Deletion of <i>Trpm4</i> Alters the Function of the Na<sub>v</sub>1.5 Channel in Murine Cardiac Myocytes
Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca<sup>2+</sup>-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in <i>TRPM4</i> have been reported in patients with inherited...
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/7/3401 |
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| author | Lijo Cherian Ozhathil Jean-Sébastien Rougier Prakash Arullampalam Maria C. Essers Daniela Ross-Kaschitza Hugues Abriel |
| author_facet | Lijo Cherian Ozhathil Jean-Sébastien Rougier Prakash Arullampalam Maria C. Essers Daniela Ross-Kaschitza Hugues Abriel |
| author_sort | Lijo Cherian Ozhathil |
| collection | DOAJ |
| description | Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca<sup>2+</sup>-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in <i>TRPM4</i> 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 <i>Trpm4</i> knockdown mouse models remain incompletely characterized. To study the functional consequences of <i>Trpm4</i> 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 <i>Trpm4</i> unexpectedly reduces the peak Na<sup>+</sup> currents in myocytes. Hearts from <i>Trpm4<sup>−/−</sup></i> mice presented increased sensitivity towards mexiletine, a Na<sup>+</sup> channel blocker, and slower intraventricular conduction, consistent with the reduction of the peak Na<sup>+</sup> current observed in the isolated cardiac myocytes. This study suggests that TRPM4 expression impacts the Na<sup>+</sup> current in murine cardiac myocytes and points towards a novel function of TRPM4 regulating the Na<sub>v</sub>1.5 function in murine cardiac myocytes. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:53:13Z |
| publishDate | 2021-03-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-62e02cdbd860450b9ff3aff5754c97842023-11-21T12:06:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01227340110.3390/ijms22073401Deletion of <i>Trpm4</i> Alters the Function of the Na<sub>v</sub>1.5 Channel in Murine Cardiac MyocytesLijo Cherian Ozhathil0Jean-Sébastien Rougier1Prakash Arullampalam2Maria C. Essers3Daniela Ross-Kaschitza4Hugues Abriel5Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandInstitute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, 3012 Bern, SwitzerlandTransient receptor potential melastatin member 4 (TRPM4) encodes a Ca<sup>2+</sup>-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in <i>TRPM4</i> 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 <i>Trpm4</i> knockdown mouse models remain incompletely characterized. To study the functional consequences of <i>Trpm4</i> 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 <i>Trpm4</i> unexpectedly reduces the peak Na<sup>+</sup> currents in myocytes. Hearts from <i>Trpm4<sup>−/−</sup></i> mice presented increased sensitivity towards mexiletine, a Na<sup>+</sup> channel blocker, and slower intraventricular conduction, consistent with the reduction of the peak Na<sup>+</sup> current observed in the isolated cardiac myocytes. This study suggests that TRPM4 expression impacts the Na<sup>+</sup> current in murine cardiac myocytes and points towards a novel function of TRPM4 regulating the Na<sub>v</sub>1.5 function in murine cardiac myocytes.https://www.mdpi.com/1422-0067/22/7/3401TRPM4SCN5Aintracardiac ECGmexiletinecardiac conduction disorderchannelosome |
| spellingShingle | Lijo Cherian Ozhathil Jean-Sébastien Rougier Prakash Arullampalam Maria C. Essers Daniela Ross-Kaschitza Hugues Abriel Deletion of <i>Trpm4</i> Alters the Function of the Na<sub>v</sub>1.5 Channel in Murine Cardiac Myocytes International Journal of Molecular Sciences TRPM4 SCN5A intracardiac ECG mexiletine cardiac conduction disorder channelosome |
| title | Deletion of <i>Trpm4</i> Alters the Function of the Na<sub>v</sub>1.5 Channel in Murine Cardiac Myocytes |
| title_full | Deletion of <i>Trpm4</i> Alters the Function of the Na<sub>v</sub>1.5 Channel in Murine Cardiac Myocytes |
| title_fullStr | Deletion of <i>Trpm4</i> Alters the Function of the Na<sub>v</sub>1.5 Channel in Murine Cardiac Myocytes |
| title_full_unstemmed | Deletion of <i>Trpm4</i> Alters the Function of the Na<sub>v</sub>1.5 Channel in Murine Cardiac Myocytes |
| title_short | Deletion of <i>Trpm4</i> Alters the Function of the Na<sub>v</sub>1.5 Channel in Murine Cardiac Myocytes |
| title_sort | deletion of i trpm4 i alters the function of the na sub v sub 1 5 channel in murine cardiac myocytes |
| topic | TRPM4 SCN5A intracardiac ECG mexiletine cardiac conduction disorder channelosome |
| url | https://www.mdpi.com/1422-0067/22/7/3401 |
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