Serotonin in the heart: the beauty and the beast

Existence of a crosstalk between administration of antidepressants targeting serotonin re-uptake and its degradation and heart development in foetus has been acknowledged at a terrible price. The use of selective serotonin reuptake inhibitor (SSRI) – paroxetine – during the first trimester of pregnancy was associated with an increased risk in development of heart defects and late first trimester spontaneous abortions to which severe heart defects contributed (Sadler 2011). As the importance of serotonin during myocardial development was recognized, pieces of the puzzle began to assemble on multiple actions of 5-hydroxytryptamine (5-HT) in embryonic and adult heart. Many of these pieces are still missing. From four classes of serotonin receptors, one (5-HT3 receptors) is comprised of ligand-gated ion channels, whereas the other three (5-HT1/5, 5-HT2 and 5-HT4/6/7 receptors) are G-protein-coupled receptors. 5-HT2B and 5-HT4 receptors are present in the heart. 5-HT2B receptors play an important role in cardiac development during embryogenesis, promoting proliferation and differentiation of cardiomyoblasts (Nebigil et al. 2000). In adult heart, this receptor is involved in the progression of myocardial hypertrophic remodelling (Nebigil & Maroteaux 2003). 5-HT4 receptor controls Ca currents through L-type calcium channels and modulates pacemaker currents in atrial myocytes and, when hyperactivated, promotes arrhythmia (Gergs et al. 2010). Antagonists of this receptor are tested as antiarrhythmic drugs (Doggrell 2003). Apart from receptor-mediated 5-HT signalling, hydrogen peroxide produced from serotonin during its degradation inside the cells serves as a second messenger or as a damaging pro-oxidant (Cooper et al. 2003). The underlying reactions catalysed by monoamine oxidases (MAO) in the mitochondria of multiple cell types including cardiomyocytes (Sivasubramaniam et al. 2003) are as follows: