Deletion of Trpm4 Alters the Function of the Nav1.5 Channel in Murine Cardiac Myocytes.

Ozhathil, Lijo Cherian; Rougier, Jean-Sébastien; Arullampalam, Prakash; Essers, Maria C.; Ross-Kaschitza, Daniela; Abriel, Hugues (2021). Deletion of Trpm4 Alters the Function of the Nav1.5 Channel in Murine Cardiac Myocytes. International journal of molecular sciences, 22(7) MDPI 10.3390/ijms22073401

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Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca2+-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases, including conduction blockage and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunoblotting studies on isolated atrial and ventricular cardiac myocytes and surfaces, as well as on pseudo- and intracardiac ECGs, either in vivo or in Langendorff-perfused explanted mouse hearts. We observed that TRPM4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na+ currents in myocytes. Hearts from Trpm4-/- mice presented increased sensitivity towards mexiletine, a Na+ channel blocker, and slower intraventricular conduction, consistent with the reduction of the peak Na+ current observed in the isolated cardiac myocytes. This study suggests that TRPM4 expression impacts the Na+ current in murine cardiac myocytes and points towards a novel function of TRPM4 regulating the Nav1.5 function in murine cardiac myocytes.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Ozhathil, Lijo Cherian; Rougier, Jean-Sébastien; Arullampalam, Prakash; Essers, Maria Cristina; Ross, Daniela and Abriel, Hugues

Subjects:

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

ISSN:

1422-0067

Publisher:

MDPI

Language:

English

Submitter:

Kevin Marc Rupp

Date Deposited:

06 May 2021 11:34

Last Modified:

06 May 2021 11:34

Publisher DOI:

10.3390/ijms22073401

PubMed ID:

33810249

Uncontrolled Keywords:

SCN5A TRPM4 cardiac conduction disorder channelosome intracardiac ECG mexiletine

BORIS DOI:

10.48350/155671

URI:

https://boris.unibe.ch/id/eprint/155671

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