Encyclopedia of Molecular Pharmacology

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Encyclopedia of Molecular Pharmacology(2nd edition)

With 487 Figures* and 171 TablesSTEFAN OFFERMANNS AND WALTER RO*For color figures please see our Electronic Reference on www.springerlink.com

A C.I.P. Catalog record for this book is available from the Library of Congress

ISBN: 978-3-540-38916-3This publication is available also as:Electronic publication under ISBN 978-3-540-38918-7 andPrint and electronic bundle under ISBN 978-3-540-38921-7

Library of Congress Control Number: 2008921487

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights oftranslation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks.Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, inits current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under theGerman Copyright Law.

Springer-Verlag Berlin Heidelberg New York 2008

ote f

inmuSpringer is part of Springer Science+Business Media

springer.comThe use of registered names, trademarks, etc. in this publication does nexempt from the relevant protective laws and regulations and therefor

Product liability: The publishers cannot guarantee the accuracy of anymedications contained in this book. In every individual case the userPrinted on acid-free paper SPIN: 191230 2109 5 4 3 2 1 0imply, even in the absence of a specific statement, that such names areree for general use.

formation about the application of operative techniques andst check such information by consulting the relevant literature.Editors:Professor Dr. Stefan OffermannsPharmakologisches InstitutUniversitt HeidelbergIm Neuenheimer Feld 366D-69120 HeidelbergGermanyStefan.Offermanns@pharma.uni-heidelberg.de

Professor Dr. Walter RosenthalLeibniz-Institut fr Molekulare Pharmakologie (FMP)Campus Berlin-BuchRobert-Rssle-Str. 10D-13125 BerlinGermanyRosenthal@fmp-berlin.de

to Frank Krabbes for his technical expertise. Finally, we would like to express our gratitude to Dr. Claudia Lange

for successfully managing the project and for her encouraging support. It has been a pleasure to work with her.Preface to the First Edition

The era of pharmacology, the science concerned with the understanding of drug action, began only about 150 yearsago when Rudolf Buchheim established the first pharmacological laboratory in Dorpat (now, Tartu, Estonia). Sincethen, pharmacology has always been a lively discipline with open borders, reaching out not only to other lifesciences such as physiology, biochemistry, cell biology and clinical medicine, but also to chemistry and physics.In a rather successful initial phase, pharmacologists devoted their time to describing drug actions either at the singleorgan level or on an entire organism. Over the last few decades, however, research has focused on the molecularmechanisms by which drugs exert their effects. Here, cultured cells or even cell-free systems have served as models.As a consequence, our knowledge of the molecular basis of drug actions has increased enormously. The aim ofEncyclopedic Reference of Molecular Pharmacology is to cover this rapidly developing field.

The reductionist approach described above has made it increasingly important to relate the molecular processesunderlying drug actions to the drug effect on the level of an organ or whole organism. Only this integrated view willallow the full understanding and prediction of drug actions, and enable a rational approach to drug development. Onthe molecular or even atomic level, new disciplines such as bioinformatics and structural biology have evolved.They have gained major importance within the field but are particularly relevant for the rational development anddesign of new drugs. Finally, the availability of the complete genome sequence of an increasing number of speciesprovides a basis for systematic, genome-wide pharmacological research aimed at the identification of new drugtargets and individualised drug treatment (pharmacogenomics and pharmacogenetics). All these aspects areconsidered in this encyclopedia.

The main goal of the Encyclopedia is to provide up-to-date information on the molecular mechanisms of drugaction. Leading experts in the field have provided 159 essays, which form the core structure of this publication.

Most of the essays describe groups of drugs and drug targets, with the emphasis not only on already exploited drugtargets, but also on potential drug targets as well. Several essays deal with the more general principles ofpharmacology, such as drug tolerance, drug addiction or drug metabolism. Others portray important cellularprocesses or pathological situations and describe how they can be influenced by drugs. The essays arecomplemented by more than 1600 keywords, for which links are provided. By looking up the keywords or titles ofessays highlighted in each essay, the reader can obtain further information on the subject. The alphabetical order ofentries makes the Encyclopedia very easy to use and helps the reader to search successfully. In addition, the namesof authors are listed alphabetically, together with the title of their essay, to allow a search by author name.

Apart from very few exceptions, the entries in the main text do not contain drug names in their titles. Instead, drugsthat are commonly used all over the world are listed in the Appendix. Also included in the Appendix are fourextensive sections that contain tables listing proteins such as receptors, transporters or ion channels, which are ofparticular interest as drug targets or modulators of drug action.

The Encyclopedia provides valuable information for readers with different expectations and backgrounds (fromscientists, students and lecturers to informed lay-people) and fills the gap between pharmacology textbooks andspecialized reviews.

All the contributing authors as well as the editors have taken great care to provide up-to-date information. However,inconsistencies or errors may remain, for which we assume full responsibility. We welcome comments, suggestionsor corrections and look forward to a stimulating dialog with the readers of the Encyclopedic Reference of MolecularPharmacology whether their comments concern the content of an individual entry or the entire concept.

We are indebted to our colleagues for their excellent contributions. It has been a great experience, both personallyand scientifically, to interact with and learn from the 200 plus contributing authors. We would also like to thankMs. Hana Deuchert andMs. Katharina Schmalfeld for their excellent and invaluable secretarial assistance during allthe stages of this project. Within Springer-Verlag, we are grateful to Dr. Thomas Mager for suggesting the project andHeidelberg/Berlin, June 2003STEFAN OFFERMANNS AND WALTER ROSENTHAL

Preface to the Second Edition

The first edition of the Encyclopedic Reference of Molecular Pharmacologywas well received by its readers, thanksto the excellent work done by the authors, of whom most have contributed to the second edition as well. The basicstructure of the Encyclopedia has remained unchanged. It is primarily based on essays, which have been updated,and their number has been increased to 225 to include many new exciting areas. These essays cover important drugsand drug targets, but also general principles of pharmacology as well as cellular processes and pathologicalsituations which are relevant for drug action. In addition, there are about xy key words linked to the essays. TheEncyclopedia is complemented by an Appendix, which has been greatly enlarged, listing more than 700 drugs andmore than 4,000 proteins that act as receptors, membrane transport proteins, transcription factors, enzymes oradhesion molecules.

During the preparation, we greatly enjoyed the interaction with all our colleagues who contributed to this referencework. It has been a pleasure and an enriching experience to deal with so many facets of pharmacology. We are verythankful to the contributing authors for the careful updating of their essays, and, in particular, we would like toexpress our gratitude to the more than xy new authors who have written excellent essays on novel topics. Finally, wewould like to thank Dr. Michaela Bilic and Simone Giesler from Springer for their enthusiasm throughout theproject and their constant support.

Heidelberg/Berlin, November 2007STEFAN OFFERMANNS AND WALTER ROSENTHAL

FABIO ANTONIOLI ANDREAS BARTHEL

Bochum

The Weizmann Institute of ScienceRehovot

Israel Germany

Andreas.Barthel@post.rwth-aachen.deFabio.Antonioli@weizmann.ac.ilDepartment of Biological Regulation BG-Kliniken BergmannsheilRuhr-UniversityList of Contributors

AMY N. ABELLUniversity of North CarolinaChapel Hill, NCUSAAmy_Abell@med.unc.edu

IAN M. ADCOCKImperial CollegeLondonUKian.adcock@ic.ac.uk

GEORGE K. AGHAJANIANYale School of MedicineNew Haven, CTUSAgeorge.aghajanian@yale.edu

KLAUS AKTORIESInstitut fr Experimentelle und Klinische Pharmakologie undToxikologie, Albert-Ludwigs-Universitt FreiburgFreiburgGermanyklaus.aktories@pharmakol.uni-freiburg.de

NEIL ANDERSONDepartment of NeuropharmacologyCopenhagenDenmark

ION ANGHELESCUDepartment of Psychiatry and PsychotherapyCharit, CBFBerlinGermanyion.anghelescu@charite.de

LUCIO ANNUNZIATODivision of Pharmacology, Department of NeuroscienceSchool of Medicine, Federico II University of NaplesNaplesItalylannunzi@unina.it

MARINA P. ANTOCHDepartment of Molecular and Cancer BiologyRoswell Park Cancer InstituteNYUSAantochm@ccf.orgHELLMUT G. AUGUSTINJoint Research Division Vascular Biology of the MedicalFaculty MannheimUniversity of Heidelberg, and the German Cancer ResearchCenter (DKFZ)Mannheim and HeidelbergGermanyh.augustin@dkfz-heidelberg.de

JOHAN AUWERXInstitut de Gntique et Biologie Molculaire et Cellulaire-Institut Clinique de la SourisIllkirchFranceauwerx@igbmc.u-strasbg.fr

CHRISTIAN AYMANNSNephrology Division, Department of Internal Medicine IUniversity HospitalUlmGermany

WILLIAM BABBITTUCSF School of MedicineSan Francisco, CAUSAwilliam.babbitt@ucsf.edu

EVELYN BACKNovartis Pharma GmbHNrnbergGermanyevelyn_back@hotmail.com

MICHAEL BADERMax Delbrck Center for Molecular Medicine (MDC)Campus Berlin-BuchGermanymbader@mdc-berlin.de

CLIFFORD J. BAILEYSchool of Life and Health SciencesAston UniversityBirminghamUKc.j.bailey@aston.ac.uk

JILLIAN G. BAKERUniversity of NottinghamUKjillian.baker@nottingham.ac.uk.

HOLGER BASTIANSInstitute for Molecular Biology and Tumor Research (IMT)Philipps-University MarburgGermanybastians@imt.uni-marburg.de

JOSEPH A. BEAVODepartment of PharmacologyUniversity of WashingtonSeattle, WAUSAbeavo@u.washington.edu

HEINZ BECKLabor fr Experimentelle Epileptologie, Klinik frEpileptologieUniversittskliniken BonnBonnGermanyheinz.beck@ukb.uni-bonn.de

CORD-MICHAEL BECKERInstitut fr BiochemieEmil-Fischer-Zentrum, Universitt Erlangen-NrnbergErlangenGermanycmb@biochem.uni-erlangen.de

JRGEN BEHRENSNikolaus-Fiebiger-Center for Molecular MedicineErlangenGermanyjbehrens@molmed.uni-erlangen.de

FABRIZIO BENEDETTIDepartment of NeuroscienceUniversity of Turin Medical SchoolTurinItalyfabrizio.benedetti@unito.it

MARTIN R. BERGERDKFZ, Toxicology and Chemotherapy UnitIm Neuenheimer FeldHeidelbergGermanym.berger@dkfz.de

FELICITY K. R. BERTRAMSackler Institute of Pulmonary PharmacologyKings College LondonLondonUKfelicity.bertram@kcl.ac.uk

MARTIN BIELMunich Center for Integrated Protein Science CiPSM andDepartment of Pharmacy Center for Drug ResearchLudwig-Maximilians-Universitt MnchenMnchen

x List of ContributorsGermanymbiel@cup.uni-muenchen.deHANS K. BIESALSKIInstitute of Biological Chemistry and NutritionUniversity of HohenheimStuttgartGermanybiesal@uni-hohenheim.de

TIFFANY BLAKELaboratory of GI Developmental BiologyDepartment of SurgeryMedicine & Lombardi Cancer CenterGeorgetown UniversityWashington, DCUSAgutresearch@yahoo.com

GREGORY LE BLATCHDepartment of Biochemistry, Microbiology andBiotechnologyRhodes UniversityGrahamstownSouth Africag.blatch@ru.ac.za

CLARK M. BLATTEISUniversity of Tennessee Health Science CenterCollege of MedicineMemphis, TNUSAblatteis@physio1.utmem.edu

ANDREE BLAUKATTA Oncology, Merck Serono ResearchMerck KGaADarmstadtGermanyAndree.Blaukat@merck.de

MICHAEL BHMKlinik fr Innere Medizin IIIHomburg/SaarGermanyboehm@med-in.uni-saarland.de

MICHELLE BOONEDepartment of PhysiologyRadboud University Nijmegen Medical CenterNijmegenThe Netherlands

ARNDT BORKHARDTChildrens University Hospital, Department of PaediatricHaematology & Oncology & Clinical ImmunologyUniversitt DsseldorfDsseldorfGermanyarndt.borkhardt@med.uni-duesseldorf.de

JACK BOTTINGWilliam Harvey Research InstituteSchool of Medicine and DentistrySt. Bartholomews and Royal LondonLondon

UKr.m.botting@qmul.ac.uk

REGINA BOTTINGWilliam Harvey Research InstituteSchool of Medicine and DentistrySt. Bartholomews and Royal LondonLondonUKr.m.botting@qmul.ac.uk

STEFAN-MARTIN BRAND-HERRMANNLeibniz-Institut fr ArterioskleroseforschungUniversitt MnsterMnsterGermanybrandher@uni-muenster.de

MICHAEL BRUAbteilung Anaesthesiologie und Operative IntensivmedizinJustus-Liebig-UniversittGieenGermanymeb@anesthesiologie.de

MATTHEW D. BREYERDivision of NephrologyMedical Center, Vanderbilt UniversityNashville, TNUSArich.breyer@vanderbilt.edu

RICHARD M. BREYERDivision of NephrologyMedical Center, Vanderbilt UniversityNashville, TNUSArich.breyer@vanderbilt.edu

JRGEN BROCKMLLERZentrum Pharmakologie und ToxikologieGeorg-August-Universitt GttingenGttingenGermanyjurgen.brockmoller@med.uni-goettingen.de

MATTHEW D. BROWNDepartment of Pathology, Brigham and Womens HospitalHarvard Medical SchoolBoston, MAUSA

EDWARD M. BROWNDivision of Endocrinology, Diabetes and HypertensionBrigham and Womens HospitalBoston, MAUSAembrown@rics.bwh.harvard.edu

EREZ M. BUBLILDepartment of Biological RegulationThe Weizmann Institute of ScienceRehovot

IsraelErez.Bublil@weizmann.ac.ilFRED BUNZThe Sidney Kimmel Comprehensive Cancer Center at JohnsHopkins, The Johns Hopkins School of MedicineBaltimore, MDUSAbunzfre@mail.jhmi.edu

RMY BURCELINInstitute of Molecular MedicineINSERM, IFR 31Universit Paul SabatierToulouseFranceburcelin@toulouse.inserm.fr

GEOFFREY BURNSTOCKAutonomic Neuroscience CentreRoyal Free and University College Medical SchoolLondonUKg.burnstock@ucl.ac.uk

AMAN U. BUZDARDepartment of Breast Medical OncologyThe University of Texas, M.D. Anderson Cancer CenterHouston, TXUSAAbuzdar@mdanderson.org

PATRICE D. CANIInstitute of Molecular MedicineINSERM, IFR 31Universit Paul SabatierToulouseFrance

PATRICK J. CASEYDuke University Medical CenterDurham, NCUSACasey006@mc.duke.edu

TAMARA CASTANEDADepartment of PsychiatryObesity Research Center, University of CincinnatiCincinnati, OHUSAcastant@ucmail.uc.edu

THOMAS K. H. CHANGFaculty of Pharmaceutical SciencesThe University of British ColumbiaVancouver, BCCanadatchang@interchange.ubc.ca

DI CHENANZAC Research InstituteThe University of RochesterNY, USA

BENJAMIN N. R. CHEYETTEUniversity of CaliforniaSan Francisco, CA

List of Contributors xiUSAbc@lppi.ucsf.edu

RUSSELL COMPTONSchool of BiosciencesThe University of BirminghamUKrmc095@bham.ac.uk

MARGARET R. CUNNINGHAMStrathclyde Institute of Pharmacy and Biomedical SciencesUniversity of StrathclydeGlasgow, UKmargaret.r.cunningham@strath.ac.uk

DAVID CZOCKNephrology Division, Department of Internal Medicine IUniversity HospitalUlmGermany

ANTHONY P. DAVENPORTClinical Pharmacology UnitUniversity of CambridgeLevel 6, Centre for Clinical Investigation, AddenbrookesHospital, Cambridge, CB2 2QQUKApd10@medschl.cam.ac.uk

SHAHEEHAH DAWOODDepartment of Breast Medical OncologyThe University of Texas, M.D. Anderson Cancer CenterHouston, TXUSAs.dawood@mdanderson.org

WIM DECLERCQDepartment of Molecular BiologyGhent UniversityBelgium

PETER M.T. DEENDepartment of PhysiologyRadboud University Nijmegen Medical CenterNijmegenThe Netherlandsp.deen@ncmls.ru.nl

VINCENZO DI MARZOEndocannabinoid Research Group, Institute of BiomolecularChemistryPozzuoliItalyvdimarzo@icmib.na.cnr.it

MIREILLE DELHASEDepartment of PharmacologyUniversity of CaliforniaSan Diego, CAUSAmdelhase@ucsd.edu

STEFAN DHEINUniversitt Leipzig, Herzzentrum LeipzigKlinik fr HerzchirurgieLeipzig

xii List of ContributorsGermanydhes@medizin.uni-leipzig.deHOLGER J. DOEGEEli Lilly & Company, Intergrative BiologyGreenfield, IN 46140USAdoegehj@lilly.com

ANDREAS DRAGUHNInstitut fr Physiologie und PathophysiologieUniversitt HeidelbergHeidelbergGermanyandreas.draguhn@urz.uni-heidelberg.de

COLIN ROBERT DUNSTANHead, Bone Research ProgramANZAC Research Institute, The University of SydneyConcord, NSWAustralia

ANNE DURKANHospital for Sick ChildrenToronto, ONTCanada

BJARKE EBERTDepartment of ElectrophysiologyCopenhagenDenmarkbjeb@lundbeck com

ROBERT EDWARDSDepartments of Neurology and PhysiologyUniversity of California at San FranciscoSan Francisco, CAUSAedwards@itsa.ucsf.edu

MICHEL EICHELBAUMDr. Margarete Fischer-Bosch Institute of ClinicalPharmacologyStuttgartGermanymichel.eichelbaum@ikp-stuttgart.de

JOHN H. EXTONHoward Hughes Medical Institute and Department ofMolecular Physiology and BiophysicsVanderbilt UniversityNashville, TNUSAjohn.exton@mcmail.vanderbilt.edu

SANDRINE FAIVREDepartment of Medical OncologyBeaujon University HospitalClichy CedexFrance

FRANCESCO FALCIANISchool of BiosciencesThe University of Birmingham

UKf.falciani@bham.ac.uk

NAPOLEONE FERRARAGenentech, Inc.South San Francisco, CAUSAnf@gene.com

THOMAS J. FEUERSTEINSektion Klinische Neuropharmakologie, NeurozentrumNeurochirurgische UniversittsklinikFreiburgGermanythomas.feuerstein@uniklinik-freiburg.de

VEIT FLOCKERZIInstitut fr Pharmakologie und ToxikologieUniversitt des SaarlandesHomburgGermanyveit.flockerzi@uniklinik-saarland.de

MARYANN FOOTEM A Foote Associates, Westlake VillageCA and Department of MicrobiologyMonash UniversityAustraliafmawriter@aol.com

ULRICH FRSTERMANNJohannes Gutenberg UniversityMainzGermanyulrich.forstermann@uni-mainz.de

JRGEN FRANKzet - Centre for Alternative and Complementary Methods toAnimal TestingLinzAustriaj.frank@zet.or.at

JEAN-MARIE FRERECentre dIngenierie des ProtinesUniversity of LigeLigeBelgiumjmfrere@ulg.ac.be

CHRISTIAN FREUNDProtein Engineering GroupLeibniz-Institute for Molecular PharmacologyBerlinGermanyfreund@fmp-berlin.de

ELKE C. FUCHSAbteilung Klinische NeurobiologieInterdisziplinres Zentrum fr Neurowissenschaften (IZN)HeidelbergGermanyE.Fuchs@urz.uni-heidelberg.de

RUTH GEISS-FRIEDLANDERDepartment of Biochemie I, Faculty of MedicineUniversity GoettingenGoettingen

Germanyf.melchior@medizin.uni-goettingen.deGERD GEISSLINGERInstitut fr Klinische Pharmakologie, Klinikum der JohannWolfgang Goethe-Universitt Frankfurt am MainFrankfurtGermanygeisslinger@em.uni-frankfurt.de

TOM GELDARTDepartment of Medical OncologySouthampton General HospitalSouthamptonUKtomgeldart@doctors.org.uk

NANCY GERITSDepartment of Microbiology and VirologyInstitute of Medical Biology, University of TromsoTromsoNorwaynancyg@fagmed.uit.no

PIERRE GERMAINDepartment of Cell Biology and Signal TransductionInstitut de Genetique et de Biologie Moleculaire et Cellulaire(IGBMC)Illkirch CedexFrancegermain@igbmc.u-strasbg.fr

STEPHEN J. GETTINGDepartment of Human and Health Sciences, School ofBiosciencesUniversity of WestminsterLondonUKs.getting@wmin.ac.uk

JEAN-MARIE GHUYSENCentre dIngenierie des ProtinesUniversity of LigeLigeBelgium

ERIC GLASGOWLaboratory of GI Developmental Biology, Department ofSurgeryMedicine & Lombardi Cancer Center Georgetown UniversityWashington, DCUSA

JENNIFER L. GLICKDepartment of PharmacologyUniversity of WashingtonSeattle, WAUSAjendogger@yahoo.com

MURALI GOPALAKRISHNANGlobal Pharmaceutical Research and DevelopmentAbbott LaboratoriesAbbott Park, IL

List of Contributors xiiiUSAmurali.gopalakrishnan@abbott.com

ANDREAS GREINACHERErnst-Moritz-Arndt-Universitt GreifswaldGreifswaldGermanygreinach@mail.uni-greifswald.de

SERGIO GRINSTEINHospital for Sick ChildrenToronto, ONTCanadasga@sickkids.ca

HINRICH GRONEMEYERDepartment of Cell Biology and Signal TransductionInstitut de Genetique et de Biologie Moleculaire et Cellulaire(IGBMC)Illkirch CedexFrancehg@igbmc.u-strasbg.fr

MARKUS GRUBEDepartment of Pharmacology, Center of Pharmacology andExperimental TherapeuticsErnst-Moritz-Arndt University GreifswaldGreifswaldGermany

THOMAS GUDERMANNPhilipps-Universitt MarburgMarburgGermanyguderman@mailer.uni-marburg.de

JULIE M. HALLHamner Institutes of Health SciencesResearch Triangle Park, NCUSAhall0130@mc.duke.edu

D. GRAHAME HARDIECollege of Life SciencesUniversity of DundeeScotlandUKd.g.hardie@dundee.ac.uk

AARON N. HATADivision of NephrologyMedical Center, Vanderbilt UniversityNashville, TN,USA

JULIA HEADDepartment of Medical OncologySouthampton General HospitalSouthamptonUKjulia.head@icr.ac.uk

LUTZ HEINUniversity of FreiburgFreiburg

xiv List of ContributorsGermanylutz.hein@pharmakol.uni-freiburg.deUWE HEINEMANNJohannes-Mller-Institut fr PhysiologieUniversittsklinikum CharitHumboldt-Universitt zu BerlinBerlinGermanyuwe.heinemann@charite.de

MATTHIAS HEINZEProtein Engineering GroupLeibniz-Institute for Molecular PharmacologyBerlinGermany

PETER HEISIGPharm. Biology and MicrobiologyUniversity of HamburgHamburgGermanyheisig@chemie.uni-hamburg.de

CLAUS W. HEIZMANNDepartment of Pediatrics, Division of Clinical Chemistry andBiochemistryUniversity of ZurichZurichSwitzerlandheizmann@access.unizh.ch

RICARDO HERMOSILLADepartment of Molecular Pharmacology and Cell BiologyCharit Medical University BerlinBerlinGermanyricardo.hermosilla@charite.de

MLANIE HROULTJoint Research Division Vascular Biology of the MedicalFaculty MannheimUniversity of Heidelberg, and the German Cancer ResearchCenter (DKFZ)Mannheim and HeidelbergGermany

PETER HERRLICHLeibniz Institute for Age Research Fritz-Lipmann-InstituteJenaGermanypherrlich@fli-leibniz.de

HEIKO HERWALDLund UniversityLundSwedenHeiko.Herwald@med.lu.se

ISABELLA HEUSERDepartment of Psychiatry and PsychotherapyCharit, CBFBerlin

Germanyisabella.heuser@charite.de

STEPHEN J. HILLUniversity of NottinghamUKstephen.hill@nottingham.ac.uk

MARIUS C. HOENERF. Hoffmann-La Roche, Pharmaceuticals Division,Discovery NeuroscienceBaselSwitzerlandmarius.hoener@roche.com

FRANZ HOFMANNInstitut fr Pharmakologie und ToxikologieTU MnchenMnchenGermanyPharma@ipt.med.tu-muenchen.de

VOLKER HLLTOtto-von-Guericke-Universitt MagdeburgMagdeburgGermanyVolker.Hoellt@medizin.uni-magdeburg.de

HELMUT HOLTMANNRudolf-Buchheim-Institut fr PharmakologieFrankfurter Strae 107D-35392 GieenHoltmann.Helmut@MH-Hannover.de

LSZL HOMOLYAResearch Group of Membrane Biology, Hungarian Academyof SciencesHungary

RICHARD HORUKDepartment of ImmunologyBerlex BiosciencesRichmond CAUSAhoruk@pacbell.net

SANDER M. HOUTENLaboratory Genetic Metabolic DiseasesAcademic Medical CenterAmsterdamThe Netherlandss.m.houten@amc.uva.nl

DANIEL HOYERPsychiatry/Neuroscience ResearchNovartis Institutes for Biomedical Research BaselBaselSwitzerlanddaniel.hoyer@novartis.com

NORBERT HBNERMDC for Molecular MedicineBerlin

Germanynhuebner@mdc-berlin.deCHRISTINE HUPPERTZPharma ResearchNovartis Pharma AGSwitzerlandchristine.huppertz@novartis.com

ANDREA HUWILERpharmazentrum frankfurtJohann Wolfgang Goethe-Universitt Frankfurt am MainGermanyhuwiler@em.uni-frankfurt.de

KEIJI IMOTONational Institute for Physiological Sciences and School ofLife ScienceThe Graduate University for Advanced StudiesOkazakiJapankeiji@nips.ac.jp

KIYOMI ITODepartment of Clinical PharmacokineticsHoshi UniversityTokyo, Japank-ito@hoshi.ac.jp

KENNETH A. JACOBSONMolecular Recognition Section, Laboratory of BioorganicChemistry, National Institute of Diabetes Digestive andKidney DiseasesNational Institutes of HealthBethesda, MDUSAkajacobs@helix.nih.gov

REINHARD JAHNMax-Planck-Institut fr biophysikalische ChemieGttingenGermanyrjahn@gwdg.de

ELISABETH M. JEANCLOSUniversittsklinikum DsseldorfDsseldorfGermanyElisabeth.Jeanclos@uni-duesseldorf.de

THOMAS J. JENTSCHLeibniz-Institut fr Molekulare Pharmakologie (FMP) andMax-Delbrck-Centrum fr Molekulare Medizin (MDC)BerlinGermanyjentsch@fmp-berlin.de

GARY L. JOHNSONUniversity of North CarolinaChapel Hill, NCUSAGary_Johnson@med.unc.edu

ROGER A. JOHNSONDepartment of Physiology and BiophysicsState University of New YorkNew York, NY

List of Contributors xvUSAroger.johnson@stonybrook.edu

HANS-GEORG JOOSTDepartment of PharmacologyGerman Institute of Human NutritionPotsdam-RehbrueckeGermanyjoost@dife.de

THOMAS JUNGHANSSSection of Clinical Tropical MedicineUniversity Hospital HeidelbergHeidelbergGermanyThomas.Junghanss@urz.uni-heidelberg.de

VOLKHARD KAEVERInstitute of Pharmacology, Medical School HannoverHannoverGermanykaever.volkhard@mh-hannover.de

SHITIJ KAPURPET Centre - Schizophrenia DivisionCentre for Addiction and Mental HealthToronto, ONTCanadashitij_kapur@camh.net

JOHN J. P. KASTELEINDepartment of Vascular MedicineAcademic Medical Center, University of AmsterdamAmsterdamThe Netherlandsj.j.kastelein@amc.uva.nl

STEPHAN KELLENBERGERDpartement de pharmacologie et de toxicologie delUniversitLausanneSwitzerlandStephan.Kellenberger@unil.ch

FRIEDER KELLERNephrology Division, Department of Internal Medicine IUniversity HospitalUlmGermanyFrieder.Keller@uniklinik-ulm.de

TERRY P. KENAKINReceptor BiochemistryGlaxo Wellcome ResearchResearch Triangle Park, NCUSAtpk1348@GlaxoWellcome.com

ELAINE F. KENNYSchool of Biochemistry and ImmunologyTrinity College DublinIrelandkennyef@tcd.ie

KRISTOF KERSSEDepartment of Molecular Biology

xvi List of ContributorsGhent UniversityBelgiumHEIKO KILTERKlinik fr Innere Medizin IIIHomburg/SaarGermanykilter@med-in.uni-saarland.de

PATRICK KITABGIINSERM U732/Universit Pierre et Marie CurieHopital St-AntoineParis cedex 12Francekitabgi@st-antoine.inserm.fr

SUSANNE KLUMPPInstitut fr Pharmazeutische und Medizinische ChemieWestflische Wilhelms-UniversittMnsterGermanyseklumpp@uni-muenster.de

ENNO KLUSSMANNLeibniz-Institut frMolekulare Pharmakologie Department ofMolecular Pharmacology and Cell BiologyCharit-Universittsmedizin BerlinBerlinGermanyklussmann@fmp-berlin.de

CLAUDE KNAUFInstitute of Molecular MedicineINSERM, IFR 31Universit Paul SabatierToulouseFrance

KLAUS-PETER KNOBELOCHLeibniz-Institut fr Molekulare PharmakologieBerlinGermanyknobeloch@fmp-berlin.de

BRIAN K. KOBILKAStanford University Medical SchoolStanford, CAUSAkobilka@stanford.edu

DORIS KOESLINGPharmakologie und ToxikologieRuhr-Universitt BochumBochumGermanydoris.koesling@ruhr-uni-bochum.de

SPIRO M. KONSTANTINOVDepartment of Pharmacology and ToxicologyMedical University in Sofia, Faculty of PharmacySofiaBulgariakonstantinov.spiromihaylov@gmail.com

KENNETH S. KORACHNational Institute of Environmental Health SciencesResearch Triangle Park, NC

USAkorach@niehs.nih.gov

MICHAEL KRACHTMedizinische Hochschule HannoverHannoverGermanyKracht.Michael@MH-Hannover.de

EBERHARD KRAUSELeibniz-Institut fr Molekulare PharmakologieBerlinGermanyekrause@fmp-berlin.de

GERD KRAUSEForschungsinstitut fr Molekulare PharmakologieCampus Berlin-BuchGermanygkrause@fmp-berlin.de

HANS-GEORG KRUSSLICHAbteilung VirologieUniversittsklinikum HeidelbergHeidelbergGermanyHans-Georg_Kraeusslich@med.uni-heidelberg.de

REINHOLD KREUTZFreie Universitt BerlinBerlinGermanykreutz@medizin.fu-berlin.de

KERSTIN KRIEGLSTEINUniversitt GttingenGttingenGermanykkriegl@gwdg.de

JOSEF KRIEGLSTEINWestflische Wilhelms-Universitt, Institut frPharmazeutische und Medizinische ChemieMnsterGermanykrieglst@uni-muenster.de

ANJA KRIPPNER-HEIDENREICHInstitut of Cellular MedicineNewcastle UniversityNewcastle upon TyneUKanja.krippner@izi.uni-stuttgart.de

HEYO K. KROEMERDepartment of Pharmacology, Center of Pharmacology andExperimental TherapeuticsErnst-Moritz-Arndt University GreifswaldGreifswaldGermanykroemer@uni-greifswald.de

ROHINI KUNERInstitute for PharmacologyUniversity of HeidelbergHeidelberg

Germanyrohini.kuner@pharma.uni-heidelberg.deNAGOMI KUREBAYASHIDepartment of PharmacologyJuntendo University School of MedicineTokyoJapannagomik@med.juntendo.ac.jp

THORSTEN LANGMax-Planck-Institut fr biophysikalische ChemieGttingenGermanytlang@.gwdg.de

MICHAEL LANZERDepartment of ParasitologyUniversity Hospital HeidelbergHeidelbergGermanyMichael_Lanzer@med.uni-heidelberg.de

DAVID S. LATCHMANInstitute of Child HealthUniversity College LondonLondonUKd.latchman@ich.ncl.ac.uk

MOGENS LYTKEN LARSENOdense University Hospital and Department of CardiologyAalborg HospitalDenmarkmogenslytkenlarsen@dadlnet.dk

ALESSANDRO LECCIClinical Research Dept (AL) and Direction (CAM) ofMenarini RicercheFlorenceItalyalecci@menarini-ricerche.it

ALAN R. LEFFDepartment of MedicineUniversity of ChicagoChicago, ILUSAaleff@medicine.bsd.uchicago.edu

PETER LIBBYDivision of Cardiovascular Medicine, Department ofMedicineBrigham and Womens Hospital, Harvard Medical SchoolBoston, MAUSAplibby@rics.bwh.harvard.edu

LOTHAR LINDEMANNF. Hoffmann-La Roche, Pharmaceuticals Division, DiscoveryNeuroscienceBaselSwitzerlandlothar.lindemann@roche.com

JENS P. LINGEJoint Research Centre of the European Commission

List of Contributors xviiIspraItaly

MARIA LIOUMISchool of BiosciencesThe University of BirminghamUKmaria.lioumi@cancer.org.uk

ROBBIE LOEWITHDpartement de Biologie MolculaireUniversit de GenveSwitzerlandRobbie.Loewith@molbio.unige.ch

MARTIN J. LOHSEUniversitt WrzburgWrzburgGermanylohse@toxi.uni-wuerzburg.de

KATHERINE S. LONGDepartment of Molecular BiologyUniversity of CopenhagenCopenhagenDenmarklong@mermaid.molbio.ku.dk

ANATOLI N. LOPATINUniversity of MichiganAnn Arbor, MIUSAalopatin@umich.edu

JOURN LTSCHInstitut fr Klinische Pharmakologie, Klinikum der JohannWolfgang Goethe-Universitt Frankfurt am MainFrankfurtGermanyj.loetsch@em.uni-frankfurt.de

MARIE-GABRIELLE LUDWIGNovartis Institutes for Biomedical ResearchSwitzerlandMarie-gabrielle.Ludwig@novartis.com

RAYMUND MACHOVICHDepartment of Medical BiochemistrySemmelweis UniversityBudapestHungarymr@puskin.sote.hu

FERNANDO MACIANAlbert Einstein College of MedicineBronx, NYUSAfmacianj@aecom.yu.edu

CARLO ALBERTO MAGGIClinical Research Dept (AL) and Direction (CAM) ofMenarini RicercheFlorence

xviii List of ContributorsItalycamaggi@menarini-ricerche.itJANET J. MAGUIREClinical Pharmacology UnitUniversity of CambridgeLevel 6, Centre for Clinical Investigation, AddenbrookesHospitalCambridgeUK

DAVID C. MAMOPET Centre - Schizophrenia DivisionCentre for Addiction and Mental HealthToronto, ONTCanadaDavid_Mamo@camh.net

PEKKA T. MNNISTDivision of Pharmacology and Toxicology, Faculty ofPharmacyUniversity of HelsinkiHelsinkiFinlandPekka.Mannisto@helsinki.fi

CHRISTIAN MARTINInstitute of Experimental and Clinical Pharmacology andToxicologyUniversittsklinikum AachenAachenGermanychmartin@ukaachen.de

MICHAEL U. MARTINImmuology FB 08Justus-Liebig-University GiessenGiessenGermanyMichael.Martin@bio.uni-giessen.de

FRAUKE MELCHIORDepartment of Biochemie I, Faculty of MedicineUniversity GoettingenGoettingenGermanyf.melchior@medizin.uni-goettingen.de

PIERANTONIO MENNADepartment of Drug Sciences and Center of Excellence onAgingG. dAnnunzio University School of MedicineChietiItaly

AXEL H. MEYERAbteilung Klinische NeurobiologieInterdisziplinres Zentrum fr Neurowissenschaften (IZN)HeidelbergGermanyaxmeyer@urz.uni-hd.de

DIETER K. MEYERInstitut fr Experimentelle und Klinische Pharmakologie undToxikologieAlbert-Ludwigs-Universitt FreiburgFreiburg

Germanydieter.meyer@pharmakol-uni-freiburg.de

THOMAS MEYERAbteilung Psychosomatische Medizin und PsychotherapieUniversitt MarburgGermanyuwe.vinkemeier@nottingham.ac.uk

DAGMAR MEYER ZU HERINGDORFInstitut fr PharmakologieUniversitt Duisburg-EssenGermanydagmar.meyer-heringdorf@uni-due.de

WOLFGANG MEYERHOFDepartment of Molecular GeneticsGerman Institute of Human Nutrition Potsdam-RehbrueckeNuthetalGermanymeyerhof@dife.de

MARTIN C. MICHELAcademisch Medisch CentrumAmsterdamThe Netherlandsm.c.michel@amc.nl

NICO MICHELUniversittsklinikum Heidelberg, HeidelbergGermanyNico.Michel@med.uni-heidelberg.de

GIORGIO MINOTTIDepartment of Drug Sciences and Center of Excellence onAgingG. dAnnunzio University School of MedicineChietiItalygminotti@unich.it

BIBHUTI MISHRALaboratory of GI Developmental Biology, Department ofSurgeryMedicine & Lombardi Cancer Center Georgetown UniversityWashington, DCUSA

LOPA MISHRAVeterans Affairs Medical CenterWashington, DCUSAlm229@georgetown.edu

FREDERICK JOHN MITCHELSONDepartment of PharmacologyUniversity of MelbourneMelbourne, VICAustraliafjmitc@unimelb.edu.au

UGO MOENSUniversity of Tromso, Department of Microbiology andVirologyInstitute of Medical Biology, University of TromsoTromso

Norwayugom@fagmed.uit.noHANNAH MONYERAbteilung Klinische NeurobiologieInterdisziplinres Zentrum fr Neurowissenschaften (IZN)HeidelbergGermanymonyer@urz-hd.de

GREG B. G. MOORHEADDepartment of Biological SciencesUniversity of CalgaryCalgary, ABCanadamoorhead@ucalgary.ca

GEORGE MORSTYNM A Foote Associates, Westlake Village, CA and Departmentof MicrobiologyMonash UniversityAustraliarmorstyn@bigpond.net.au

SHAKER A. MOUSAAlbany College of PharmacyAlbany, NYUSAmousas@acp.edu

K. S. MHLBERGIII. Medical DepartmentUniversity of LeipzigLeipzigGermanypasr@medizin.uni-leipzig.de

BARBARA MLLERAbteilung VirologieUniversittsklinikum HeidelbergHeidelbergGermanybarbara_mueller@med.uni-heidelberg.de

JUDITH M. MLLERUniversitts-Frauenklinik und Zentrum fr KlinischeForschung, Klinikum der Universitt FreiburgFreiburgGermanyjudith.mueller@uniklinik-freiburg.de

MARTIN MLLERDeutsches Krebsforschungszentrum HeidelbergHeidelbergGermanyMartin.Mueller@dkfz.de

ROLF MLLERInstitute for Molecular Biology and Tumor Research (IMT)Philipps-University MarburgGermanymueller@imt.uni-marburg.de

WERNER MLLER-ESTERLUniversity of Frankfurt Medical SchoolFrankfurt

List of Contributors xixGermanywme@biochem2.de

GERD MULTHAUPInstitut fr Chemie und BiochemieFreie Universitt BerlinBerlinGermanymulthaup@biochemie.fu-berlin.de

NILDA M. MUOZDepartment of MedicineUniversity of ChicagoChicago, ILUSAnmunoz@medicine.bsd.uchicago.edu

LISA MUNTERInstitut fr Chemie und BiochemieFreie Universitt BerlinBerlinGermanylisamuen@chemie.fu-berlin.de

TAKASHI MURAYAMADepartment of PharmacologyJuntendo University School of MedicineTokyoJapantakashim@med.juntendo.ac.jp

CHRISTIAN NANOFFInstitut fr Pharmakologie, and Christian Pifl, Zentrum frHirnforschungMedizinische Universitt WienAustriachristian.nanoff@meduniwien.ac.at

PAUL A. NEGULESCUVertex Pharmaceuticals IncorporatedSan Diego, CAUSApaul_negulescu@sd.vrtx.com

JENS NEUMEYERInstitut fr Zellbiologie und ImmunologieUniversitt StuttgartStuttgartGermanyjens.neumeyer@izi.uni-stuttgart.de

ALEXANDRA C. NEWTONDepartment of PharmacologyUniversity of California at San DiegoLa Jolla, CAUSAanewton@ucsd.edu

COLIN G. NICHOLSWashington University School of MedicineSt. Louis, MOUSAcnichols@wustl.edu

MICHAEL NILGESUnit de BioInformatique StructuraleInstitut PasteurParis

xx List of ContributorsFrancenilges@pasteur.frDONATUS NOHRInstitute of Biological Chemistry and NutritionUniversity of HohenheimStuttgartGermanynohr@uni-hohenheim.de

HANS-PETER NOTHACKERDepartment of PharmacologyUniversity of CaliforniaIrvine, CAUSAhnothack@uci.edu

ASTRID NOVOSELChildrens University Hospital, Department of PaediatricHaematology & Oncology & Clinical ImmunologyUniversitt DsseldorfDsseldorfGermanyAstrid.Novosel@med.uni-duesseldorf.de

BERND NRNBERGUniversittsklinikum DsseldorfDsseldorfGermanyBernd.Nuernberg@uni-duesseldorf.de

JAMES N. OAKCentre for Addiction & Mental HealthUniversity of TorontoToronto, ONTCanadajames.oak@utoronto.ca

STEFAN OFFERMANNSInstitute of PharmacologyUniversity of HeidelbergHeidelbergGermanystefan.offermanns@pharma.uni-heidelberg.de

YASUO OGAWADepartment of PharmacologyJuntendo University School of MedicineTokyoJapanysogawa@med.juntendo.ac.jp

NATHAN D. OKERLUNDUniversity of CaliforniaSan Francisco, CAUSA

ALEXANDER OKSCHEMundipharma Research GmbHLimburgGermanyAlexander.oksche@mundipharma-rd.eu

GISELA OLIASDepartment of Molecular GeneticsGerman Institute of Human NutritionPotsdam-RehbrueckeNuthetal

Germanyolias@mail.dife.de

LUKE A. J. ONEILLSchool of Biochemistry and ImmunologyTrinity College DublinIrelandlaoneill@tcd.ie

HARTMUT OSCHKINATLeibniz-Institut fr Molekulare PharmakologieBerlinGermanyoschkinat@fmp-berlin.de

REN R. S. PACKARDDivision of Cardiovascular Medicine, Department ofMedicineBrigham and Womens Hospital, Harvard Medical SchoolBoston, MAUSArpackard@rics.bwh.harvard.edu

MATHIVANAN PACKIARAJANLundbeck Research USAParamus, NJUSAmatp@lundbeck.com

CLIVE P. PAGESackler Institute of Pulmonary PharmacologyKings College LondonLondonUKclive.page@kcl.ac.uk

RALPH PASCHKEIII. Medical DepartmentUniversity of LeipzigLeipzigGermanypasr@medizin.uni-leipzig.de

JRG PETERSPhysiologisches Institut der Universitt GreifswaldGreifswaldGermanyjoerg.peters@urz.uni-heidelberg.de

ALEXANDER PFEIFERUniversity of BonnInstitute of Pharmacology and ToxicologyBonnGermanyalexander.pfeifer@uni-bonn.de

JOSEF PFEILSCHIFTERPharmazentrum FrankfurtJohann Wolfgang Goethe-Universitt Frankfurt am MainGermanypfeilschifter@em.uni-frankfurt.de

JEAN-PHILIPPE PINInstitut de Gnomique FonctionnelleCNRS UMR5203, INSERM U661Universits de Montpellier 1&2Montpellier

Francejppin@igf.cnrs.frJANE A. PINAIRELilly Research LaboratoriesEli Lilly and CompanyIndiana, INUSAjpinaire@lilly.com

SARAH L. PITKINClinical Pharmacology UnitUniversity of CambridgeLevel 6, Centre for Clinical Investigation, AddenbrookesHospitalCambridgeUK

ROBIN PLEVINStrathclyde Institute of Pharmacy and Biomedical SciencesUniversity of StrathclydeGlasgowUKr.plevin@strath.ac.uk

EREZ PODOLYThe Life Sciences InstituteThe Hebrew University of JerusalemIsrael

ANNEMARIE POLAKF. Hoffmann-La Roche LtdAesch, BaselSwitzerlandannemarie.polak@bluemail.ch

YVES POMMIERLaboratory of Molecular Pharmacology, Center for CancerResearchNational Cancer Institute, National Institutes of HealthBethesda, MDUSApommier@nih.gov

OLAF PONGSInstitut fr Neurale Signalverarbeitung, Zentrum frMolekulare Neurobiologie HamburgHamburgGermanypointuri@uke.uni-hamburg.de

BERND PTZSCHUniversittsklinikum BonnBonnGermany

IRENE PUGAAlbert Einstein College of MedicineBronx, NYUSA

JRG RADEMANNLeibniz Institut fr Molekulare Pharmakologie (FMP)Berlin

List of Contributors xxiGermanyrademann@fmp-berlin.de

DANIEL J. RADERInstitute for Translational Medicine and TherapeuticsUniversity of Pennsylvania School of MedicinePhiladelphia, PAUSArader@mail.med.upenn.edu

NEIL D. RAWLINGSWellcome Trust Sanger Institute, Wellcome Trust GenomeCampusHinxton, CambridgeshireUKndr@sanger.ac.uk

ERIC RAYMONDDepartment of Medical OncologyBeaujon University HospitalClichy CedexFranceeric.raymond@bjn.ap-hop-paris.fr

HOLGER M. REICHARDTDepartment of Cellular and Molecular ImmunologyUniversity of GttingenGttingenGermanyholger.reichardt@mail.uni-wuerzburg.de

ANNE REIFEL-MILLERLilly Research LaboratoriesEli Lilly and CompanyIndianapolis, INUSAa.r.miller@lilly.com

RICHARD REIMERDepartment of Neurology and Neurological SciencesStanford UniversityStanford, CAUSArjreimer@stanford.edu

CONSTANZE REINHARDK.U.Leuven and VIBLeuvenBelgiumConstanze.Reinhard@med.kuleuven.be

YVONNE REISSJoint Research Division Vascular Biology of the MedicalFaculty MannheimUniversity of Heidelberg, and the German Cancer ResearchCenter (DKFZ)Mannheim and HeidelbergGermany

THOMAS RENNUniversity of WrzburgWrzburg

xxii List of ContributorsGermanythomas@renne.netKLAUS RESCHInstitute of PharmacologyHannover Medical SchoolHannoverGermanyResch.Klaus@MH-Hannover.de

ELKE ROEBGastroenterologyJustus-Liebig-UniversityGieenGermanyelke.roeb@innere.med.uni-giessen.de

HANS ROMMELSPACHERDepartment of Clinical NeurobiologyUniversity Hospital Benjamin FranklinFree University BerlinBerlinGermanyhans.rommelspacher@medizin.fu-berlin.de

THOMAS C. ROOSReha Klinik Neuharlingersiel, Interdisciplinary Center forDermatology, Pneumology and AllergologyNeuharlingersielGermanyroos@rehaklinik-neuharlingersiel-klinik.de

WALTER ROSENTHALInstitut fr PharmakologieFreie Universitt BerlinBerlinGermanywalter.rosenthal@charite.de

ANA M. ROSSIDepartment of PharmacologyUniversity of CambridgeUKamr50@cam.ac.uk

BERNARD C. ROSSIERDpartement de Pharmacologie et de Toxicologie delUniversitLausanneSwitzerlandBernard.Rossier@unil.ch

UWE RUDOLPHInstitute of Pharmacology and ToxicologyUniversity of ZrichZrichSwitzerlandrudolph@pharma.unizh.ch

GEORGE SACHSDavid Geffen School of MedicineUniversity of California at Los Angeles and VeteransAdministration Greater Los Angeles Healthcare SystemLos Angeles, CA

USAgsachs@ucla.edu

DAVID B. SACKSDepartment of Pathology, Brigham and Womens HospitalHarvard Medical SchoolBoston, MAUSAdsacks@rics.bwh.harvard.edu

ANAN H. SAIDLaboratory of GI Developmental Biology, Department ofSurgeryMedicine & Lombardi Cancer Center Georgetown UniversityWashington, DCUSA

EMANUELA SALVATORELLIDepartment of Drug Sciences and Center of Excellence onAgingG. dAnnunzio University School of MedicineChietiItaly

BALZS SARKADIResearch Group of Membrane BiologyHungarian Academy of SciencesHungary

MICHAEL SCHAEFERCharit Universittsmedizin BerlinPharmakologisches InstitutCampus Benjamin FranklinBerlinGermanym.schaefer@charite.de

GEORGIOS SCHEINER-BOBISInstitute of Biochemistry and EndocrinologyJustus Liebig University GiessenGiessenGermany

LAURENT SCHILDDpartement de Pharmacologie et de Toxicologie delUniversitLausanneSwitzerlandLaurent.Schild@unil.ch

GUDULA SCHMIDTInstitut fr Experimentelle und Klinische Pharmakologie undToxikologie, Albert-Ludwigs-Universitt FreiburgFreiburgGermanygudula.schmidt@pharmakol.uni-freiburg.de

ERIK BERG SCHMIDTOdense University Hospital and Department of CardiologyAalborg HospitalDenmarkebs@dadlnet.dk

GERD SCHMITZInstitute of Clinical Chemistry and Laboratory MedicineUniversity of RegensburgRegensburg

Germanygerd.schmitz@klinik.uni-regensburg.deJURGEN SCHNERMANNNational Institutes of HealthBethesda, MDUSAjurgens@intra.niddk.nih.gov

TORSTEN SCHNEBERGInstitut fr Biochemie, Medizinische FakulttUniversitt LeipzigLeipzigGermanyTorsten.Schoeneberg@medizin.uni-leipzig.de

WILHELM SCHONERInstitute of Biochemistry and EndocrinologyJustus Liebig University GiessenGiessenGermany

ROLAND SCHLEUniversitts-Frauenklinik und Zentrum fr KlinischeForschung, Klinikum der Universitt FreiburgFreiburgGermanyroland.schuele@uniklinik-freiburg.de

RALF SCHLEINLeibniz-Institut fr Molekulare Pharmakologie BerlinGermanyschuelein@fmp-berlin.de

GNTER SCHULTZCharit Universittsmedizin BerlinPharmakologisches InstitutCampus Benjamin FranklinBerlinGermanyguenter.schultz@charite.de

ANNETTE SCHRMANNDepartment of PharmacologyGerman Institute of Human NutritionPotsdam-RehbrueckeGermanyschuermann@dife.de

CHRISTINA SCHWANSTECHERMolekulare Pharmakologie und ToxikologieTechnische Universitt BraunschweigBraunschweigGermanym.schwanstecher@tu-braunschweig.de

MATHIAS SCHWANSTECHERMolekulare Pharmakologie und ToxikologieTechnische Universitt BraunschweigBraunschweigGermanyM.Schwanstecher@tu-braunschweig.de

DIRK SCHWARZERLeibniz-Institut fr Molekulare Pharmakologie (FMP)Berlin

List of Contributors xxiiiGermanyschwarzer_biochemie@email.de

MARKUS JOACHIM SEIBELBone Research ProgramANZAC Research Institute, The University of SydneyConcord, NSWAustraliamjs@anzac.edu.au

ROLAND SEIFERTDepartment of Pharmacology and ToxicologyUniversity of Regensburg, RegensburgGermanyroland.seifert@chemie.uni-regensburg.de

OLIVER SELBACHInstitute of NeurophysiologyHeinrich-Heine University, DsseldorfGermanyselbach@uni-duesseldorf.de

KLAUS SEUWENNovartis Institutes for Biomedical ResearchSwitzerlandKlaus.seuwen@novartis.com

CHAR-CHANG SHIEHGlobal Pharmaceutical Research and Development, AbbottLaboratoriesAbbott Park, ILUSAchar-chang.shieh@abbott.com

JAI MOO SHINDavid Geffen School of MedicineUniversity of California at Los Angeles and VeteransAdministration Greater Los Angeles Healthcare SystemLos Angeles, CAUSAjaishin@ucla.edu

KELLI E. SMITHLundbeck Research USAParamus, NJUSAkels@lundbeck.com

HERMONA SOREQThe Life Sciences InstituteThe Hebrew University of JerusalemIsraelsoreq@cc.huji.ac.il

NOEMI SOTO-NIEVESAlbert Einstein college of MedicineBronx, NYUSA

RAINER SPANAGELCentral Institute of Mental HealthMannheim

xxiv List of ContributorsGermanyrainer.spanagel@zi-mannheim.deULRICH SPECKUniversittsklinikum CharitHumboldt-Universitt BerlinBerlinGermanyulrich.speck@charite.de

ANDREAS STAHLUniversity of CaliforniaDepartment of Nutritional Science and ToxicologyBerkeley, CA 94720, USAandreas.stahl@berkeley.edu

RALF STAHLMANNInstitut fr Klinische Pharmakologie und ToxikologieCharit Universittsmedizin BerlinCampus Benjamin FranklinBerlinGermanyralf.stahlmann@charite.de

KLAUS STARKEInstitut fr Experimentelle und Klinische Pharmakologie undToxikologieUniversitt FreiburgFreiburgGermanyKlaus.starke@pharmakol.uni-freiburg.de

ALESSANDRA STARLINGHuman Genome Research Center, Biosciences InstituteUniversity of So PauloSo PauloBrazil

WIM A. VAN DER STEEGDepartment of Vascular MedicineAcademic Medical Center, University of AmsterdamAmsterdamThe Netherlandsw.a.vandersteeg@amc.uva.nl

CHRISTOPH STEINKlinik fr Anaesthesiologie und Operative IntensivmedizinFreie Universitt BerlinCharit CampusBenjamin FranklinBerlinGermanychristoph.stein@charite.de

CHRISTIAN STEINKHLERIRBM Merck Research LaboratoriesPomeziaItalyChristian_Steinkuhler@Merck.Com

JRG STRIESSNIGInstitut fr Pharmazie, Abteilung Pharmakologie undToxikologieLeopold-Franzens-Universitt InsbruckInnsbruck

Austriajoerg.striessnig@uibk.ac.at.

YUICHI SUGIYAMADepartment of Molecular Pharmacokinetics, Graduate Schoolof Pharmaceutical Sciences, The University of TokyoTokyo, Japansugiyama@mol.f.u-tokyo.ac.jp

GERGELY SZAKCSInstitute of EnzymologyHungarian Academy of Sciences

MARTA SZAMELInstitute of Pharmacology, Medical School HannoverHannoverGermanyszamel.marta@mh-hannover.de

GRAZIA TAMMADepartment of General and Environmental PhysiologyUniversity of BariItaly

COLIN W. TAYLORDepartment of PharmacologyUniversity of CambridgeUKcwt1000@cam.ac.uk

PETER C. TAYLORThe Kennedy Institute of Rheumatology Division, Faculty ofMedicineImperial College LondonLondon, UKpeter.c.taylor@imperial.ac.uk

ALVIN V. TERRY JRDepartments of Pharmacology and ToxicologyMedical College of GeorgiaAugusta, GAUSAaterry@mcg.edu

MARIE-CHRISTIN THISSENWestflische Wilhelms-Universitt, Institut frPharmazeutische und Medizinische ChemieMnsterGermany

NOBORU TODAToyama Institute for Cardiovascular Pharmacology ResearchOsakaJapann.toda.toyama-bldg@orion.ocn.ne.jp

ARIE VAN TOLDepartment of Cell Biology & GeneticsErasmus University Medical CenterRotterdamThe Netherlandsa.vantol@erasmusmc.nl

CHRISTOPHE LE TOURNEAUDepartment of Medical OncologyBeaujon University Hospital

Clichy CedexFrancePAUL TRAYHURNObesity Biology Unit, Division of Metabolic and CellularMedicineUniversity of LiverpoolUKp.trayhurn@liverpool.ac.uk

JAN TUCKERMANNLeibniz Institute for Age Research Fritz-Lipmann-InstituteJenaGermanyjan@fli-leibniz.de

STEFAN UHLIGInstitute of Experimental and Clinical Pharmacology andToxicologyUniversitsklinikum AachenRWTH AachenGermanysuhlig@ukaachen.de

HUBERT H. M. VAN TOLCentre for Addiction & Mental HealthUniversity of TorontoToronto, ONTCanadahubert.van.tol@utoronto.ca

PETER VANDENABEELEDepartment for Molecular Biomedical ResearchVIBGhentBelgiumPeter.Vandenabeele@dmbr.ugent.be

UWE VINKEMEIERChair of Cell BiologyUniversity of Nottingham Medical SchoolSchool of Biomedical SciencesNottingham, NG7 2UHuwe.vinkemeier@nottingham.ac.uk

ANDRS VRADIInstitute of EnzymologyHungarian Academy of SciencesHungaryvaradi@enzim.hu

GIRISH VYASDepartment of Laboratory MedicineUniversity of CaliforniaSan Francisco, CAUSAgirish.vyas@ucsf.edu

KEITH WAFFORDLilly and Co. Eri Wood Manor WindlesshanSurreyUK

KEITH WAFFORDMerck, Sharp & Dohme Research LaboratoriesHarlow, Essex

List of Contributors xxvUKkeith_wafford@merck.com

HENNING WALCZAKDepartment of Immunology, Division of MedicineImperial College LondonLondonUKh.walczak@Dkfz-Heidelberg.de

MARY W. WALKERLundbeck Research USAParamus, NJUSAmmw@lundbeck.com

RUI WANGLakehead UniversityThunder Bay, ONTCanadarwang@lakeheadu.ca

THEODORE E. WARKENTINHamilton Regional Laboratory Medicine ProgramHamilton Health Sciences, and Department of Pathologyand Molecular MedicineMichael G. DeGroote School of MedicalMcMaster UniversityHamilton, ONTCanadatwarken@mcmaster.ca

TANYA M. WATTERSSchool of Biochemistry and ImmunologyTrinity College DublinIreland

DAVID J. WAXMANDivision of Cell and Molecular BiologyDepartment of BiologyBoston UniversityBoston, MAUSAdjw@bu.edu

JRGEN WESSLaboratory of Bioorganic Chemistry, National Institutes ofHealth (NIDDK)Bethesda, MDUSAjwess@helix.nih.gov

BERND WIEDEMANNRheinische Friedrich-Wilhelms-UniversittBonnGermanypharmic@t-online.de

IRITH WIEGANDRheinische Friedrich-Wilhelms-UniversittBonn

xxvi List of ContributorsGermanyWiegand@uni-bonn.deFELIX T. WIELANDBiochemie-Zentrum HeidelbergUniversity HeidelbergHeidelbergGermanyfelix.wieland@bzh.uni-heidelberg.de

THOMAS E. WILLNOWMax-Delbrueck-Center for Molecular MedicineBerlinGermanywillnow@mdc-berlin.de

SUSAN WONNACOTTDepartment of Biology and BiochemistryUniversity of BathUKbsssw@bath.ac.uk

THOMAS WORZFELDInstitute of PharmacologyUniversity of HeidelbergHeidelbergGermany

YOSEF YARDENDepartment of Biological RegulationThe Weizmann Institute of ScienceRehovotIsraelYosef.Yarden@weizmann.ac.il

MOUSSA B. H. YOUDIMTechnion-Rappaport Faculty of MedicineEva Topf Center of Excellence for NeurodegenerativeDiseasesDepartment of PharmacologyHaifaIsraelyoudim@tx.technion.ac.il

ULRICH M. ZANGERDr. Margarete Fischer-Bosch Institute of ClinicalPharmacologyStuttgartGermanyuli.zanger@ikp-stuttgart.de

MAYANA ZATZHuman Genome Research Center, Biosciences InstituteUniversity of So PauloSo PauloBrazilmayanazatz@uol.com.br

RAINER ZAWATZKYDeutsches Krebsforschungszentrum HeidelbergGermanyr.zawatzky@dkfz.de

HONG ZHOUBone Research ProgramANZAC Research Institute, The University of Sydney

Concord, NSWAustralia

HEIKE ZIMDAHLBoehringer IngelheimPharma GmbH & Co KGBiberachGermanyheike.zimdahl@bc.boehringer-ingelheim.com

RICHARD ZIMMERMANNMedizinische Biochemie und MolekularbiologieUniversitt des SaarlandesHomburgGermanybcrzim@uks.eu

List of Contributors xxvii

Two-dimensional Electrophoresis

with other family members, but 14-3-3 preferentiallyforms homodimers in cells. Three amino acids that

in 14-3-3-specific ligand discrimination.

ENNO KLUSSMANNLeibniz-Institut fr Molekulare Pharmakologie,Berlin-BuchDepartment of Molecular Pharmacology and CellBiology, Charit-Universittsmedizin Berlin, Berlin,Germany

and temporal coordination of PKA signalling throughcompartmentalization by AKAPs is considered essen-tial for the specificity of PKA-dependent cellularresponses to a particular external stimulus [3, 4].AKAPPKA interactions play a role in a variety ofcellular processes including -adrenoceptor-dependentregulation of cardiac myocyte contraction (Fig. 2),vasopressin-mediated water reabsorption, proton secre-Protein kinase A anchoring proteins

Synonyms

tion from gastric parietal cells, modulation of insulinsecretion from pancreatic cells and T cell receptorsignalling. A typical AKAP is AKAP18, also termedAKAP15. It tethers PKA to L-type Ca2+ channels inA Kinase Anchoring Proteins (AKAPs)14-3-3 Proteinsare completely conserved in all other 14-3-3s, arenot present in 14-3-3. These amino acids unique to14-3-3 confer a second ligand-binding site involvedProteomics

14-3-3s

The 14-3-3 proteins constitute a family of abundant,highly conserved and broadly expressed acidic poly-peptides. One member of this family, the 14-3-3isoform {sigma}, is expressed only in epithelial cellsand is frequently down-regulated in a variety of humancancers and plays a role in the cellular response to DNAdamage. The 14-3-3s generally form heterodimers2DEA

DefinitionAKAPs are a diverse family of about 75 scaffoldingproteins. They are defined by the presence of astructurally conserved protein kinase A (PKA)-bindingdomain. AKAPs tether PKA and other signallingproteins to cellular compartments and thereby limitand integrate cellular signalling processes at specificsites. This compartmentalization of signalling byAKAPs contributes to the specificity of a cellularresponse to a given external stimulus (e.g. a particularhormone or neurotransmitter).

Basic MechanismsAKAP-dependent Control of cAMP/PKA SignallingA large variety of extracellular stimuli includinghormones and neurotransmitters elicit the generationof the second messenger cyclic adenosine monopho-sphate (cAMP). Cyclic AMP binds to several effectorproteins including ion channels, cAMP-dependentguanine-nucleotide-exchange factors (Epacs) andPKA. The latter is the main effector of cAMP. Bindingof four molecules of cAMP activates the kinase.Activated PKA transfers a phosphate group fromadenosine triphosphate (ATP) to consensus sites onmany different substrate proteins and thereby mod-ulates their activity. It appears that different externalstimuli mediate activation of specific pools of PKAlocated at defined sites within cells (compartments)including, for example mitochondria, nuclei, exocyticvesicles, sarcoplasmic reticulum and the cytosol [1].A kinase anchoring proteins (AKAPs; Fig. 1) tetherPKA to such cellular compartments and allow for itslocal activation, and consequent phosphorylation ofparticular substrates in close proximity [2]. Spatial

2 A Kinase Anchoring Proteins (AKAPs)cardiac myocytes and skeletal muscle cells andfacilitates their phosphorylation in response to -adrenoceptor activation. The phosphorylation increasesthe open probability of the channel.The tethering of PKA through AKAPs by itself is not

sufficient to compartmentalize and control a cAMP/PKA-dependent pathway. Cyclic AMP readily diffusesthroughout the cell. Therefore, discrete cAMP/PKAsignalling compartments are only conceivable if thisdiffusion is limited. Phosphodiesterases (PDE) estab-lish gradients of cAMP by local hydrolysis of the

A Kinase Anchoring Proteins (AKAPs).Figure 1 Model of an A kinase anchoring protein(AKAP). The unifying characteristic of AKAPs is thepresence of a structurally conserved binding domain forthe dimer of regulatory (R) subunits of PKA (RBD,regulatory subunit binding domain). In the inactive state,PKA forms a tetramer consisting of a dimer of R subunitseach bound to one catalytic subunit (C). Binding of twomolecules of cAMP to each R subunit causes aconformational change and release of the C subunits,which in the free form phosphorylate substrate proteinsin close proximity. The RBD in all AKAPs with pericentrinas the only exception forms an amphipathic helix thatdocks into a hydrophobic pocket formed by thedimerization and docking domain of R subunits. Thetargeting domain, which tethers the AKAP complex tocellular compartments and docking domains, which bindfurther signalling proteins (e.g. phosphodiesterases,phosphatases or other kinases) are specific forindividual AKAPs. A few AKAPs possess catalyticactivity such as the RhoGEF-activity in AKAP-Lbcconferred by a DH domain. The proteins within the AKAPfamily are without obvious sequence homology.second messenger and thereby regulate PKA activitylocally. Several AKAPs interact with PDEs and thusplay a role at this level of control. For example, theinteraction of muscle-specific mAKAP with cAMP-specific PDE4D3 and the ryanodine receptor (RyR)

A Kinase Anchoring Proteins (AKAPs).Figure 2 -adrenoceptor-induced increases in cardiacmyocyte contractility depend on AKAPPKAinteractions. Stimulation of -adrenoceptors (1AR) onthe surface of cardiac myocytes by binding of adrenergicagonists such as norepinephrine (NE), epinephrine orisoproterenol increases contractility of the heart. Agonistbinding to the receptors activates the G protein Gs andadenylyl cyclase (AC), and consequent synthesis ofcAMP which binds to regulatory (R) subunits of proteinkinase A (PKA) inducing dissociation of catalytic(C) subunits (see also Fig. 1). The C subunitsphosphorylate L-type Ca2+ channels located in theplasma membrane (plasmalemma) and ryanodinereceptors (RyR2) embedded in the membrane of thesarcoplasmic reticulum (SR). Phosphorylation of the twochannel proteins increases their open probability andleads to an increase in cytosolic Ca2+ causing increasedcontractility. For the relaxation of cardiacmyocytes, Ca2+

has to be removed from the cytosol. A pivotal role in thisplays sarcoplasmic Ca2+ ATPase (SERCA). It pumpsCa2+ back into the SR. SERCA is inhibited when boundto phospholamban (PLB) and activated upondissociation from PLB, which is induced by-adrenoceptor-mediated PKA phosphorylation.Collectively, the PKA phosphorylation events increasecardiac myocyte contractility. The efficientphosphorylation of L-type Ca2+ channels occurs only ifPKA is anchored to the channel by AKAP18. For thephosphorylation of RyR, PKA anchoring to this channelby mAKAP is a prerequisite. Further AKAPs are likely tobe involved in PKA-dependent phosphorylation eventsin response to -adrenoceptor stimulation (e.g. PLB).

A Kinase Anchoring Proteins (AKAPs) 3

Afacilitates hydrolysis of cAMP in the vicinity of RyR atthe sarcoplasmic reticulum of cardiac myocytes. LocalcAMP hydrolysis keeps mAKAP-associated PKAactivity low. An increase in the cAMP level exceedingthe PDE4D3 hydrolyzing capacity activates PKA,which phosphorylates RyR and increases the openprobability of this Ca2+ channel. PKA also phosphor-ylates mAKAP-bound PDE4D3 and thereby enhancesPDE4D3 activity. This again increases local cAMPhydrolysis, switches off PKA, and eventually reducesRyR phosphorylation. This negative feedback loopregulating RyR phosphorylation is completed byassociation of mAKAP with protein phosphatase 2A(PP2A), dephosphorylating RyR. Dephosphorylationdecreases the channel open probability of RyR.

AKAP-dependent Integration of Cellular SignallingIn addition to PKA, PDEs and protein phosphatasesinvolved in cAMP signalling, AKAPs interact withother signalling proteins whose activation dependson second messengers other than cAMP, e.g. Ca2+.AKAPs may bind additional kinases such as pro-tein kinases C (PKC) and D (PKD), and further proteinphosphatases such as calcium/calmodulin-dependentphosphatase (calcineurin, protein phosphatase 2B,PP2B). This scaffolding function allows AKAPs tointegrate cellular signalling processes. For example, ratAKAP150 and its human ortholog AKAP79 bind PKA,PKC and calcineurin. In neurons, AKAP150-boundPKC is activated through a M1 muscarinic receptor-induced pathway that depends on the G protein Gq andleads to elevation of cytosolic Ca2+ and diacylglycerol.AKAP150 interacts directly with M channels(K+ channel negatively regulating neuronal excitabi-lity) and facilitates PKC phosphorylation and therebyinhibition of this channel. AKAP79 coordinates thephosphorylation of AMPA channels. Cyclic AMP-activated AKAP79-bound PKA phosphorylates andthereby activates the channels. A raise of cytosolic Ca2+

activates AKAP79-bound calcineurin, which in turndephosphorylates the channels. The dephosphorylationmediates the rundown of AMPA channel currents.AKAP-Lbc binds PKA, PKC and PKD and possesses

intrinsic catalytic activity (Rho guanine nucleotideexchange factor (RhoGEF) activity). Through its Rho-GEFactivity it catalyses the exchangeofGDP forGTPonthesmall GTPase Rho. The GTP form of Rho is activeand induces the formation of F-actin-containing stressfibres. Agonists stimulating receptors coupled to the Gprotein Gs may mediate activation of AKAP-Lbc-boundPKA, which in turn phosphorylates AKAP-Lbc. Subse-quently, a protein of the 1433 family binds to thephosphorylated site and inhibits the RhoGEF activity. Incontrast, agonists stimulating receptors coupled to the G

protein G12 increase the RhoGEF activity.PKA phosphorylation and subsequent redistribution ofaquaporin-2 (AQP2) from intracellular vesicles intowater reabsorption from primary urine by triggeringAKAPs Optimise the Limited Repertoire of CellularSignalling ProteinsIntriguingly, the same AKAP may coordinate regula-tion of different target proteins. In hippocampalneurons, AKAP150 positions PKA and calcineurin tomodulate AMPA channels and maintains PKC inactive.In superior ganglial neurons, AKAP150 facilitates PKCphophorylation of M channels while keeping PKA andcalcineurin inactive. The difference is due to theinteraction of AKAP150 with the scaffolding proteinSAP97, which occurs in hippocampal neurons but notin superior ganglial neurons. SAP97 positionsAKAP150 such that PKA and calcineurin are in closeproximity to AMPA channels. Thus by variation of asingle interacting partner an AKAP optimises the usageof the limited set of cellular signalling proteins.In summary, the function of AKAPs goes far beyond

controlling cAMP/PKA signalling by simply tetheringPKA to cellular compartments and confining the accessof PKA to a limited set of local substrates. AKAPs arescaffolds forming multiprotein signal transductionmodules, recently termed AKAPosomes that coordi-nate and integrate cellular signalling processes.

Pharmacological InterventionDisturbances of compartmentalized cAMP signalling inprocesses such as the ones mentioned above cause orare associated with major diseases including congestiveheart failure, diabetes insipidus, diabetes mellitus,obesity, diseases of the immune system (e.g. AIDS),cancer and neurological disorders including schizo-phrenia. However, AKAPs participating in compart-mentalized cAMP signalling networks are not targetedby drugs which are currently applied for the treatmentof such diseases.Recently, clinically relevant intracellular protein

protein interactions have gained much interest aspotential drug targets. The cell-type specificity of suchinteractions and the finding that mostly only selectedisoforms of proteins interact with each other offers greatopportunities for highly selective pharmacologicalintervention. For targeting AKAP-dependent proteinprotein interactions, peptides non-selectively displacingPKA from all AKAPs have been developed so far. Forexample, the peptides functionally uncouple, PKA fromL-type Ca2+ channels in cardiac myocytes by disruptionof the AKAP18PKA interaction that facilitatesL-type Ca2+ channel phosphorylation (see above). Thisprevents -adrenoceptor-induced increases in cytosolicCa2+, an effect resembling that of -blockers. In renalcollecting duct principal cells, vasopressin regulates

thethe plasma membrane. The redistribution depends on

cardiac myocytes. Science 295:171117152. Langeberg LK, Scott JD (2005) A-kinase-anchoring

4. Wong W, Scott JD (2004) AKAP signalling complexes:

proteinprotein interactions: progressing towards thedream. Nat Rev Drug Discov 3:301331ABC-proteins

ABC Transporters

ABC Transporters

MARKUS GRUBE, HEYO K. KROEMERDepartment of Pharmacology, Center of Pharmacologyand Experimental Therapeutics, Ernst-Moritz-ArndtUniversity Greifswald, Greifswald, Germany

SynonymsATP-binding cassette proteins; ABC-proteins

DefinitionThe ABC-transporter superfamily represents a largegroup of transmembrane proteins. Members of thisfamily are mainly involved in ATP-dependent transportfocal points in space and time. Nat Rev Mol Cell Biol5:959970

5. Arkin MR, Wells JA (2004) Small-molecule inhibitors ofproteins. J Cell Sci 118:321732203. Tasken K, Aandahl EM (2004) Localized effects of cAMP

mediated by distinct routes of protein kinase A. PhysiolRev 84:137167the compartmentalization of PKA by AKAPs, one ofwhich is AKAP18. The PKA anchoring disruptorpeptides displace PKA from AQP2-bearing vesiclesand inhibit vasopressin-mediated water reabsorption,i.e. have an aquaretic effect. These examples suggestthat cell-type specific pharmacological intervention atselected AKAPPKA interactions is a feasible conceptfor the treatment of human diseases (e.g. cardiovasculardisease or diseases associated with water retention).

References1. Zaccolo M, Pozzan T (2002) Discrete microdomains with

high concentration of cAMP in stimulated rat neonatal

4 ABC-proteinsprocesses across cellular membranes. These proteinsare of special interest from a pharmacological point ofview because of their ability to transport numerousdrugs, thereby modifying intracellular concentrationsand hence effects.

Basic CharacteristicsATP-binding cassette (ABC-) proteins have beenidentified in all living organisms; they are present inplants, bacteria, and mammalians. In humans the ABC-superfamily comprises about 50 members; on the basisof homology relationships this superfamily is organizedin several subfamilies named ABCA to ABCF. Not allof them are pharmacologically important, for example,members of the A branch are mainly involved in lipidtrafficking. ABCB2 as well as ABCB3, which arealso termed as transporter associated with antigenprocessing (TAP), are involved in the transport ofpeptides presented by Class I HLA molecules.However, other ABC-transporters like ABCB1(P-glycoprotein, P-gp), ABCG2 (breast cancerresistance protein, BCRP) and several members of theC-branch are of high pharmacological relevancebecause they are involved in transport of several drugs;thereby affecting pharmacokinetic parameters.ABCB1, for example, which is also known as

P-glycoprotein (P-gp) and probably the best character-ized ABC-transporter, has been identified as theunderlying mechanism of a cancer-related phenomenoncalled multidrug resistance (therefore, P-gp is alsotermedmultidrug resistance protein (MDR1)), which ischaracterized by the resistance of cancer cells againstdrug therapy. Interestingly, this phenomenon is notdirected against a single drug or structurally relatedentities, but comprises unrelated compounds withdifferent target structures. Meanwhile, besides P-gpfurther ABC-transporters have been identified to beinvolved in this process. For example, in 1992 Coleet al. identified the first member of the so-calledmultidrug resistance related proteins (MRP). TheMRP-proteins (MRP1MRP9) belong to the C-branchof the ABC-superfamily, which currently consists of atotal of 13 members (ABCC1ABCC13). In additiontoABCB1and theABCCfamily, amember of theABCGfamily has recently been demonstrated to confer drugresistance. This protein called breast cancer resistantprotein (BCRP/ABCG2) was first identified in mitox-antrone resistant cell lines, which lack expression of P-gpor MRP1.

Topology and StructureMost ABC-transporters, especially those located inthe plasma membrane, are phosphorylated and gly-cosylated transmembrane proteins of different molecu-lar weights (e.g., P-gp: 170 kDa; MRP2: 190 kDa;BCRP: 72 kDa). Topologically, most ABC-transporter

show a similar structure: they are organized in twotransmembrane domains (TMD), each consisting of six

-helical, transmembranal segments and two ATPbinding domains linked to the C-terminus of the TMDs.These domains, which are also termed nucleotidebinding folds (NBFs), contain the highly conservedWalker A and B consensus motifs and the LSGGQmotif(also called C- or signature motif ). While the Walker Aand B motifs are also found in other ATP-hydrolyzingATP proteins, the LSGGQ motif is unique for the ABC-transporters. The ATP hydrolysis catalyzed by the NBFsis a prerequisite for substrate binding and enablestransport against a substrate gradient. In addition tothese general characteristics, several members ofthe ABCC-family (e.g., ABCC13) contain a furtherN-terminal TMD, which, however, is not requiredfor transport activity. In contrast to the other TMDs,this N-terminal TMD contains five transmembranalsegments and lacks the NBF. Besides this structuralvariant some other ABC-transporters (e.g., ABCB2, 3(TAB1 and 2), as well as ABCG2) contain only one

TMD and NBF (Fig. 1). Therefore, these transporters aretermed half transporter (in contrast to full transporter);however, to achieve functional activity they have to formhetero- or homodimers.

Tissue Distribution and ExpressionAlthough initially detected in cancer cell lines ABC-transporters show a wide tissue distribution. Severalmembers of drug transporting ABC-proteins, for exam-ple, are highly expressed in physiological barriers suchas the apical membrane of gut enterocytes, theendothelial cells of the bloodbrain barrier or thematernal facing (apical) membrane of the placentalsyncytiotrophoblast. In all of these organs they protectsensitive tissues like brain or the growing fetus againstpotentially toxic compounds. In addition, ABC-transporter expression is highly abundant in hepato-cytes (Fig. 2). Here, ABC-transporters are involved indetoxification of many endogenous and exogenous

ABC Transporters 5

AABC Transporters. Figure 1 Structure of ABCB1, ABCC1transmembrane domaine. Modified according to www.iw, and ABCG2 (NBF: nucleotide binding fold; TMD:aki-kk.co.jp/bio/specialedition/se02.htm).

nagents and are therefore expressed both in thecanalicular and sinusoidal membrane. The canalicularexpression is a prerequisite for bilary elimination. Forexample, the bile salt export pump (BSEP/ABCB11) istransporting bile salts, MRP2 (ABCC2) is involved inthe elimination of organic anions like bilirubin-glucuronide or glutathione-conjugates and finally, P-gp (ABCB1) eliminates a wide variety of drugs into thebile. In contrast, other ABC-transporters like MRP1(ABCC1) and 3 (ABCC3) are mainly located in thebasal membrane of hepatocytes. They transport xeno-biotics and several conjugates back to the blood andseem to be important under certain pathophysiologicalconditions, for example, hepatic expression of both

ABC Transporters. Figure 2 ABC-transporter expressiowww.iwaki-kk.co.jp/bio/specialedition/se02.htm).

6 ABC Transporterstransporters is enhanced during cholestasis, therebyprotecting the hepatocytes against toxic bile acidconcentrations by transport into the blood followed byincreased renal elimination.Various ABC-transporters are expressed in organs

like heart, lung, pancreas, or cellular blood compounds.They may be important both for physiological process-es and local drug concentrations. In this context, it isnoteworthy that many of these transporters not onlyeliminate xenobiotic and toxic compounds from thecell, but also endogonous compounds. For example,MRP4, 5, and 8 (ABCC4, 5, and 11), which areexpressed in many tissues and cancer cells, not onlytransport xenobiotics like nucleotide-based anticancerdrugs but also the second messenger molecules cAMPand cGMP. Thereby, these transporters may play a rolein regulating intra- and extracellular cyclic nucleotideconcentrations.

ABC-Transporters and DiseaseBased on their physiological function it is not surprisingthat genetic polymorphisms affecting expression andfunction of ABC-proteins have been identified asthe underlying mechanisms for some diseases. Forexample, mutations in theMRP2 (ABCC2) gene, whichlead to the loss of this protein from the canalicularmembrane of hepatocytes, are the mechanism of theDubinJohnson Syndrome. Here, the bilary elimina-tion of MRP2 substrates like bilirubin and bilirubin-glucuronide is blocked; therefore the respective plasmalevels are elevated leading to the disease. Anotherexample is ABCC7, which is also called cystic fibrosistransmembrane conductance regulator (CFTR) andforms an anion channel in different tissues like theepithelial surfaces of the respiratory and intestinaltract. As its alias indicates, ABCC7 is involved in the

in hepatocytes and enterocytes (modified according topathogenesis of cystic fibrosis, because mutations in theABCC7 gene associated with dysfunction or epithe-lial absence of the transporter are the underlying rea-son for the incorrect ion homeostasis, especially forchloride, which is the predominate anion transported byABCC7 under physiological conditions.

DrugsIn this context, two aspects are important. First, manydrugs are substrates of ABC-transporters and thereforethese transporters might affect the bioavailability ofthese substances. Tissues like liver, intestine, andkidney exhibit high expression levels of differenttransport proteins. Therefore, substrates of thesetransporters may be intensively eliminated to the bileand urine or transported back to the intestine, therebylimiting oral bioavailability. Besides these pharmacoki-netic important organs, ABC-transporters are expressedin target tissues of certain drugs. As already mentionedthis point carries an unsolved problem in chemotherapybecause many anticancer drugs are ABC-transportersubstrates and tumor cells often show an enhanced

transporter expression and therefore MDR. However,this problem is not restricted to cancer therapy. Forexample, ABC-transporters are also expressed in thebloodbrain barrier; thereby limiting the access ofdrugs to the brain. While this is useful for drugs likeloperamide, a morphine-based drug against diarrhea, itmight be a problem in the case of antipoychotic andantiepileptic drugs. A list of ABC-transporters and theirsubstrates is given in Table 1.Second, as already shown for P450 enzymes before,

there is also a drug-interaction potential on thetransporter level. The promoter regions of some ABC-transporter genes (e.g., P-gp) contain transcriptionfactor binding sites like the pregnane X receptor(PXR), the constitutive androstane receptor (CAR),the farnesoid X receptor (FXR), the steroid andxenobiotic receptor (SXR) or the peroxisome prolif-erator-activated receptor (PPAR). Therefore, theseproteins are not only regulated by endogenouscompounds like bile acids or steroid hormones but alsoby therapeutic agents like phenobarbital, rifampicin, or

plasma levels after coadministration of substrates forthese transporters.In addition, ABC-transporters demonstrate interindi-

vidual variability caused by genetic polymorphisms.Again, the ABCB1 (P-gp) is the best characterizedtransporter in this field. Here, various synonymous andnonsynonymous polymorphisms as well as deletionsand insertions have been described. Some of thenonsynonymous single nucleotide polymorphisms(SNPs) have already been shown to be associated withan altered transport activity of the protein. Interestingly,this observation has also been made for the C- toT-variant at position 3435, which represents the mostfrequent synonymous SNP of ABCB1. This C3435Tpolymorphism could be associated with an alteredprotein expression and function of P-gp, becauseindividuals homozygous for this polymorphism showa significant lower intestinal P-gp expression. Thisfinding was underlined by elevated digoxin plasmalevels in patients homozygous for this SNP incomparison with the wild type. Recent data suggest

rs

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ABC Transporters 7

Adexamethasone. This regulation might be accompaniedby an altered bioavailability of transporter substrates,when coadministered with these compounds. Forexample, the decreased bioavailability of digoxin, aP-gp substrate, after coadministration of rifampicin isdue to an enhanced intestinal P-gp expression. On theother hand, many compounds are inhibitors of ABC-transporters (in the case of P-gp, for example,verapamil, ketoconazole, amiodarone, progesterone,indinavir, clarithromycin, cyclosporine, chlorproma-zine, or methadone), which in turn leads to higher

ABC Transporters. Table 1 Substrates of ABC-transporte

ABC-transporter

P-gp (ABCB1) Verapamil, digoxin, mitoxantronedexamethasone, colchicine, lopeitraconazole, cyclosporine, methoand others

MRP1 (ABCC1) Glucuronides and sulfate conjugadoxorubicin, daunorubicin, epirubvincristine, and others

MRP2 (ABCC2) LTC4, bilirubin-glucuronide, estraconjugates, glutathione disulfide,

MRP3 (ABCC3) Organic anions including bile sal

MRP4 (ABCC4) PMEA, PMEG, ganciclovir, AZT,cGMP, estradiol 17-glucuronideand others

MRP5 (ABCC5) PMEA, PMEG, cladribine, gemcicAMP,cGMP, glutathione, DNP-SG, CdBCRP (ABCG2) Cisplatin, folate, methotrexate, mitotestosterone, progesterone), certainthat the altered protein expression and function of thisvariant may be due to the presence of a rare codon,which affects the timing of cotranslational folding andinsertion of the protein into the membrane.Taken together ABC-transporters represent a large

family of proteins affecting the pharmacokineticparameters of various drugs. Here, P-gp is currentlythe best characterized member and it may also be one ofthe most important ABC-transporters with regard todrug transport. However, it becomes more and moreapparent that ABC-transporter act in a coordinated

involved in multidrug resistance (MDR)

ransporter substrates

inblastine, doxorubicin, losartan, talinolol, cortisol,mide, domperidone, indinavir, erythromycin, tetracycline,exate, amitryptyline, phenobarbital, morphine, cimetidine,

s of steroid hormones and bile salts, colchicine,in, folate, irinotecan, methotrexate, pacitaxel, vinblastine,

ol 17-glucuronide, dianionic bile salts, anionicnd others

mercaptopurin, thioguanine, methotrexate, cAMP,HEAS, sulphated bile acids, glutathione, PGE1, PGE2,

ine, cytarabine, 5-FU, 6-mercaptopurine, thioguanine,

2, and othersxantrone, topotecan, irinotecan, steroids (cholesterol,chlorophyll metabolites, and others

fashion with other detoxification systems like P450

ABC drug transporter gene MDR1. Pharmacogenomics J1:5964

from bacteria to man. Academic press

Abstinence Syndrome

tom) is observed after withdrawal of a drug to which a

Drug Addiction

AcadesineABPs

Actin Binding Proteins

Absence Epilepsy

Absence Epilepsies are a group of epileptic syndromestypically starting in childhood or adolescence andcharacterized by a sudden lack of attention and mildautomatic movements for some seconds to minutes.Absence epilepsies are generalized, i.e. the wholeneocortex shifts into a state of sleep-like oscillations.

Antiepileptic Drugs

Absorption3. Chan LM, Lowes S, Hirst BH (2004) The ABCs of drugtransport in intestine and liver: efflux proteins limiting drugabsorption and bioavailability. Eur J Pharm Sci 21:2551

4. Gottesman MM, Ling V (2006) The Molecular basisof multidrug resistance in cancer: the early years ofP-glycoprotein research. FEBS Lett 580:9981009

5. Holland IB,KuchlerK,Higgins CF (2003)ABC-proteins enzymes and uptake transporters. In particular,P-glycoprotein and Cytochrome P450 3A4 are closelyintertwined in terms of regulation and function. Thus,further reviews have to address the combined action ofvarious systems.

MDR-ABC-TransportersATP-dependent K+ ChannelAntracyclins

References1. Borst P, Elferink RO (2002) Mammalian ABC transporters

in health and disease. Annu Rev Biochem 71:5375922. BrinkmannU, EichelbaumM (2001) Polymorphisms in the8 ABPsAbsorption is defined as the disappearance of a drugfrom the site of administration and its appearance in the5-Aminoimidazole-4-carboxamide ribonucleoside (al-so known as AICA riboside or AICAR). An adenosineanalogue that is taken up into cells by adenosinetransporters and converted by adenosine kinase tothe monophosphorylated nucleotide form, ZMP. ZMPis an analogue of AMP that activates the AMP-activated protein kinase (AMPK), for which acade-sine or AICAR can be used as a pharmacologicalactivator.Dependence

Abused Drugs

Drug Addiction/Dependenceperson is addicted. For example, the abstinencesyndrome after alcohol withdrawal is characterized bytremor, nausea, tachycardia, sweating and sometimeshallucinations.The abstinence syndrome (synonym, withdrawal symp-blood (central compartment) or at its site of action.The main routes of administration are oral or parenteral(injection). After oral administration, a drug has to betaken up (is absorbed) from the gut. Here, the main siteof absorption is the small intestine. In this case, only aportion of drug reaches the blood and arrives at its siteof action.

PharmacokineticsAMP-activated Protein Kinase

In some patients with hypertension and in all patients

Aactivated to an undesired degree, burdening the heart.The consequences of diminished ANG II genera-exhibit high aldosterone levels even when taking ACEwith cardiac failure, the reninangiotensin system is

tion by ACE inhibitors are multiple. In patients withrole in cardiovascular hemostasis. Its major function isthe generation of angiotensin (ANG) II from ANG I andthe degradation of bradykinin. Both peptides haveprofound impact on the cardiovascular system andbeyond. ACE inhibitors are used to decrease bloodpressure in hypertensive patients, to improve cardiacfunction, and to reduce work load of the heart in patientswith cardiac failure.

Mechanism of ActionACE inhibitors inhibit the enzymatic activity ofangiotensin converting enzyme (ACE). This enzymecleaves a variety of pairs of amino acids from thecarboxy-terminal part of several peptide substrates. Theconversion of ANG I to ANG II and the degradation ofbradykinin to inactive fragments are considered themost important functions of ACE [13]. ACE inhibitorsare nonpeptide analogues of ANG I. They bind tightlyto the active sites of ACE, where they complex with azinc ion and interact with a positively charged group aswell as with a hydrophibic pocket. They competitivelyinhibit ACE with Ki values in the range between 1010

and 1011 [3].

Effects of ACE Inhibitors Mediated by the Inhibition ofANG II GenerationANG II is the effector peptide of the reninangiotensinsystem [1, 2]. ANG II is one of the most potentvasoconstrictors, fascilitates norepinephrine release,stimulates aldosterone production, and increases renalsodium retention. In addition, ANG II is considered tobe a growth factor, stimulating proliferation of variouscell types. The actions of ANG II are mediated throughtwoangiotensin receptors, termed AT1 and AT2. Mostof the cardiovascular functions of ANG II are mediatedthrough the AT1 receptor.Angiotensin converting enzyme (ACE) plays a cenACE Inhibitors

JORG PETERSPhysiologisches Institut der Universitt Greifswald,Greifswald, Germany

SynonymsAngiotensin-converting enzyme inhibitors

Definitiontralhypertension, blood pressure is reduced as a resultof (i) decreased peripheral vascular resistance,(ii) decreased sympathetic activity, and (iii) reducedsodium and water retention. In patients with cardiacfailure, cardiac functions are improved as a result of(i) reduced sodium and water retention (preload andafterload reduction), (ii) diminished total peripheralresistance (afterload reduction), and (iii) reducedstimulation of the heart by the sympathetic nervoussystem. A reduction of cardiac hypertrophy appearsto be another desired effect of ACE inhibitors. Itis mediated at least partially by the reduction ofintracardiac ANG II levels. ACE inhibitors furthermoreprotect the heart from arrhythmia during reperfusionafter ischemia, and improve local blood flow and themetabolic state of the heart. These effects are largelymediated by Bradykinin (see below).In the vasculature, ANG II not only increases

contraction of smooth muscle cells, but is also able toinduce vascular injury. This can be prevented byblocking NFB activation [3] suggesting a linkbetween ANG II and inflammation processes involvedin the pathogenesis of arteriosclerosis (see below).Thus, ACE inhibitors not only decrease vascular tonebut probably also exert vasoprotective effects.In the kidney, ANG II reduces renal blood flow and

constricts preferentially the efferent arteriole of theglomerulus with the result of increased glomerularfiltration pressure. ANG II further enhances renalsodium and water reabsorption at the proximal tubulus.ACE inhibitors thus increase renal blood flow anddecrease sodium and water retention. Furthermore,ACE inhibitors are nephroprotective, delaying theprogression of glomerulosclerosis. This also appearsto be a result of reduced ANG II levels and is at leastpartially independent from pressure reduction. On theother hand, ACE inhibitors decrease glomerularfiltration pressure due to the lack of ANG II-mediatedconstriction of the efferent arterioles. Thus, oneimportant undesired effect of ACE inhibitors isimpaired glomerular filtration rate and impaired kidneyfunction.Another effect of ANG II is the stimulation of

aldosterone production in the adrenal cortex. ANG IIincreases the expression of steroidogenic enzymes,such as aldosterone synthase and stimulates theproliferation of the aldosterone-producing zona glo-merulosa cells. Aldosterone increases sodium andwater reabsorbtion at the distal tubuli. More recentlyit has been recognized that aldosterone is a fibroticfactor in the heart. ACE inhibitors decrease plasmaaldosterone levels on a short-term scale, thereby notonly reducing sodium retention but also preventingaldosterone-induced cardiac fibrotic processes. On along-term scale, however, patients with cardiac failure

ACE Inhibitors 9inhibitors.

of bradykinin are explained by the fact that the peptidepotently stimulates the NO-pathway and increasesprostaglandin synthesis in endothelial cells. In smoothmuscle cells and platelets, NO stimulates the solubleguanylate cyclase, which increases cyclic GMP that inturn activates protein kinase G. As a consequence,vascular tone and subsequently systemic blood pressureis decreased, local blood flow is improved, and plateletaggregation is prevented.ACE inhibitors inhibit the degradation of bradykinin

and potentiate the effects of bradykinin by about50100-fold. The prevention of bradykinin degradationby ACE inhibitors is particularly protective for theheart. Increased bradykinin levels prevent postischemicreperfusion arrhythmia, delays manifestations of cardi-ac ischemia, prevents platelet aggregation, and proba-bly also reduces the degree of arteriosclerosis and thedevelopment of cardiac hypertrophy. The role ofbradykinin and bradykinin-induced NO release for theimprovement of cardiac functions by convertingenzyme inhibitors has been demonstrated convincinglywith use of a specific bradykinin receptor antagonistand inhibitors of NO-synthase.molecular weight (LMW) kininogen. Several effeIn this context, it is important to note that circulatingANG II levels do not remain reduced during long-termtreatment with ACE inhibitors. This is likely the resultof activation of alternative, ACE-independent pathwaysof ANG II generation. The protective effects of ACEinhibitors on a long-term scale, therefore, are notexplained by a reduction of circulating ANG II levels.They are either unrelated to inhibition of ANG IIgeneration, or a result of the inhibition of localgeneration of ANG II. Indeed, due to the ubiquitouspresence of ACE in endothelial cells, large amounts ofANG II are generated locally within tissues such askidney, blood vessels, adrenal gland, heart, and brain,and exert local functions without appearing in thecirculation [2]. Membrane-bound endothelial ACE, andconsequently local ANG II genera