Handbook of Experimental Pharmacology Volume 162 Editor-in-Chief K.Starke, Freiburg i.Br. Editorial Board G.V.R. Born, London M. Eichelbaum, Stuttgart D.Ganten, Berlin F. Hofmann, Miinchen B.Kobilka, Stanford, CA w. Rosenthal, Berlin G.Rubanyi, Richmond, CA Springer-Verlag Berlin Heidelberg GmbH Neuropeptide Y and Related Peptides Contributors M. Alfalah, A. Beck-Sickinger, S. Bedoui, A. Brennauer, A. Buschauer, e. Carvajal, H.M. Cox, W.R. Crowley, O.Della-Zuana, S.Dove, Y. Dumont, J.-1. Fauchere, M. Feletou, J.P.Galizzi, M. Heilig, H. Herzog, S.von Horsten, T. Hoffmann, N.P. Hyland, S.P. Kalra, P.S. Kalra, T. Karl, A. Kask, M. Lonchampt, N.R. Levens, M.e. Michel, K. Morl, R. Pabst, J.P.Redrobe, R. Quirion, K. Tatemoto, T.E. Thiele, CiD. Wrann Editor Martin C. Michel , Springer Professor Martin C. Michel Academisch Medisch Centrum Afd. Farmacologie & Farmacotherapie Meibergdreef 15, 1105 AZ Amsterdam The Netherlands e-mail: [email protected] With 81 Figures and 23 Tables ISSN 0171-2004 ISBN 978-3-642-62282-3 Library of Congress Cataloging-in-Publication Data Neuropeptide Yand related peptides / contributors M. Alfalah ... [et al.) ; editor Martin C. Michel. p. cm. - (Handbook of experimental pharmacology ; v. 162) Includes bibliographical references and index ISBN 978-3-642-62282-3 ISBN 978-3-642-18764-3 (eBook) DOI 10.1007/978-3-642-18764-3 1. Neuropeptide Y- Physiological effect. 2. Neuropeptide Y- Derivatives-Physiological effect. 1. Alfa lah, M. (Marwan) II. Michel, Martin C., 1959-III. Series. QP905.H3 voI. 162 [QP552.N38) 615'.5. s-dc22 [573.8'48) 20030556335'.5 This work is subject to copyright. AII rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broad casting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current vers ion, and permission for use must always be obtained from Springer-Verlag. Violations are liable for Prosecution under the German Copyright Law. springeronline.com © Springer-Verlag Berlin Heidelberg 2004 Originally published by Springer-Verlag Berlin Heidelberg New York in 2004 Softcover reprint of the hardcover 1s t edition 2004 The use of general descriptive names, registered names, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consuIting the relevant literature. Cover design: design & production GmbH, Heidelberg Typesetting: Stiirtz AG, 97080 Wiirzburg Printed on acid-free paper 27/3150 hs - 5 4 3 2 1 O Preface Alittle more than 20years have now passedsincethe original discoveryofneuro peptide Y(NPY)by Tatemoto and colleagues.Meanwhilea Medlinesearch for the keyword 'NPY' yields more than 7,000hits, with a steady400-500 per year in the last decade. 500 ... 400 C1I CII .>... 300 CII Q. ... III 200 CII Q. C1I Q. 100 0 1980 1985 1990 1995 2000 2005 year Fig.1 Numberofpapersretrieved byyearofpublicationfrom Medlineunderthekeyword'NPV' Papers devoted exclusively to the closely related peptide YYand pancreatic po lypeptide are not even included in this statistic.Thus,it is not surprising that the field ofNPYresearch has made remarkableprogress and is comingofage. Phylogenetic research has shown that NPY is an evolutionary very old and highlyconserved peptide. Members ofthe NPYfamily ofpeptides act on specific G-protein coupled receptors, ofwhich fivesubtypes have been cloned in avariety ofspecies and whose signaltransduction is beingunraveled. Cloning of the genes for NPYand its receptors has enabled the generation of transgenic and knockout animals. Using such tools we now understand major aspects ofthe physiological role of NPY not only in the brain but also, for example, in the peripheral tissues ofthe cardiovascular, gastrointestinal and immune system. While NPYlargelyex erts these effects as a neurotransmitter, the related peptide YYand pancreatic po lypeptide predominantly act as hormones. Numerous peptide analogs and non- VI Preface peptide ligands acting on NPYreceptors, often in a subtype-selective manner, havebeen described.Theyset the stagefor the finalact,the definition ofthe role of NPY in human health and disease and ultimately the manipulation of this sy stemintreatingpatients. The present volume addresses allofthe above topics byestablished leaders in their respective areas. Iwould liketo take this opportunity to thank allcontribu tors for the time and effort they have spent in preparing their chapters and also Mrs. Susanne Dathe of Springer-Verlagwho expertly supported the project. On behalf of all contributors Ihope that experienced NPYaficionados willfind new and usefuladditional information in this volume and that newcomers to the field willdiscoverhowmuch excitingresearch this stillhasto offer. August2003 Martin C.Michel,Amsterdam List ofContributors (Theiraddressescanbefoundatthebeginningoftheirrespectivechapters.) Alfalah, M. 23 Kalra, S.P. 221 Kalra, P.S. 221 Beck-Sickinger, A.G. 479 Karl,T. 23 Bedoui, S. 23,409 Kask, A. 101 Brennauer, A. 505 Buschauer,A. 505 Larhammar, D. 75 Larson, E.T. 75 Carvajal, e. 101 Levens,N.R. 283 Cox, H.M. 45,389 Lonchampt,M. 283 Crowley, W.R. 185 Michel,M.e. 45,361 Della-Zuana, O. 283 Morl, K. 479 Dove,S. 505 Morris,M.J. 327 Dumont, Y. 101 Pabst, R. 23,409 Fauchere,J.-L. 283 Peletou,M. 283 Quirion,R. 101 Fredriksson, R. 75 Redrobe,J.P. 101 Galizzi, J.-P. 283 Salaneck, E. 75 Heilig, M. 251 Herzog, H. 447 Tatemoto, K. 1 Horsten, S.von 23,409 Thiele, T.E. 251 Hoffmann,T. 23 Holliday,N.D. 45 Westfall, T.e. 137 Hyland, N.P. 389 Wrann, e.D. 23 List ofContents Neuropeptide Y: Historyand Overview . K. Tatemoto PP,PYYand NPY:Synthesis, Storage, Releaseand Degradation. ......... 23 S.vonHtirsten, T. Hoffmann,M.Alfalah,C.D. Wrann, T. Karl, R.Pabst, S.Bedoui NPYReceptor Subtypes and TheirSignal Transduction. ............... 45 N.D.Holliday, M.C.Michel,H.M.Cox Phylogeny ofNPY-FamilyPeptides and Their Receptors. .............. 75 D.Larhammar,R.Fredriksson, E.T. Larson, E.Salaneck Neuropeptide Yand Its ReceptorSubtypes in the Central Nervous System: Emphasis on TheirRolein Animal Models ofPsychiatricDisorders. ..... 101 ].P. Redrobe, C.Carvajal,A.Kask, Y. Dumont,R.Quirion PrejunctionalEffectsofNeuropeptide Yand Its Roleas aCotransmitter. .. 137 T.C. Westfall Neuroendocrine Actions OfNeuropeptide Y......................... 185 WR. Crowley NPY: ANovelOnlOffSwitch for Control ofAppetite and Reproduction. .. 221 S.P. Kalra, P.S. Kalra Behavioral EffectsofNeuropeptide Y. .............................. 251 T.E.Thiele,M. Heilig X ListofContents NPYEffectson Food Intake and Metabolism......................... 283 N.R. Levens, M.Feletou,I.-P. Galizzi, I.-I.Fauchere,O.Della-Zuana, M.Lonchampt Neuropeptide YandCardiovascularFunction ........................ 327 M,J.Morris Neuropeptide Yand the Kidney.................................... 361 M.e. Michel NPY-Like Peptides, YReceptors and Gastrointestinal Function. ......... 389 N.P. Hyland,H.M.Cox NPYand ImmuneFunctions: Implications for Health and Disease ....... 409 S.Bedoui, R.Pabst,S.von Horsten Transgenic and KnockoutModels in NPYResearch ................... 447 H. Herzog Structure-Activity Relationship ofPeptide-Derived Ligandsat NPYReceptors. ....................... 479 K.Morl,A.G.Beck-Sickinger Structure-ActivityRelationships ofNonpeptide Neuropeptide YReceptor Antagonists. ................. 505 A.Brennauer, S.Dove,A.Buschauer Subject Index.................................................. 547 Neuropeptide Y: History and Overview K.Tatemoto DepartmentofMolecularPhysiology,InstituteforMolecularandCellularRegulation, Gunma University,371-8512 Maebashi,Japan e-mail:[email protected] Introduction . . . . . . . . . . . . . . . . . 2 2 IsolationandPrimaryStructuresofNPY. 2 2.1 DiscoveryofNPY . . . . . 2 2.2 PrimaryStructureofNPY. . . 3 2.3 NPYmRNA. . . . . . . . . . . 4 3 CellularLocalizationofNPY. 4 3.1 NPYinthe Peripheral Nervous System. 4 3.2 NPYinthe Central Nervous System . . 5 4 Studieson the Receptorsand PhysiologicalFunctionsofNPY(1982-1992). 5 4.1 PeripheralActions ofNPY . 5 4.1.1Cardiovascular Response . . 5 4.1.2 HormoneSecretion . . . . . 6 4.2 CentralActions ofNPY . . . 6 4.2.1 Cardiovascular Response . . 6 4.2.2CircadianRhythms . . . . . 6 4.2.3 Food Intakeand Energy Expenditure 6 4.2.4 HormoneSecretion and Reproduction. 7 4.2.5Stress,Depression,Anxiety,and Pain . 7 4.2.6Seizures. . . . . . . . . . . . . . . . . . 8 4.3 NPYReceptor Bindingand IntracellularSignaling. 8 4.4 NPYReceptor Agonistsand Antagonists. . . . . . . 8 4.5 NPYReceptor Subtypes. . . . . . . . . . . . . . . . 8 5 Studieson the ReceptorsandPhysiologicalFunctionsofNPY(1992-2002). 9 5.1 Cloning ofNPYReceptor Subtypes. 9 5.1.1Y1Receptor. . . . . . 10 5.1.2Y2Receptor. . . . . . 10 5.1.3PutativeY3Receptor. 10 5.1.4Y Receptor. 10 4 5.1.5 Y5Receptor. . . . . . 11 5.1.6Y6Receptor . . . . . . 11 5.2 SelectiveNPYReceptor Agonistsand Antagonists . 11 5.3 NPYReceptor Subtypesand TheirPhysiological Functions . 12 5.3.1CardiovascularResponse. . . . . . . 12 5.3.2Circadian Rhythms . . . . . . . . . . 12 5.3.3Food Intake and EnergyExpenditure 12