The Serotonin Receptors From Molecular Pharmacology to Human Therapeutics Edited by Bryan L. Roth, MD, PhD THE SEROTONIN RECEPTORS T HE RECEPTORS KIM A. NEVE, SERIES EDITOR The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics, EDITED BY Bryan L. Roth, 2006 The Adrenergic Receptors: In the 21st Century, EDITED BY Dianne M. Perez, 2005 The Melanocortin Receptors, EDITED BY Roger D. Cone, 2000 The GABA Receptors, Second Edition, EDITED BY S. J. Enna and Norman G. Bowery, 1997 The Ionotropic Glutamate Receptors, EDITED BY Daniel T. Monaghan and Robert Wenthold, 1997 The Dopamine Receptors, EDITED BY Kim A. Neve and Rachael L. Neve, 1997 The Metabotropic Glutamate Receptors, EDITED BY P. Jeffrey Conn and Jitendra Patel, 1994 The Tachykinin Receptors, EDITED BY Stephen H. Buck, 1994 The Beta-Adrenergic Receptors, EDITED BY John P. Perkins, 1991 Adenosine and Adenosine Receptors, EDITED BY Michael Williams, 1990 The Muscarinic Receptors, EDITED BY Joan Heller Brown, 1989 The Serotonin Receptors, EDITED BY Elaine Sanders-Bush, 1988 The Alpha-2 Adrenergic Receptors, EDITED BY Lee Limbird, 1988 The Opiate Receptors, EDITED BY Gavril W. Pasternak, 1988 The Alpha-1 Adrenergic Receptors, EDITED BY Robert R. Ruffolo, Jr., 1987 The GABA Receptors, EDITED BY S. J. Enna, 1983 The Serotonin Receptors From Molecular Pharmacology to Human Therapeutics Edited by Bryan L. Roth, MD, PhD Department of Biochemistry Case Western Reserve University–School of Medicine Cleveland, OH © 2006 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 www.humanapress.com For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341, E-mail: orders@humanapr.com; or visit our Website: http://www. humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. Cover design by Patricia F. Cleary Cover illustration: Figure 3 from Chapter 9, “Cellular and Subcellular Localization of Serotonin Receptors in the Central Nervous System,” by L. Descarries, V. Cornea-Hébert, and M. Riad This publication is printed on acid-free paper. ∞ ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256- 1699; Fax: 973-256-8341; E-mail: orders@humanapr.com; or visit our Website: www. humanapress.com. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $30.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [1-58829-568-0/06 $30.00]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 eISBN 1-59745-080-9 Library of Congress Cataloging-in-Publication Data The serotonin receptors : from molecular pharmacology to human therapeutics / edited by Bryan L. Roth. p. cm. — (The receptors) Includes bibliographical references and index. ISBN 1-58829-568-0 (alk. paper) 1. Serotonin—Receptors. 2. Serotonin—Physiological effect. 3. Serotoninergic mecha nisms. I. Roth, Bryan L. II. Series. QP801.S4.S474 2006 612.8’042—dc22 2005029055 Preface It has been nearly 20 years since the last Humana Press book devoted to serotonin (5-hydroxytryptamine; 5-HT) receptors has appeared. Since then, the field of 5-HT receptors has undergone a revolution due to the discovery of many additional 5-HT receptors. Although 5-HT was chemically elucidated in 1948 by Page and colleagues (Rapport et al., 1948) and 5-HT receptors initially classified in 1957 (Gaddum and Picarelli, 1957), the complexity of 5-HT pharmacology was not fully appreciated until the late 1970s and early 1980s when many puta- tive 5-HT receptors were identified by radioligand binding studies (e.g., 5-HT1A, 5-HT2, 5-HT1E and so on) (Leysen et al., 1979; Hamon et al., 1980; Peroutka et al., 1981; Leonhardt et al., 1989). The first 5-HT receptors were cloned in 1988 (Fargin et al., 1988; Julius et al., 1988) and the discovery of 14 distinct human 5-HT receptors since then ushered in the era of 5-HT receptor molecular biology (Kroeze et al., 2003). The cloning and sequencing of 5-HT receptors has also revealed the presence of post-transcriptionally modified mRNA species (RNA editing) (Burns et al., 1997) as well as naturally occurring mutations and their relations to various diseases (e.g., single nucleotide polymorphisms; SNPs) (Arranz et al., 1995). The identification of the amino acid sequences of 5-HT receptors has allowed us to predict how 5-HT and related agonists bind to and activate 5-HT receptors (Shapiro et al., 2000; Shapiro et al., 2002). The hope has been that this informa- tion will lead, eventually, to the development of novel, subtype-selective 5-HT receptor agonists and antagonists (Kroeze et al., 2002). The first several chapters of The Serotonin Receptors: From Molecular Phar- macology to Human Therapeutics are aimed at reviewing our knowledge of the molecular and structural biology of 5-HT receptors, followed by our current under- standing of 5-HT receptor pharmacology. The elucidation of the sequences of 5- HT receptors has also facilitated the development of highly selective tools for mapping the distribution of 5-HT receptors. These tools include selective 5-HT receptor antibodies and hybridization probes. The use of these biochemical probes has revealed an unexpected complexity in both the cellular and subcellular distri- bution of 5-HT receptors. The next few chapters describe the anatomical, cellular, and subcellular dis- tribution of 5-HT receptors. Because of the plethora of receptors and receptor subtypes, however, it has been exceedingly difficult to identify the physiological role of various 5-HT receptors using pharmacological tools. A powerful approach v to elucidating the physiological role of 5-HT receptors was to use mice in which 5-HT receptors were deleted (e.g., knockout mice); the first 5-HT receptor knock- outs were reported in 1994 (Saudou et al., 1994) and, since then, nearly all 5-HT receptors have been “knocked-out”—typically with novel phenotypes (Tecott et al., 1995; Brunner et al., 1999). The final chapters review our understanding the physiological role(s) of 5-HT receptors based mainly on studies performed in genetically engineered mice. This book represents our collective attempts to provide the reader with a “snap- shot” of the 5-HT receptor field circa 2006. The scope of the book is vast, proceeding from the genomic to the therapeutic. Because it is unlikely that any reader will devote the time to reading the entire book cover-to-cover, each chap- ter has been designed to represent a complete review of the particular field. Thus, each chapter begins with a short introduction to 5-HT receptors and then pro- ceeds to review the particular subfield in depth. Not surprisingly, therefore, the enterprising reader will find some overlap between various introductory sec- tions. Acknowledgments I would like to especially thank Mr. Jon Evans who has tirelessly collected, edited, and collated the finished chapters and who has done most of the “leg work” associated with this book. Without Jon’s devotion to this task, the book would never have been completed. Any omissions and errors are my sole respon- sibility. I would also like to thank my wife Judith and my daughter Rachel for their warmth and understanding during the gestation of this book. Lastly, I dedi- cate this book to “beings throughout the ten directions—hands palm-to-palm.” Bryan L. Roth, MD, PhD References Arranz M, Collier D, Sodhi M, Ball D, Roberts G, Price J, Sham P, and Kerwin R. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet 1995;346:281–282. Brunner D, Buhot MC, Hen R, and Hofer M. Anxiety, motor activation, and maternal- infant interactions in 5HT1B knockout mice. Behav Neurosci 1999;113:587–601. Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, and Emeson RB. Regulation of serotonin-2C receptor G-protein coupling by RNA editing [see comments]. Nature 1997;387:303–308. Fargin A, Raymond JR, Regan JW, Cotecchia S, Lefkowitz RJ, and Caron MG. The genomic clone G-21 which resembles a beta-adrenergic receptor sequence encodes the 5-HT1A receptor. Nature 1988;335:358–360. Gaddum JH and Picarelli ZP. Two kinds of tryptamine receptors. Br J Pharmacol 1957;12:323–328. vi Preface Hamon M, Nelson DL, Herbet A. and Glowinski J. Multiple receptors for serotonin in the rat brain. Adv Biochem Psychopharmacol 1980;21:223–233. Julius D, MacDermott AB, Axel R, and Jessell TM. Molecular characterization of a functional cDNA encoding the serotonin 1c receptor. Science 1988;241:558–564. Kroeze WK, Kristiansen K, and Roth BL. Molecular biology of serotonin receptors structure and function at the molecular level. Curr Top Med Chem 2002;2:507–528. Kroeze WK, Sheffler DJ, and Roth BL. G-protein-coupled receptors at a glance. J Cell Sci 2002;116:4867-9. Leonhardt S, Herrick-Davis K, and Titeler M. Detection of a novel serotonin receptor subtype (5-HT1E) in human brain: interaction with a GTP-binding protein. J Neurochem 1989;53:465–471. Leysen JE, Gommeren W, Laduron PM, et al. Distinction between dopaminergic and serotonergic components of neuroleptic binding sites in limbic brain areas. Biochem Pharmacol 1979;28:447–448. Peroutka SJ, Lebovitz RM, and Snyder SH. Two distinct serotonin receptors with distinct physiological functions. Science 1981;212:827-829. Rapport MM, Green AA, and Page IH. Crystalline serotonin. Science 1948;108:329. Saudou F, Amara DA, Dierich A, et al. Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 1994;265:1875–1878. Shapiro DA, Kristiansen K, Kroeze WK, and Roth BL. Differential modes of agonist binding to 5-hydroxytryptamine(2A) serotonin receptors revealed by mutation and molecular modeling of conserved residues in transmembrane region 5. Mol Pharmacol 2000;58:877–886. Shapiro DA, Kristiansen K, Weiner DM, Kroeze WK, and Roth BL. Evidence for a model of agonist-induced activation of 5-HT2A serotonin receptors which involves the disruption of a strong ionic interaction between helices 3 and 6. J Biol Chem 2002;18:18. Tecott LH, Sun LM, Akana SF, et al. Eating disorder and epilepsy in mice lacking 5- HT2c serotonin receptors [see comments]. Nature 1995;374:542–546. Preface vii Contents ix Preface v Contributors xi Color Plate xvii 1 Molecular Biology and Genomic Organization of G Protein–Coupled Serotonin Receptors Wesley K. Kroeze and Bryan L. Roth 1 2 Structure and Function Reveal Insights in the Pharmacology of 5-HT Receptor Subtypes Richard B. Westkaemper and Bryan L. Roth 39 3 Polymorphic and Posttranscriptional Modifications of 5-HT Receptor Structure: Functional and Pathological Implications Marilyn A. Davies, Chiao-ying Chang, and Bryan L. Roth 59 4 Strategies for the Development of Selective Serotonergic Agents Richard A. Glennon 91 5 5-HT Receptor Signal Transduction Pathways John R. Raymond, Justin H. Turner, Andrew K. Gelasco, Henry B. Ayiku, Sonya D. Coaxum, John M. Arthur, and Maria N. Garnovskaya 143 6 Agonist-Directed Trafficking of 5-HT Receptor-Mediated Signal Transduction Kelly A. Berg and William P. Clarke 207 7 Identification of 5-HT 2 and 5-HT 4 Receptor-Interacting Proteins: A Proteomic Approach Joël Bockaert, Carine Bécamel, Lara Joubert, Sophie Gavarini, Aline Dumuis, and Philippe Marin 237 [...]... (5-hydroxytryptamine; 5-HT) receptors are typical group A rhodopsin-like G protein–coupled receptors (GPCRs) in that they are predicted to possess seven transmembrane spanning helices, three intracellular and three extracellular loops, an extracellular amino-terminus, and From: The Receptors: The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics Edited by: B L Roth © Humana Press Inc., Totowa, NJ... carboxy-terminus The true structures of these receptors remain unknown, although the crystallization of the bovine rhodopsin receptor (1) provides promise for the solution of the structures of the G protein–coupled 5-HT receptors in the near future Functionally, the transmembrane regions serve to bind ligands, especially the endogenous ligand serotonin, the intracellular domains couple these receptors to various... vertebrates and from several invertebrate species Study of these 5-HT receptors should provide additional information on the nature of the residues essential for binding of at least the natural ligand, serotonin, to 5-HT receptors and might provide insight into how these receptors evolved For example, residues that are completely conserved among all 5-HT receptors are likely to have essential roles in the function... 5-HT2C receptors are retained It is possible that 5-HT2C receptors of birds are in fact very different from the 5-HT2C receptors of other species, as the current sequence data imply, or that the chicken 5-HT2C receptor sequence in the database is incorrect Which of these alternatives is found to be true awaits further research As can be seen from the alignment shown in Fig 2, the sequence given in the. .. 5-HT7 These classes are further subdivided as follows The 5-HT1 receptor class contains the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptor subclasses The 5-HT2 receptor class contains the 5-HT2A, 5-HT2B, and 5-HT2C receptors The 5-HT5 receptor class contains the 5-HT5A, and 5-HT5B receptor subclasses For the most part, the 5-HT4, 5-HT6, and 5-HT7 classes do not contain subclasses of receptors per... resemblance to the human 5-HT2C receptor, and the “true” 5-HT2C receptor sequence of the chimpanzee protein as listed in the database begins about halfway through TM4 In the chimpanzee 5-HT4 receptor sequence (accession number XP–518024), the “Y” of the highly conserved DRY motif at the intracellular end of TM3, the i2 intracellular loop, and TM4 are missing from the database sequence The chimpanzee 5-HT5A Molecular. .. subclasses of 5-HT receptors, and numerous single-nucleotide polymorphisms (SNPs) and splice variants are known to exist in many subclasses of these receptors Editing of 5-HT receptors will be reviewed in this chapter, and SNPs and splice variants will be reviewed in subsequent chapters In addition to the 5-HT receptors identified from mammals, many 5-HT receptors have also been cloned from nonmammalian... those from other mammals, or (3) whether further investigation of the genomic sequences with expert curation will reveal 5-HT receptor sequences more like those from other primate or mammalian species Of these three possibilities, the third seems most likely The chicken 5-HT2C receptor sequence in the database (accession number XP–426265) is 1337 residues long, as compared to 458 residues for the human. .. receptors, much remains to be done to gain a full appreciation of the natural variation in sequence of the 5-HT receptors, even in relatively frequently studied animal species For example, of the 13 likely G protein–coupled 5-HT receptors in mammalian genomes, only 2 have been described from rabbits, 5 from pigs and dogs, 7 from guinea pigs, and 3 from hamsters Table 1 lists the G protein–coupled 5-HT receptors. .. that an error in the reading of this sequence may have resulted in the abnormally long aminoterminus Obviously, many of these chimpanzee sequences as listed would represent nonfunctional receptors Therefore, it remains an open question (1) whether these represent aberrant splicing isoforms among the chimpanzee 5-HT receptors that do not exist in humans, (2) whether chimpanzee 5-HT receptors are truly . The Serotonin Receptors From Molecular Pharmacology to Human Therapeutics Edited by Bryan L. Roth, MD, PhD THE SEROTONIN RECEPTORS T HE RECEPTORS KIM A. NEVE, SERIES EDITOR The Serotonin Receptors: . extracellular amino-terminus, and From: The Receptors: The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics Edited by: B. L. Roth © Humana Press Inc., Totowa, NJ . Alpha-1 Adrenergic Receptors, EDITED BY Robert R. Ruffolo, Jr., 1987 The GABA Receptors, EDITED BY S. J. Enna, 1983 The Serotonin Receptors From Molecular Pharmacology to Human Therapeutics Edited