Journal
CIRCULATION RESEARCH
Volume 114, Issue 2, Pages 283-294Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.114.302835
Keywords
action potentials; calcium signaling; excitation contraction coupling; ion channels; mice; knockout; TRPM4 protein; mouse
Funding
- Fonds voor Wtenschappelijk Onderzoek Vlaanderen [G.0761.10N, ASP/11, G.0596.12, G.0565.07]
- Interuniversitary Attraction Poles program from the Belgian Federal Government [P7/13]
- KULeuven Bijzonder Onderzoeksfonds [STRT1/09/046, GOA 2009/07, EF/95/010, TRPLe]
- Klinische Forschergruppe 196 der Deutschen Forschungsgemeinschaft
- DZHK (German Centre for Cardiovascular Research)
- BMBF (German Ministry of Education and Research)
- Forschungsausschuss program der Universitat des Saarlandes
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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 -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 -adrenergic stimulation on the ventricular heart muscle.
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