title: Human 5-HT₄receptor stimulation in atria of transgenic mice.
abstract: In human atrium, serotonin (5-HT) exerts pleiotropic effects, which are thought to be mediated via 5-HT4 receptors. Here, we used transgenic mice (TG) that overexpress the human 5-HT4(a) receptor under control of the heart-specific α-myosin heavy chain promoter in the atria (and ventricles). Contractile studies were performed in isolated electrically driven left atrial preparations and spontaneously beating right atrial preparation of TG and littermate control mice (wild type (WT)). 5-HT increased force of contraction and phospholamban phosphorylation on serine 16 only in left atrial preparations from TG but not from WT. In contrast, β-adrenoceptor stimulation of left atrial preparations by isoprenaline increased force of contraction with similar pEC50 values and to a similar maximum extent in both TG and WT. The contractile effects of 5-HT in left atrial preparations from TG could be blocked by the 5-HT4 receptor-specific antagonists GR125487 or GR113808. In right atrial preparations from WT and TG, the β-adrenoceptor agonist isoprenaline exerted a positive chronotropic effect with similar pEC50 values and similar maximum effects. Only in right atrial preparations from TG but not WT, 5-HT exerted a positive chronotropic effect that could be attenuated by 5-HT4 receptor-specific antagonists. Finally, in left atrial preparations of TG, a higher incidence of arrhythmias was noted compared to WT. The present data indicate that the human 5-HT4 receptors expressed in mouse atria are functional. This is the first transgenic model to study this human receptor in the atrium ex vivo or in vivo.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Str. 4, 06112 Halle, Germany. ulrich.gergs@medizin.uni-halle.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gergs
authors.forename: Anne
authors.initials: A
authors.lastname: Böckler
authors.forename: Henning
authors.initials: H
authors.lastname: Ebelt
authors.forename: Steffen
authors.initials: S
authors.lastname: Hauptmann
authors.forename: Nicolas
authors.initials: N
authors.lastname: Keller
authors.forename: Volker
authors.initials: V
authors.lastname: Otto
authors.forename: Klaus
authors.initials: K
authors.lastname: Pönicke
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
authors.forename: Joachim
authors.initials: J
authors.lastname: Neumann
mesh_terms: D000818:Animals; D016275:Atrial Function / Q000187:drug effects / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology
chemical_list: D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D007545:Isoproterenol