The Receptors

Volume 26

Series Editor Giuseppe Di Giovanni Department of Physiology & Biochemistry Faculty of Medicine and Surgery, University of Malta, Malta. The Receptors book Series, founded in the 1980’s, is a broad-based and wellrespected series on all aspects of receptor neurophysiology. The series presents published volumes that comprehensively review neural receptors for a speciﬁ c hormone or neurotransmitter by invited leading specialists. Particular attention is paid to in-depth studies of receptors’ role in health and neuropathological processes. Recent volumes in the series cover chemical, physical, modeling, biological, pharmacological, anatomical aspects and drug discovery regarding different receptors. All books in this series have, with a rigorous editing, a strong reference value and provide essential up-to-date resources for neuroscience researchers, lecturers, students and pharmaceutical research.

More information about this series at http://www.springer.com/series/7668

Robin A.J. Lester Editor

Nicotinic Receptors Editor Robin A.J. Lester Department of Neurobiology University of Alabama at Birmingham Birmingham , AL , USA

ISBN 978-1-4939-1166-0 ISBN 978-1-4939-1167-7 (eBook) DOI 10.1007/978-1-4939-1167-7 Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2014947538

© Springer Science+Business Media New York 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

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Humana Press is a brand of Springer Springer is part of Springer Science+Business Media (www.springer.com) Foreword

Few molecules in the nervous system have been studied as intensively by so many scientists as the family of nicotinic acetylcholine receptors (nAChRs). From the fi rst description of the “receptive substance” by Langley in 1905 to ongoing development of medications for smoking cessation, pain, cognitive dysfunction, and other neurological or psychiatric illnesses, studies of nAChRs have served as models for exploration of receptors in the nervous system for more than 100 years. nAChRs were the fi rst receptors to be reconstituted into a lipid bilayer, the fi rst channels to be recorded in a patch clamp preparation, and the fi rst neurotransmitter receptors to be cloned. The presence of nAChRs at the neuromuscular junction and the high conservation of these receptors from Caenorhabditis elegans to Torpedo electricus up to Homo sapiens has made them a model for biophysical and structure- function studies. The ubiquity of the nAChRs in the brain, peripheral nervous system, and non-neuronal tissues has allowed studies to be performed on complex functions in areas as diverse as homeostasis, motor control, mood, reward, and cognition. The community of nicotinians (scientists studying nAChRs) includes structural biologists, biophysicists, biochemists, cell biologists, physiologists, anatomists, pharmacologists, behavioral scientists, radiologists, clinicians, and more. The nicotinians provide an excellent example of how data obtained at one level of complexity can provide insights into many other levels of biological inquiry. The study of nAChRs provides the ultimate potential for translation of very basic science to studies of therapeutic relevance for human patients. A unique bioassay for the function of nAChRs in a complex system comes from the addiction to tobacco smoking in humans that was imported from the Americas to Europe by Sir Walter Raleigh in the late sixteenth century. Many clues to the behavioral consequences of nAChR function and dysfunction come from human subjects who report the effects of the nicotine in tobacco on their subjective experi- ence. An understanding of the role of nAChRs in nicotine reinforcement and withdrawal, as well as clues about the genetic basis for susceptibility to addiction, has come from studies of these receptors in human smokers. A fundamental understanding of the biophysical properties of nAChRs has been an important tool in medication

v vi Foreword development for smoking cessation, and this, in turn, has led the way to development of potential therapeutics to treat other indications as diverse as myasthenia gravis to schizophrenia. The multiple levels at which studies of nAChR structure, localization, and function have enhanced our understanding of fundamental biological systems are covered in this volume. A historical perspective from Dr. Robin A.J. Lester sets the stage for understanding how pioneering studies of these receptors have paved the way for studies of neurotransmitter receptors of many classes. Several chapters provide an understanding of the nAChR family at the molecular level. Dr. Steen Pedersen discusses structure-function relationships in nAChR gating, Dr. Paul Gardner describes the determinants of transcriptional regulation of the receptor family, and Dr. Michael Marks and Dr. Sharon Grady review the presynaptic function of nAChRs in neurotransmitter release from synaptosomes. Another set of chapters provides a framework for understanding how the electrophysiological properties of these receptors can alter the function of different brain circuits. Dr. John Dani reviews the homomeric α7 nAChR subtype and the effects of nAChR signaling during development are covered by Dr. Darwin Berg. Chapters on the distribution and function of nAChRs by Dr. Jerry Yakel, the presynaptic regulation of network activity by nAChRs from Dr. Lorna Role, and the slow nicotinic responses seen in several brain areas covered by Dr. Rory McQuiston complete the reviews at the electrophysiological level. At the systems level, reviews of the effects of nAChRs in the autonomic ganglia by Dr. Peter Sargent and the spinal cord by Dr. Philippe Ascher show how nAChRs play essential roles in the physiology of critical neurobiological systems that carry out essential homeostatic functions. At the behavioral level, a review of the role of nAChRs in learning and memory by Dr. Tom Gould provides a larger context in which to understand how the modulation of neuronal excitability and brain net- works by this receptor family can alter complex responses to the environment. Numerous levels of nAChR function are critical to understanding smoking behavior, including the role of nAChRs in reward and withdrawal reviewed by Dr. Andrew Tapper and Dr. Mariella De Debiasi, respectively; the genetics of human nAChR variants affecting tobacco addiction discussed by Dr. Jerry Stitzel, Dr. Laura Bierut, and Dr. Inez Ibanez-Tallon; and the interactions with other neurotransmitter systems, such as the serotonin system, outlined by Dr. Giuseppe Di Giovanni. It is ﬁ tting that the volume closes with a number of reviews outlining how dysfunction of various nAChRs can contribute to human illness, such as the neurodegeneration in Alzheimer’s and Parkinson’s disease covered by Dr. Kelly Dineley and the cognitive dysfunction in schizophrenia summarized by Dr. Sherry Leonard, and how nAChRs may be therapeutic targets for treatment of human disorders from pain, discussed by Dr. M. Imad Damaj, and other CNS disorders, reviewed by Dr. Stephen Arneric and Dr. Mani Sher. This is a rich volume that ties together the historical context for studies of nAChRs to current-day problems in systems neurobiology and human disease that can be approached only because of the fundamental molecular studies that have provided information on the structure, function, and anatomy of the nAChR Foreword vii family. This book provides optimism about how far the nicotinic ﬁ eld has advanced, and provides guideposts for where we need continued focus to move this knowledge forward to solve fundamental neurobiological problems that are critical to human health.

Marina Picciotto [email protected] http://psychiatry.yale.edu/people/marina_picciotto-1.proﬁ l e

Pref ace

Not so long ago, there was nothing known about receptors, neurotransmitters, and synapses. This was all to change, beginning around the middle of the nineteenth century, with the investigations of Claude Bernard into the mechanisms underlying drug-induced muscle paralysis, which together with a desire to understand autonomic transmission has led to fundamental insights into synaptic function (refl ected by Nobel Prizes awarded in Physiology and Medicine), much of it derived from the cholinergic-nicotinic system. About a hundred years ago, several scientists, in particular the anatomists, Santiago Ramon Y Cajal and Camillo Golgi (1906), together with the physiologists, Charles Sherrington and Edgar Adrian (1932), convinced the scientifi c community that the basic building blocks of the nervous system were individual neurons that communicated with each other via synapses. Soon after, Henry Dale and Otto Loewi (1936) provided clarity in the “soups and sparks” communication conundrum by identifying acetylcholine as one of the fi rst synaptic neurotransmitters. Next, Julius Axelrod, Ulf von Euler, and Bernard Katz (1970) demonstrated that neurotransmitters were stored in vesicles in the presynaptic terminal, and that chemical transmission was initiated by the infl ux of cal- cium ions. While these pioneering studies spurred the fi eld forwards, the postsynaptic nicotinic acetylcholine receptor remained elusive, and it was not until the last quarter of the twentieth century, when Erwin Neher and Bert Sakmann (1991) had suffi ciently refi ned existing techniques, were researchers able to observe the activation of single-nicotinic receptors by the neurotransmitter acetylcholine. By the end of the twentieth century, it had been fi rmly established that reliable neuromuscular synaptic transmission occurred as a result of the random combination of presynaptically released acetylcholine molecules with postsynaptic nicotinic acetylcholine receptors. We now know more about this receptor than any other and are starting to see how the binding of transmitter/drug initiates the structural twists and turns that open, close, and desensitize the channel. A compre- hensive understanding of how nicotinic receptors function, at the molecular level, seems at last to be just over the horizon.

ix x Preface

I view nicotinic receptors as one of the heroes of a multi-plot adventure story. By demystifying the spiritual usage of the drug nicotine, we have defi ned synaptic transmission, from its beginnings at the neuromuscular junction to its seemingly more cryptic deployment in the central nervous system. In doing so we have made major inroads into understanding how cholinergic-nicotinic circuitry contributes to fundamental aspects of sensation and movement, in addition to more complex brain states and behaviors including motivation and reward, learning and memory, and our nebulous conception of consciousness. Along the way we have had to dig deeper into the genetic basis that controls the expression and distribution of this family of receptors, their regulatory importance during development, and their interactions with other neurotransmitter systems, in particular dopamine and serotonin. In turn we have gained valuable insights into mechanisms of neurologic and psychiatric disease, and as a consequence, potential drug intervention strategies are emerging. Moreover, the discrete localization of receptor subtypes throughout the nervous system makes them particularly attractive drug targets if we want to restrict and tweak their activity within specifi c brain regions. While nicotinic receptors are the locks under discussion in this book, nicotine remains one of the major keys used to access brain function. As such, addiction to nicotine must be a central theme, not only due to its societal impact, affecting more than 20% of the world’s population, but also because it ties together genes, proteins, synapses, circuitry, and behavior, and continues to provide much motivation to understand nicotinic receptors and the brain. Recently by delving into the fl ip side of reward, and gaining an understanding of the mechanisms of aversion and withdrawal, we have unmasked additional regions of the brain that contribute to the devastation produced, not only by nicotine, but possibly by all drugs of abuse. Nicotine is a somewhat unique drug, a double-edged sword, neither an upper nor a downer, in some ways a mood stabilizer, which not only helps to explain why it is so addictive through self-medication, but also provides an explanation for the involvement of nicotinic receptors in so many psychological states, and as a consequence so many psychiatric disorders. Nicotine addiction, through gene linkage studies that correlate smoking behavior with specifi c DNA mutations, has more recently reopened the debate into nature versus nurture, and thus presents us with opportunities for tackling this disease on multiple levels. It is true that good science is inspired and moved forward by rigorous and honest competition, but effi cient progress requires the unselfi sh sharing of ideas and col- laborative research. The nicotinic receptor “family” has provided me a relative late arrival to the fi eld, a nurturing environment, in which to develop my own ideas about the role of these receptors in the brain. I feel honored to have been asked to assemble this collection of chapters, which I hope as a compilation refl ects the breadth of the fi eld, not only as it stands now, but also its growth towards the future. It is obviously an impossible task to invite everyone to contribute to this volume, although one thing is clear: none of these chapters would have been possible without Preface xi substantial research from all who work on nicotinic receptors. My personal bias will be apparent in the selection of topics, which I have organized around a synaptic theme, but which I hope successfully brings together genes, molecules, and circuitry in order to explain behavior and disease. I have tried to include all parts of the nicotinic receptor story in the book.

Birmingham, AL, USA Robin A. J. Lester

Contents

1 On the Discovery of the Nicotinic Acetylcholine Receptor Channel ...... 1 Richard Martindale and Robin A. J. Lester 2 Molecular Structure, Gating, and Regulation ...... 17 Steen E. Pedersen 3 Molecular Underpinnings of Neuronal Nicotinic Acetylcholine Receptor Expression ...... 39 Michael D. Scoﬁ eld and Paul D. Gardner 4 Presynaptic Nicotinic Acetylcholine Receptors: Subtypes and Functions ...... 61 Michael J. Marks, Sharon R. Grady, Tristan D. McClure-Begley, Heidi C. O’Neill, and Cristian A. Zambrano 5 Functional Distribution and Regulation of Neuronal Nicotinic ACh Receptors in the Mammalian Brain ...... 93 Jerrel L. Yakel 6 Nicotinic Signaling in Development...... 115 Catarina C. Fernandes, Adrian F. Lozada, and Darwin K. Berg 7 Presynaptic Nicotinic Acetylcholine Receptors and the Modulation of Circuit Excitability ...... 137 Chongbo Zhong, Gretchen Y. Lopez-Hernandez, David A. Talmage, and Lorna W. Role 8 Autonomic Nervous System Transmission ...... 169 Peter B. Sargent 9 Nicotinic Receptors in the Spinal Cord ...... 185 Boris Lamotte d’Incamps and Philippe Ascher

xiii xiv Contents

10 Slow Synaptic Transmission in the Central Nervous System...... 201 A. Rory McQuiston 11 The Effects of Nicotine on Learning and Memory ...... 217 Thomas J. Gould 12 Nicotinic Receptors as Targets for Novel Analgesics and Anti-inﬂ ammatory Drugs ...... 239 M. Imad Damaj, Kelen Freitas, Deniz Bagdas, and Pamela Flood 13 Nicotinic Acetylcholine Receptors and the Roles of the Alpha7 Subunit ...... 255 Michael Paolini, Mariella De Biasi, and John A. Dani 14 Role of Central Serotonin Receptors in Nicotine Addiction ...... 279 Massimo Pierucci, Stephanie Chambers, Lucy Partridge, Philippe De Deurwaerdère, and Giuseppe Di Giovanni 15 Neuronal Nicotinic Acetylcholine Receptors in Reward and Addiction ...... 307 Linzy M. Hendrickson and Andrew R. Tapper 16 Genetic Contributions of the α5 Nicotinic Receptor Subunit to Smoking Behavior ...... 327 Laura J. Bierut and Jerry A. Stitzel 17 Smoking-Related Genes and Functional Consequences ...... 341 Ines Ibañez-Tallon and Jessica L. Ables 18 Nicotinic Acetylcholine Receptors Along the Habenulo-Interpeduncular Pathway: Roles in Nicotine Withdrawal and Other Aversive Aspects ...... 363 Dang Q. Dao, Ramiro Salas, and Mariella De Biasi 19 Nicotinic Acetylcholine Receptors in Alzheimer’s and Parkinson’s Disease ...... 383 Kelly T. Dineley 20 Nicotinic Receptors and Mental Illness ...... 417 Sherry Leonard 21 Current and Future Trends in Drug Discovery and Development Related to Nicotinic Receptors ...... 435 Stephen P. Arneric and Emanuele Sher Contributors

Jessica L. Ables, M.D., Ph.D. Laboratory of Molecular Biology , The Rockefeller University , New York , NY , USA Stephen P. Arneric, Ph.D. Pain and Migraine Drug Hunting Team, Neuroscience Discovery , Lilly Research Centre, Eli Lilly and Company , Indianapolis , IN , USA Philippe Ascher, Ph.D. Laboratoire de Physiologie cérébrale , Université Paris Descartes , Paris , France Deniz Bagdas, Ph.D. Experimental Animals Breeding and Research Center, Faculty of Medicine , Uludag University , Bursa , Turkey Darwin K. Berg, Ph.D. Neurobiology Section, Division of Biological Sciences, University of California, San Diego , La Jolla, San Diego , CA 92093 , USA Mariella De Biasi, Ph.D. Department of Psychiatry, Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA Laura J. Bierut, M.D. Department of Psychiatry , Washington University School of Medicine , St. Louis , MO , USA Stephanie Chambers Department of Medical Sciences , Exeter Medical School, St. Luke’s Campus , Exeter, Devon , UK M. Imad Damaj, Ph.D. Department of Pharmacology and Toxicology , Virginia Commonwealth University, School of Medicine , Richmond , VA , USA John A. Dani, Ph.D. Department of Neuroscience, Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA Dang Q. Dao, Ph.D. Department Neuroscience , Baylor College of Medicine , Houston , TX , USA Philippe De Deurwaerdère, Ph.D. Centre National de la Recherche Scientiﬁ que, Institut des Maladies Neurodégénératives (UMR CNRS 5293) , Universitè de Bordeaux , Bordeaux Cedex , France

xv xvi Contributors

Boris Lamotte d’Incamps, Ph.D. Centre de Neurophysique, Physiologie, Pathologie , Université Paris Descartes , Paris , France Kelly T. Dineley, B.A., M.S. Ph.D. Department of Neurology , University of Texas Medical Branch , Galveston , TX , USA Catarina C. Fernandes, Ph.D. Neurobiology Section, Division of Biological Sciences , University of California, San Diego , La Jolla, San Diego , CA 92093 , USA Pamela Flood, M.D. Department of Anesthesia and Perioperative Care , University of California at San Francisco , San Francisco , CA , USA Kelen Freitas Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine , Richmond , VA , USA Paul D. Gardner, Ph.D. Department of Psychiatry , Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester , MA , USA Giuseppe Di Giovanni, Ph.D. Faculty of Medicine, Department of Physiology and Biochemistry , Malta University , Msida, Malta Thomas J. Gould, Ph.D. Department of Psychology and Neuroscience , Temple University , Philadelphia , PA , USA Sharon R. Grady, Ph.D. Institute for Behavioral Genetics , University of Colorado , Boulder , CO , USA Linzy M. Hendrickson, Ph.D. Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester , MA , USA Ines Ibañez-Tallon, Ph.D. Laboratory of Molecular Biology , The Rockefeller University , New York , NY , USA Sherry Leonard, Ph.D. Department of Psychiatry , University of Colorado, Anschutz Medical Campus , Aurora , CO , USA Robin A. J. Lester, Ph.D. Department of Neurobiology, University of Alabama at Birmingham , Birmingham , AL , USA Gretchen Y. López-Hernández, Ph.D. Department of Neurobiology and Behavior, Center for Brain and Spinal Cord Research , Stony Brook University , Stony Brook , NY , USA Adrian F. Lozada, Ph.D. Neurobiology Section, Division of Biological Sciences, University of California, San Diego , La Jolla, San Diego , CA 92093 , USA Michael J. Marks, B.S., M.S., Ph.D. Department of Psychology and Neuroscience, Institute for Behavioral Genetics , University of Colorado , Boulder , CO , USA Richard Martindale, B.S. University of Alabama at Birmingham , Birmingham , AL , USA Contributors xvii

Tristan D. McClure-Begley, Ph.D. Institute for Behavioral Genetics , University of Colorado , Boulder , CO , USA A. Rory McQuiston, Ph.D. Department of Anatomy and Neurobiology, Virginia Commonwealth University , Richmond , VA , USA Heidi C. O’Neill, Ph.D. Institute for Behavioral Genetics , University of Colorado , Boulder , CO , USA Michael Paolini, M.D. Department of Neuroscience , Baylor College of Medicine , Houston , TX , USA Lucy Partridge Department of Bioscience , Cardiff School of Biosciences , South Glamorgan , Wales , UK Steen E. Pedersen Ph.D. Department of Molecular Physiology and Biophysics , Baylor College of Medicine , Houston , TX , USA Massimo Pierucci, B.Sc. Faculty of Medicine, Department of Physiology and Biochemistry , Malta University , Msida, Malta Lorna W. Role, Ph.D. Department of Neurobiology and Behavior, Center for Brain and Spinal Cord Research , Stony Brook University , Stony Brook , NY , USA Ramiro Salas, Ph.D. Department of Psychiatry , Baylor College of Medicine , Houston , TX , USA Peter B. Sargent, Ph.D. Department of Cell and Tissue Biology , University of California at San Francisco , San Francisco , CA , USA Michael D. Scoﬁ eld, Ph.D. Department of Neurosciences , Medical University of South Carolina , Charleston , SC , USA Emanuele Sher, M.D., Ph.D. Neuroscience Discovery , Lilly Research Centre, Eli Lilly and Company , Windlesham, Surrey , UK Jerry A. Stitzel, Ph.D. Institute for Behavioral Genetics , University of Colorado , Boulder , CO , USA David A. Talmage, Ph.D. Department of Neurobiology and Behavior, Center for Brain and Spinal Cord Research , Stony Brook University , Stony Brook , NY , USA Andrew R. Tapper, Ph.D. Department of Psychiatry , Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester , MA , USA Jerrel L. Yakel, Ph.D. Department of Neurobiology , National Institute of Environmental Health Sciences , Research Triangle Park , NC , USA Cristian A. Zambrano, Ph.D. Institute for Behavioral Genetics , University of Colorado , Boulder , CO , USA Chongbo Zhong, M.D., Ph.D. Department of Neurobiology and Behavior, Center for Brain and Spinal Cord Research, Stony Brook University, Stony Brook, NY , USA