Serotonin Receptors David E. Nichols* ,† and Charles D. Nichols ‡ Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47906-2091, and Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, Louisiana 70112 Received October 19, 2007 Contents 1. Introduction 1614 1.1. The Discovery of Serotonin 1615 1.1.1. Phylogeny of Serotonin Receptors 1616 1.1.2. General Structural Features: Homologies with Rhodopsin 1616 1.2. Receptor Oligomerization 1624 1.3. Receptor Activation of Heterotrimeric G-Proteins 1625 2. Classification of Serotonin Receptors 1625 2.1. G q/11 -Coupled Receptor Types 1626 2.1.1. The 5-HT 2A Receptor 1626 2.1.2. The 5-HT 2B Receptor 1627 2.1.3. The 5-HT 2C Receptor 1628 2.2. G s -Coupled Receptor Types 1628 2.2.1. The 5-HT 4 Receptor 1629 2.2.2. The 5-HT 6 Receptor 1629 2.2.3. The 5-HT 7 Receptor 1629 2.3. G i/o -Coupled Receptor Types 1630 2.3.1. The 5-HT 1A Receptor 1630 2.3.2. The 5-HT 1B Receptor 1631 2.3.3. The 5-HT 1D Receptor 1632 2.3.4. The 5-HT 1E Receptor 1632 2.3.5. The 5-HT 1F Receptor 1633 2.3.6. The 5-HT 5A (and 5-HT 5B ) Receptors 1633 3. The 5-HT 3 Receptor, A Ligand-Gated Ion Channel 1634 4. Conclusions and Perspectives 1636 5. Acknowledgments 1636 6. References 1636 1. Introduction Serotonin, 5-hydroxytryptamine (5-HT), is one of the class of monoamine neurontransmitters, all of which have a chemical template comprised of a basic amino group separated from an aromatic nucleus by a two carbon aliphatic chain. In mammals, 5-HT is biosynthetically derived by two enzymatic steps: (1) ring hydroxylation of the essential amino acid tryptophan by tryptophan hydroxylase, the rate-limiting step, 1 and (2) side chain decarboxylation by aromatic amino acid decarboxylase (Figure 1). A second isoform of tryptophan hydroxylase was identified in 2003 by Walther et al. 2,3 The original enzyme originally character- ized, which is expressed in the gut, is now called tph1, and the isoform that is expressed exclusively within the brain is named tph2. 4,5 In the brain, serotonin is produced within axon terminals, where it is released in response to an action potential and then diffuses across the synapse to activate postsynaptic receptors. The serotonin receptor family is larger than any other family of G-protein coupled (GPCR) neu- rotransmitter receptors: 13 distinct genes encoding for receptors of the G-protein coupled seven-transmembrane class. In addition, there is one ligand-gated ion channel, the 5-HT 3 receptor. Serotonin is one of the most ancient signaling molecules. It is found in the single-celled eukaryotes paramecium and tetrahymena, where it can modulate swimming behavior and growth. 6,7 Serotonin receptors that share significant orthology are found in a very diverse range of organisms up the evolutionary tree, from planaria, Caenorhabditis elegans, and Drosophila melanogaster to humans. From this diversity, it has been speculated that the primordial serotonin receptor of the rhodopsin-GPCR family may have first appeared more than 700-750 million years ago, a time that likely predates the evolution of muscarinic, dopaminergic, and adrenergic receptor systems. 8 GPCRs as a protein family are believed to have evolved about 1.2 billion years ago. 8 Significantly, serotonin receptors appear to be among the oldest receptors within the rhodopsin-like family. 9 The three major classes of G-protein-coupled 5-HT receptors, the 5-HT 1A , 5-HT 2 , and 5-HT 7 -like receptors, which are less than 25% homologous, likely differentiated approximately 600-700 million years ago, before the time period during which vertebrates diverged from invertebrates. The fruit fly, Droso- phila melanogaster, expresses functional orthologs of the 5-HT 1A , 5-HT 2 , and 5-HT 7 receptors, as well as orthologs for many other GPCRs. 10 The mammalian 5-HT receptor subtypes have further differentiated over the past 90 million years. Not surprisingly, as a result of this long evolutionary history, serotonin plays a variety of roles in normal physiol- ogy, including developmental, cardiovascular, gastrointes- tinal, and endocrine function, sensory perception, behaviors such as aggression, appetite, sex, sleep, mood, cognition, and * To whom correspondence should be addressed. Mailing address: Dept. of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, 575 Stadium Mall Drive, West Lafayette, IN 47906-2091. Tel: 765-494-1461. Fax: 765-494-1414. E-mail: drdave@ pharmacy.purdue.edu. † Purdue University. ‡ Louisiana State University Health Sciences Center. Chem. Rev. 2008, 108, 1614–1641 1614 10.1021/cr078224o CCC: $71.00  2008 American Chemical Society Published on Web 05/14/2008