Cardiac overexpression of the human 5-HT4 receptor in mice.
Serotonin (5-HT) exerts pleiotropic effects in the human cardiovascular system. Some of the effects are thought to be mediated via 5-HT(4) receptors, which are expressed in the human atrium and in ventricular tissue. However, a true animal model to study these receptors in more detail has been hitherto lacking. Therefore, we generated, for the first time, a transgenic (TG) mouse with cardiac myocyte-specific expression of the human 5-HT(4) receptor. RT-PCR and immunohistochemistry revealed expression of the receptor at the mRNA and protein levels. Stimulation of isolated cardiac preparations by isoproterenol increased phospholamban phosphorylation at Ser(16) and Thr(17) sites. 5-HT increased phosphorylation only in TG mice but not in wild-type (WT) mice. Furthermore, 5-HT increased contractility in isolated perfused hearts from TG mice but not WT mice. These effects of 5-HT could be blocked by the 5-HT(4) receptor-selective antagonist GR-125487. An intravenous infusion of 5-HT increased left ventricular contractility in TG mice but not in WT mice. Similarly, the increase in contractility by 5-HT in isolated cardiomyocytes from TG mice was accompanied by and probably mediated through an increase in L-type Ca(2+) channel current and in Ca(2+) transients. In intact animals, echocardiography revealed an inotropic and chronotropic effect of subcutaneously injected 5-HT in TG mice but not in WT mice. In isolated hearts from TG mice, spontaneous polymorphic atrial arrhythmias were noted. These findings demonstrate the functional expression of 5-HT(4) receptors in the heart of TG mice, and a potential proarrhythmic effect in the atrium. Therefore, 5-HT(4) receptor-expressing mice might be a useful model to mimic the human heart, where 5-HT(4) receptors are present and functional in the atrium and ventricle of the healthy and failing heart, and to investigate the influence of 5-HT in the development of cardiac arrhythmias and heart failure.
Gergs
Ulrich
U
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Strasse 4, Halle D-06112, Germany. ulrich.gergs@medizin.uni-halle.de
Baumann
Martin
M
Böckler
Anne
A
Buchwalow
Igor B
IB
Ebelt
Henning
H
Fabritz
Larissa
L
Hauptmann
Steffen
S
Keller
Nicolas
N
Kirchhof
Paulus
P
Klöckner
Udo
U
Pönicke
Klaus
K
Rueckschloss
Uwe
U
Schmitz
Wilhelm
W
Werner
Franziska
F
Neumann
Joachim
J
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D004452:Echocardiography; D006321:Heart / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
D044422:Receptors, Serotonin, 5-HT4