, Stephan; Shmerling, Doron; Abriel, Hugues (2019). A Distinct Pool of Nav1.5 Channels at the Lateral Membrane of Murine Ventricular Cardiomyocytes (In Press). Frontiers in physiology, 10(834) Frontiers Research Foundation 10.3389/fphys.2019.00834

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Background: In cardiac ventricular muscle cells, the presence of voltage-gated sodium channels Nav1.5 at the lateral membrane depends in part on the interaction between the dystrophin–syntrophin complex and the Nav1.5 C-terminal PDZ-domain-binding sequence Ser-Ile-Val (SIV motif). a1-Syntrophin, a PDZ-domain adaptor protein, mediates the interaction between Nav1.5 and dystrophin at the lateral membrane of cardiac cells. Using the cell-attached patch-clamp approach on cardiomyocytes expressing Nav1.5 in which the SIV motif is deleted (1SIV), sodium current (INa) recordings from the lateral membrane revealed a SIV-motif-independent INa. Since immunostaining has suggested that Nav1.5 is expressed in transverse (T-) tubules, this remaining INa might be carried by channels in the T-tubules. Of note, a recent study using heterologous expression systems showed that a1-syntrophin also interacts with the Nav1.5 N-terminus, which may explain the SIV-motif independent INa at the lateral membrane of cardiomyocytes. Aim: To address the role of a1-syntrophin in regulating the INa at the lateral membrane of cardiac cells. Methods and Results: Patch-clamp experiments in cell-attached configuration were performed on the lateral membranes of wild-type, a1-syntrophin knockdown, and 1SIV ventricular mouse cardiomyocytes. Compared to wild-type, a reduction of the lateral INa was observed in myocytes from a1-syntrophin knockdown hearts. Similar to 1SIV myocytes, a remaining INa was still recorded. In addition, cell-attached INa recordings from lateral membrane did not differ significantly between non-detubulated and detubulated 1SIV cardiomyocytes. Lastly, we obtained evidence suggesting that cell-attached patch-clamp experiments on the lateral membrane cannot record currents carried by channels in T-tubules such as calcium channels. Conclusion: Altogether, these results suggest the presence of a sub-pool of sodium channels at the lateral membrane of cardiomyocytes that is independent of a1-syntrophin and the PDZ-binding motif of Nav1.5, located in membrane domains outside of T-tubules. The question of a T-tubular pool of Nav1.5 channels, however, remains open.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Rougier, Jean-Sébastien; Essers, Maria Cristina; Guichard, Sabrina Lucienne Anny and Abriel, Hugues

Subjects:

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

ISSN:

1664-042X

Publisher:

Frontiers Research Foundation

Language:

English

Submitter:

Kevin Marc Rupp

Date Deposited:

07 Aug 2019 12:26

Last Modified:

22 Oct 2019 16:37

Publisher DOI:

10.3389/fphys.2019.00834

BORIS DOI:

10.7892/boris.132027

URI:

https://boris.unibe.ch/id/eprint/132027

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