title: p11 modulates calcium handling through 5-HT₄R pathway in rat ventricular cardiomyocytes.
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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Meschin
authors.affiliation: 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.
authors.forename: Marie
authors.initials: M
authors.lastname: Demion
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
authors.affiliation: 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.
authors.forename: Amanda
authors.initials: A
authors.lastname: Finan
authors.affiliation: 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.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.affiliation: 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.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.affiliation: 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.
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D056966:Excitation Contraction Coupling / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017208:Rats, Wistar; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D002118:Calcium; D044422:Receptors, Serotonin, 5-HT4; D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10
keywords: Antidepressant; Brain-derived neurotrophic factor; Calcium waves; S100A10; Serotonin receptor 4