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. 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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. Printed on acid-free paper 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 develop- ment 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 sys- tem, 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 with- drawal, 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 develop- ment 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 func- tion have enhanced our understanding of fundamental biological systems are cov- ered 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 func- tion 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 cogni- tive 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,