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Cell Calcium. 2015 Dec;58(6):549-57. doi: 10.1016/j.ceca.2015.08.005. Epub 2015 Aug 20.

p11 modulates calcium handling through 5-HT₄R pathway in rat ventricular cardiomyocytes.

Author information

1
PHYMEDEXP, Physiologie et Médecine Expérimentale du Coeur et des Muscles, INSERM U1046, CNRS UMR-9214, Université Montpellier, CHU Arnaud de Villeneuve, 371 avenue du doyen Gaston Giraud, 34295 Montpellier cedex, France.
2
PHYMEDEXP, Physiologie et Médecine Expérimentale du Coeur et des Muscles, INSERM U1046, CNRS UMR-9214, Université Montpellier, CHU Arnaud de Villeneuve, 371 avenue du doyen Gaston Giraud, 34295 Montpellier cedex, France. Electronic address: sylvain.richard@inserm.fr.
3
PHYMEDEXP, Physiologie et Médecine Expérimentale du Coeur et des Muscles, INSERM U1046, CNRS UMR-9214, Université Montpellier, CHU Arnaud de Villeneuve, 371 avenue du doyen Gaston Giraud, 34295 Montpellier cedex, France. Electronic address: alain.lacampagne@inserm.fr.

Abstract

BACKGROUND:

The role of the serotonin receptor 4 (5-HT4R) pathway in cardiac excitation-contraction coupling (ECC) remains unclear. In the brain, induction of the calcium (Ca(2+))-binding protein p11 enhances 5-HT4R translocation and signaling and could therefore be considered as a modulator of the 5-HT4R pathway in the myocardium. p11 expression is increased by brain-derived neurotrophic factor (BDNF) or antidepressant drugs (imipramine). Thus, we investigated whether p11 regulates the 5-HT4R pathway in the heart in physiological conditions or under pharmacological induction and the effects on calcium handling.

METHODS AND RESULTS:

p11 expression was induced in vivo in healthy Wistar rats by imipramine (10 mg/kg/21 days) and in vitro in left ventricular cardiomyocytes exposed to BDNF (50 ng/ml/8h). Cell shortening and real-time Ca(2+) measurements were processed on field-stimulated intact cardiomyocytes with the selective 5-HT4R agonist, prucalopride (1 μM). Both imipramine and BDNF-induced cardiomyocyte p11 expression unmasked a strong response to prucalopride characterized by an increase of both cell shortening and Ca(2+) transient amplitude compared to basal prucalopride associated with a high propensity to trigger diastolic Ca(2+) events. Healthy rats treated with BDNF (180 ng/day/14 days) exhibited a sustained elevated heart rate following a single injection of prucalopride (0.1 mg/kg) which was not observed prior to treatment.

CONCLUSIONS:

We have identified a novel role for p11 in 5-HT4R signaling in healthy rat ventricular cardiomyocytes. Increased p11 expression by BDNF and imipramine unraveled a 5-HT4R-mediated modulation of cardiac Ca(2+) handling and ECC associated with deleterious Ca(2+) flux disturbances. Such mechanism could partly explain some cardiac adverse effects induced by antidepressant treatments.

KEYWORDS:

Antidepressant; Brain-derived neurotrophic factor; Calcium waves; S100A10; Serotonin receptor 4

PMID:
26427584
DOI:
10.1016/j.ceca.2015.08.005
[Indexed for MEDLINE]
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