title: 5-HT4 and 5-HT2 receptors antagonistically influence gap junctional coupling between rat auricular myocytes.
abstract: 5-hydroxytryptamine-4 (5-HT(4)) receptors have been proposed to contribute to the generation of atrial fibrillation in human atrial myocytes, but it is unclear if these receptors are present in the hearts of small laboratory animals (e.g. rat). In this study, we examined presence and functionality of 5-HT(4) receptors in auricular myocytes of newborn rats and their possible involvement in regulation of gap junctional intercellular communication (GJIC, responsible for the cell-to-cell propagation of the cardiac excitation). Western-blotting assays showed that 5-HT(4) receptors were present and real-time RT-PCR analysis revealed that 5-HT(4b) was the predominant isoform. Serotonin (1 microM) significantly reduced cAMP concentration unless a selective 5-HT(4) inhibitor (GR113808 or ML10375, both 1 microM) was present. Serotonin also reduced the amplitude of L-type calcium currents and influenced the strength of GJIC without modifying the phosphorylation profiles of the different channel-forming proteins or connexins (Cxs), namely Cx40, Cx43 and Cx45. GJIC was markedly increased when serotonin exposure occurred in presence of a 5-HT(4) inhibitor but strongly reduced when 5-HT(2A) and 5-HT(2B) receptors were inhibited, showing that activation of these receptors antagonistically regulated GJIC. The serotoninergic response was completely abolished when 5-HT(4), 5-HT(2A) and 5-HT(2B) were simultaneously inhibited. A 24 h serotonin exposure strongly reduced Cx40 expression whereas Cx45 was less affected and Cx43 still less. In conclusion, this study revealed that 5-HT(4) (mainly 5-HT(4b)), 5-HT(2A) and 5-HT(2B) receptors coexisted in auricular myocytes of newborn rat, that 5-HT(4) activation reduced cAMP concentration, I(Ca)(L) and intercellular coupling whereas 5-HT(2A) or 5-HT(2B) activation conversely enhanced GJIC.
authors.affiliation: UMR CNRS 6542, Physiologie des Cellules Cardiaques et Vasculaires, Faculté des Sciences et Techniques, Université de Tours, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Derangeon
authors.forename: Véronique
authors.initials: V
authors.lastname: Bozon
authors.forename: Norah
authors.initials: N
authors.lastname: Defamie
authors.forename: Nicolas
authors.initials: N
authors.lastname: Peineau
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bourmeyster
authors.forename: Denis
authors.initials: D
authors.lastname: Sarrouilhe
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Argibay
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Hervé
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D062365:Aminobenzoates / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D017630:Connexins / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D006325:Heart Atria / Q000166:cytology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D062366:para-Aminobenzoates
chemical_list: C117877:2-(3,5-dimethylpiperidino)ethyl 4-amino-5-chloro-2-methoxybenzoate; D062365:Aminobenzoates; D017630:Connexins; D007211:Indoles; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D013449:Sulfonamides; D062366:para-Aminobenzoates; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D000262:Adenylyl Cyclases; C082871:GR 113808