Associate editor: P. Molenaar5-Hydroxytryptamine receptors in the human cardiovascular system
Introduction
Serotonin (5-hydroxytryptamine, 5-HT) exerts its multiplicity of physiological effects through an unsurpassed diversity of receptors (Hoyer et al., 1994, Hoyer et al., 2002). At least 14 different 5-HT receptors, each encoded by a separate gene, are known in man and their roles in the human cardiovascular system summarised in Table 1. For some of these receptors, additional diversity is achieved through alternative splicing, RNA editing or posttranslational modifications. Furthermore, polymorphic variants and mutants of serotonin receptors are being unraveled, resulting in possible interindividual differences in their response to serotonin (Göthert et al., 1998, Sanders-Bush et al., 2003).
A multitude of effects of 5-HT have been demonstrated on the cardiovascular system. Some of these effects are mediated through actions of 5-HT in the central nervous system, whereas 5-HT also has multiple and diverse effects through direct interaction with 5-HT receptors in different parts of the cardiovascular system. In each of these, for example different blood vessels or different parts of the heart, the physiological effects of 5-HT depend on the 5-HT receptors involved, the intracellular signals evoked through these receptors, and their cellular localisation. The aim of this review is to present a comprehensive overview of the current knowledge about the diverse effects of 5-HT on the human cardiovascular system, with emphasis on the direct, peripheral effects, as opposed to effects through the central nervous system, and to describe how this knowledge translates into understanding and hypotheses regarding the involvement of 5-HT and 5-HT receptors in the pathogenesis and treatment of human cardiovascular disease. Particular emphasis will be put on the role of 5-HT in heart disease and blood vessel disorders. We will also survey possible effects of polymorphic 5-HT receptor variants and mutants for human cardiovascular function.
Section snippets
Molecular biology of 5-hydroxytryptamine receptors relevant to the human cardiovascular system
The 14 different 5-HT receptors are divided into 7 groups (5-HT1 through 5-HT7) based on molecular structure, signal transduction properties and pharmacological properties (Hoyer et al., 1994, Hoyer et al., 2002).
Cardiac 5-hydroxytryptamine receptors
Human cardiac 5-HT receptors are depicted in Fig. 2. Functional cardiostimulant 5-HT4 receptors have been described in right atrium (Kaumann et al., 1990), left atrium (Sanders & Kaumann, 1992) and in right and left ventricle (Brattelid et al., 2004b). Human cardiac 5-HT4 receptors mediate arrhythmias (Kaumann, 1994, Kaumann & Sanders, 1994, Pau et al., 2003, Brattelid et al., 2004b). Activation of 5-HT3 receptors, presumably located at epicardial afferent sensory nerve endings of the vagus,
Vasoconstriction
5-HT receptor subtypes mediating vasoconstriction were identified with the help of subtype-selective antagonists and by comparison with the pharmacology of recombinant receptors. Messenger RNA for both 5-HT1B and 5-HT2A receptors has been detected in smooth muscle cells of human aorta and pulmonary artery (Ullmer et al., 1995). Useful antagonists as tools have been the 5-HT2A-selective ketanserin (Van Nueten et al., 1981), 5-HT1B-selective SB224289 (Roberts et al., 1997) and 5-HT1D-selective
Genetic mutations and polymorphisms in 5-hydroxytryptamine receptors possibly relevant to the human cardiovascular system
Several polymorphic variants of human serotonin receptor genes have been reported. Polymorphisms located in the untranslated regions (UTR) may give rise to altered levels of receptor expression, through altered levels of transcription (e.g. polymorphisms in the promoter region) or through altered mRNA stability (e.g. polymorphisms in the 3′-UTR). Polymorphisms (usually single nucleotide polymorphisms or SNPs) located in the open reading frame (coding region) may be silent, either by causing no
Acknowledgements
Work in the authors' laboratories are funded by grants from the British Heart Foundation (to AJK) and from The Research Council of Norway, The Norwegian Council on Cardiovascular Diseases, Anders Jahre's Foundation for the Promotion of Science, The Novo Nordisk Foundation, The Family Blix Foundation and the University of Oslo (to FOL). AJK wishes to thank Dr. T. Christ (TU Dresden, Germany) for comments about arrhythmias and Dr. D. Pau (University of Glasgow) for sharing unpublished
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