Cardiac overexpression of the human 5-HT4 receptor in mice

Gergs U, Baumann M, Bockler A, Buchwalow IB, Ebelt H, Fabritz L, Hauptmann S, Keller N, Kirchhof P, Klockner U, Ponicke K, Rueckschloss U, Schmitz W, Werner F, Neumann J. Cardiac overexpression of the human 5-HT4 receptor in mice. Am J Physiol Heart Circ Physiol 299: H788-H798, 2010. First published July 16, 2010; doi:10.1152/ajpheart.00691.2009.-Serotonin (5-HT) exerts pleiotropic effects in the human cardiovascular system. Some of the effects are thought to be mediated via 5-HT4 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-HT4 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-HT4 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 Ca2+ channel current and in Ca2+ 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-HT4 receptors in the heart of TG mice, and a potential proarrhythmic effect in the atrium. Therefore, 5-HT4 receptor-expressing mice might be a useful model to mimic the human heart, where 5-HT4 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.