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Increased β-adrenergic inotropy in ventricular myocardium from Trpm4−/− mice

Rationale:The Trpm4 gene has recently been associated with several disorders, including cardiac conduction diseases and Brugada syndrome. Transient receptor potential member 4 (TRPM4) proteins constitute Ca2+-activated, but Ca2+-impermeable, nonselective cation channels and are expressed both in atr...

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Main Authors: Mathar, Ilka (Author) , Kecskes, Miklos (Author) , Van der Mieren, Gerry (Author) , Jacobs, Griet (Author) , Camacho Londoño, Juan Eduardo (Author) , Uhl, Sebastian (Author) , Flockerzi, Veit (Author) , Voets, Thomas (Author) , Freichel, Marc (Author) , Nilius, Bernd (Author) , Herijgers, Paul (Author) , Vennekens, Rudi (Author)
Format: Article (Journal)
Language:English
Published: 2014
In: Circulation research
Year: 2013, Volume: 114, Issue: 2, Pages: 283-294
ISSN:1524-4571
DOI:10.1161/CIRCRESAHA.114.302835
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1161/CIRCRESAHA.114.302835
Verlag, lizenzpflichtig, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.114.302835
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Author Notes:Mathar Ilka, Kecskes Miklos, Van der Mieren Gerry, Jacobs Griet, Camacho Londoño Juan E., Uhl Sebastian, Flockerzi Veit, Voets Thomas, Freichel Marc, Nilius Bernd, Herijgers Paul, Vennekens Rudi
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Summary:Rationale:The Trpm4 gene has recently been associated with several disorders, including cardiac conduction diseases and Brugada syndrome. Transient receptor potential member 4 (TRPM4) proteins constitute Ca2+-activated, but Ca2+-impermeable, nonselective cation channels and are expressed both in atrial and in ventricular cardiomyocytes. The physiological function of TRPM4 in the heart remains, however, incompletely understood.Objective:To establish the role of TRPM4 in cardiac muscle function.Methods and Results:We used TRPM4 knockout mice and performed patch-clamp experiments, membrane potential measurements, microfluorometry, contractility measurements, and in vivo pressure-volume loop analysis. We demonstrate that TRPM4 proteins are functionally present in mouse ventricular myocytes and are activated on Ca2+-induced Ca2+ release. In Trpm4−/− mice, cardiac muscle displays an increased β-adrenergic inotropic response both in vitro and in vivo. Measurements of action potential duration show a significantly decreased time for 50% and 90% repolarization in Trpm4−/− ventricular myocytes. We provide evidence that this change in action potential shape leads to an increased driving force for the L-type Ca2+ current during the action potential, which explains the altered contractility of the heart muscle.Conclusions:Our results show that functional TRPM4 proteins are novel determinants of the inotropic effect of β-adrenergic stimulation on the ventricular heart muscle.
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Originally published 13 Nov 2013
Gesehen am 29.10.2020
Physical Description:Online Resource
ISSN:1524-4571
DOI:10.1161/CIRCRESAHA.114.302835

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