Encyclopedia of Molecular Pharmacology (2nd edition) pptx

ANTOCH Department of Molecular and Cancer Biology Roswell Park Cancer Institute NY USA antochm@ccf.org FABIOANTONIOLI Department of Biological Regulation The Weizmann Institute of Scienc

Encyclopedia of Molecular Pharmacology

STEFAN OFFERMANNS AND WALTER ROSENTHAL (Eds.)

Encyclopedia of Molecular Pharmacology (2nd edition)

With 487 Figures* and 171 Tables

*For color figures please see our Electronic Reference on www.springerlink.com

Robert-Rössle-Str 10 D-13125 Berlin Germany Rosenthal@fmp-berlin.de

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

ISBN: 978-3-540-38916-3

This publication is available also as:

Electronic publication under ISBN 978-3-540-38918-7 and

Print 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 of translation, 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, in its current version, and permission for use must always be obtained from Springer-Verlag Violations are liable for prosecution under the German Copyright Law.

© Springer-Verlag Berlin Heidelberg New York 2008

The use of registered names, trademarks, 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 therefore free for general use.

Product liability: The publishers cannot guarantee the accuracy of any information about the application of operative techniques and medications contained in this book In every individual case the user must check such information by consulting the relevant literature.

Springer is part of Springer Science+Business Media

springer.com

Printed on acid-free paper SPIN: 191230 2109 — 5 4 3 2 1 0

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 names

of 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, suggestions

or 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 thank

Ms Hana Deuchert and Ms 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 and

to Frank Krabbes for his technical expertise Finally, we would like to express our gratitude to Dr Claudia Langefor successfully managing the project and for her encouraging support It has been a pleasure to work with her.Heidelberg/Berlin, June 2003

STEFANOFFERMANNS ANDWALTERROSENTHAL

Preface to the Second Edition

The first edition of the Encyclopedic Reference of Molecular Pharmacology was well received by its readers, thanks

to 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 2007

STEFANOFFERMANNS ANDWALTERROSENTHAL

Institut für Experimentelle und Klinische Pharmakologie und

Toxikologie, Albert-Ludwigs-Universität Freiburg

Division of Pharmacology, Department of Neuroscience

School of Medicine,“Federico II” University of Naples

Naples

Italy

lannunzi@unina.it

MARINAP ANTOCH

Department of Molecular and Cancer Biology

Roswell Park Cancer Institute

NY

USA

antochm@ccf.org

FABIOANTONIOLI

Department of Biological Regulation

The Weizmann Institute of Science

CHRISTIANAYMANNS

Nephrology Division, Department of Internal Medicine IUniversity Hospital

UlmGermany

WILLIAMBABBITT

UCSF School of MedicineSan Francisco, CAUSA

william.babbitt@ucsf.edu

EVELYNBACK

Novartis Pharma GmbHNürnberg

Germanyevelyn_back@hotmail.com

MICHAELBADER

Max Delbrück Center for Molecular Medicine (MDC)Campus Berlin-Buch

Germanymbader@mdc-berlin.de

CLIFFORDJ BAILEY

School of Life and Health SciencesAston University

BirminghamUKc.j.bailey@aston.ac.uk

JILLIANG BAKER

University of NottinghamUK

jillian.baker@nottingham.ac.uk

ANDREASBARTHEL

BG-Kliniken BergmannsheilRuhr-University

BochumGermanyAndreas.Barthel@post.rwth-aachen.de

Sackler Institute of Pulmonary Pharmacology

King’s College London

London

UK

felicity.bertram@kcl.ac.uk

MARTINBIEL

Munich Center for Integrated Protein Science CiPSMand

Department of Pharmacy– Center for Drug Research

CLARKM BLATTEIS

University of Tennessee Health Science CenterCollege of Medicine

Memphis, TNUSAblatteis@physio1.utmem.edu

ANDREEBLAUKAT

TA Oncology, Merck Serono ResearchMerck KGaA

DarmstadtGermanyAndree.Blaukat@merck.de

MICHAELBÖHM

Klinik für Innere Medizin IIIHomburg/Saar

Germanyboehm@med-in.uni-saarland.de

MICHELLEBOONE

Department of PhysiologyRadboud University Nijmegen Medical CenterNijmegen

The Netherlands

ARNDTBORKHARDT

Children’s University Hospital, Department of PaediatricHaematology & Oncology & Clinical ImmunologyUniversität Düsseldorf

DüsseldorfGermanyarndt.borkhardt@med.uni-duesseldorf.de

x List of Contributors

William Harvey Research Institute

School of Medicine and Dentistry

St Bartholomew’s and Royal London

Department of Pathology, Brigham and Women’s Hospital

Harvard Medical School

Boston, MA

USA

EDWARDM BROWN

Division of Endocrinology, Diabetes and Hypertension

Brigham and Women’s Hospital

Boston, MA

USA

embrown@rics.bwh.harvard.edu

EREZM BUBLIL

Department of Biological Regulation

The Weizmann Institute of Science

GEOFFREYBURNSTOCK

Autonomic Neuroscience CentreRoyal Free and University College Medical SchoolLondon

UKg.burnstock@ucl.ac.uk

AMANU BUZDAR

Department of Breast Medical OncologyThe University of Texas, M.D Anderson Cancer CenterHouston, TX

USAAbuzdar@mdanderson.org

TAMARACASTANEDA

Department of PsychiatryObesity Research Center, University of CincinnatiCincinnati, OH

USAcastant@ucmail.uc.edu

THOMASK H CHANG

Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouver, BC

Canadatchang@interchange.ubc.ca

bc@lppi.ucsf.edu

List of Contributors xi

Department of Breast Medical Oncology

The University of Texas, M.D Anderson Cancer Center

ANDREASDRAGUHN

Institut für Physiologie und PathophysiologieUniversität Heidelberg

HeidelbergGermanyandreas.draguhn@urz.uni-heidelberg.de

COLINROBERTDUNSTAN

Head, Bone Research ProgramANZAC Research Institute, The University of SydneyConcord, NSW

Denmarkbjeb@lundbeck com

ROBERTEDWARDS

Departments of Neurology and PhysiologyUniversity of California at San FranciscoSan Francisco, CA

USAedwards@itsa.ucsf.edu

MICHELEICHELBAUM

Dr Margarete Fischer-Bosch Institute of ClinicalPharmacology

StuttgartGermanymichel.eichelbaum@ikp-stuttgart.de

JOHNH EXTON

Howard Hughes Medical Institute and Department ofMolecular Physiology and Biophysics

Vanderbilt UniversityNashville, TNUSAjohn.exton@mcmail.vanderbilt.edu

SANDRINEFAIVRE

Department of Medical OncologyBeaujon University HospitalClichy Cedex

France

FRANCESCOFALCIANI

School of BiosciencesThe University of BirminghamUK

f.falciani@bham.ac.ukxii List of Contributors

Institut für Pharmakologie und Toxikologie

Universität des Saarlandes

Homburg

Germany

veit.flockerzi@uniklinik-saarland.de

MARYANNFOOTE

M A Foote Associates, Westlake Village

CA and Department of Microbiology

JEAN-MARIEFRERE

Centre d’Ingenierie des Protéines

Protein Engineering Group

Leibniz-Institute for Molecular Pharmacology

Berlin

Germany

freund@fmp-berlin.de

ELKEC FUCHS

Abteilung Klinische Neurobiologie

Interdisziplinäres Zentrum für Neurowissenschaften (IZN)

Heidelberg

Germany

E.Fuchs@urz.uni-heidelberg.de

RUTHGEISS-FRIEDLANDER

Department of Biochemie I, Faculty of Medicine

TOMGELDART

Department of Medical OncologySouthampton General HospitalSouthampton

UKtomgeldart@doctors.org.uk

NANCYGERITS

Department of Microbiology and VirologyInstitute of Medical Biology, University of TromsoTromso

Norwaynancyg@fagmed.uit.no

PIERREGERMAIN

Department of Cell Biology and Signal TransductionInstitut de Genetique et de Biologie Moleculaire et Cellulaire(IGBMC)

Illkirch CedexFrancegermain@igbmc.u-strasbg.fr

STEPHENJ GETTING

Department of Human and Health Sciences, School ofBiosciences

University of WestminsterLondon

UKs.getting@wmin.ac.uk

JEAN-MARIEGHUYSEN

Centre d’Ingenierie des ProtéinesUniversity of Liège

LiègeBelgium

USAjendogger@yahoo.com

MURALIGOPALAKRISHNAN

Global Pharmaceutical Research and DevelopmentAbbott Laboratories

Abbott Park, ILUSA

murali.gopalakrishnan@abbott.com

List of Contributors xiii

Department of Cell Biology and Signal Transduction

Institut de Genetique et de Biologie Moleculaire et Cellulaire

Hamner Institutes of Health Sciences

Research Triangle Park, NC

Department of Medical Oncology

Southampton General Hospital

Humboldt-Universität zu BerlinBerlin

Germanyuwe.heinemann@charite.de

MATTHIASHEINZE

Protein Engineering GroupLeibniz-Institute for Molecular PharmacologyBerlin

CLAUSW HEIZMANN

Department of Pediatrics, Division of Clinical Chemistry andBiochemistry

University of ZurichZurich

Switzerlandheizmann@access.unizh.ch

RICARDOHERMOSILLA

Department of Molecular Pharmacology and Cell BiologyCharité Medical University Berlin

BerlinGermanyricardo.hermosilla@charite.de

HEIKOHERWALD

Lund UniversityLund

SwedenHeiko.Herwald@med.lu.se

ISABELLAHEUSER

Department of Psychiatry and PsychotherapyCharité, CBF

BerlinGermanyisabella.heuser@charite.dexiv List of Contributors

Laboratory Genetic Metabolic Diseases

Academic Medical Center

ANDREAHUWILER

pharmazentrum frankfurtJohann Wolfgang Goethe-Universität Frankfurt am MainGermany

KIYOMIITO

Department of Clinical PharmacokineticsHoshi University

Tokyo, Japank-ito@hoshi.ac.jp

KENNETHA JACOBSON

Molecular Recognition Section, Laboratory of BioorganicChemistry, National Institute of Diabetes Digestive andKidney Diseases

National Institutes of HealthBethesda, MD

USAkajacobs@helix.nih.gov

REINHARDJAHN

Max-Planck-Institut für biophysikalische ChemieGöttingen

Germanyrjahn@gwdg.de

ELISABETHM JEANCLOS

Universitätsklinikum DüsseldorfDüsseldorf

GermanyElisabeth.Jeanclos@uni-duesseldorf.de

THOMASJ JENTSCH

Leibniz-Institut für Molekulare Pharmakologie (FMP) andMax-Delbrück-Centrum für Molekulare Medizin (MDC)Berlin

Germanyjentsch@fmp-berlin.de

GARYL JOHNSON

University of North CarolinaChapel Hill, NC

USAGary_Johnson@med.unc.edu

ROGERA JOHNSON

Department of Physiology and BiophysicsState University of New York

New York, NYUSA

roger.johnson@stonybrook.edu

List of Contributors xv

Section of Clinical Tropical Medicine

University Hospital Heidelberg

PET Centre - Schizophrenia Division

Centre for Addiction and Mental Health

Toronto, ONT

Canada

shitij_kapur@camh.net

JOHNJ P KASTELEIN

Department of Vascular Medicine

Academic Medical Center, University of Amsterdam

Glaxo Wellcome Research

Research Triangle Park, NC

USA

tpk1348@GlaxoWellcome.com

ELAINEF KENNY

School of Biochemistry and Immunology

Trinity College Dublin

PATRICKKITABGI

INSERM U732/Université Pierre et Marie CurieHopital St-Antoine

Paris cedex 12Francekitabgi@st-antoine.inserm.fr

SUSANNEKLUMPP

Institut für Pharmazeutische und Medizinische ChemieWestfälische Wilhelms-Universität

MünsterGermanyseklumpp@uni-muenster.de

ENNOKLUSSMANN

Leibniz-Institut für Molekulare Pharmakologie Department ofMolecular Pharmacology and Cell Biology

Charitè-Universitätsmedizin BerlinBerlin

Germanyklussmann@fmp-berlin.de

KLAUS-PETERKNOBELOCH

Leibniz-Institut für Molekulare PharmakologieBerlin

Germanyknobeloch@fmp-berlin.de

BRIANK KOBILKA

Stanford University Medical SchoolStanford, CA

USAkobilka@stanford.edu

DORISKOESLING

Pharmakologie und ToxikologieRuhr-Universität BochumBochum

Germanydoris.koesling@ruhr-uni-bochum.de

SPIROM KONSTANTINOV

Department of Pharmacology and ToxicologyMedical University in Sofia, Faculty of PharmacySofia

Bulgariakonstantinov.spiromihaylov@gmail.com

KENNETHS KORACH

National Institute of Environmental Health SciencesResearch Triangle Park, NC

USAkorach@niehs.nih.govxvi List of Contributors

Westfälische Wilhelms-Universität, Institut für

Pharmazeutische und Medizinische Chemie

Münster

Germany

krieglst@uni-muenster.de

ANJAKRIPPNER-HEIDENREICH

Institut of Cellular Medicine

Japannagomik@med.juntendo.ac.jp

THORSTENLANG

Max-Planck-Institut für biophysikalische ChemieGöttingen

Germanytlang@.gwdg.de

MICHAELLANZER

Department of ParasitologyUniversity Hospital HeidelbergHeidelberg

GermanyMichael_Lanzer@med.uni-heidelberg.de

DAVIDS LATCHMAN

Institute of Child HealthUniversity College LondonLondon

UKd.latchman@ich.ncl.ac.uk

MOGENSLYTKENLARSEN

Odense University Hospital and Department of CardiologyAalborg Hospital

Denmarkmogenslytkenlarsen@dadlnet.dk

ALESSANDROLECCI

Clinical Research Dept (AL) and Direction (CAM) ofMenarini Ricerche

FlorenceItalyalecci@menarini-ricerche.it

ALANR LEFF

Department of MedicineUniversity of ChicagoChicago, IL

USAaleff@medicine.bsd.uchicago.edu

LOTHARLINDEMANN

F Hoffmann-La Roche, Pharmaceuticals Division, DiscoveryNeuroscience

BaselSwitzerlandlothar.lindemann@roche.com

Institut für Klinische Pharmakologie, Klinikum der Johann

Wolfgang Goethe-Universität Frankfurt am Main

Frankfurt

Germany

j.loetsch@em.uni-frankfurt.de

MARIE-GABRIELLELUDWIG

Novartis Institutes for Biomedical Research

CARLOALBERTOMAGGI

Clinical Research Dept (AL) and Direction (CAM) of

CambridgeUK

DAVIDC MAMO

PET Centre - Schizophrenia DivisionCentre for Addiction and Mental HealthToronto, ONT

CanadaDavid_Mamo@camh.net

PEKKAT MÄNNISTÖ

Division of Pharmacology and Toxicology, Faculty ofPharmacy

University of HelsinkiHelsinki

FinlandPekka.Mannisto@helsinki.fi

CHRISTIANMARTIN

Institute of Experimental and Clinical Pharmacology andToxicology

Universitätsklinikum AachenAachen

Germanychmartin@ukaachen.de

MICHAELU MARTIN

Immuology FB 08Justus-Liebig-University GiessenGiessen

GermanyMichael.Martin@bio.uni-giessen.de

FRAUKEMELCHIOR

Department of Biochemie I, Faculty of MedicineUniversity Goettingen

GoettingenGermanyf.melchior@medizin.uni-goettingen.de

Germanyaxmeyer@urz.uni-hd.de

DIETERK MEYER

Institut für Experimentelle und Klinische Pharmakologie undToxikologie

Albert-Ludwigs-Universität FreiburgFreiburg

Germanydieter.meyer@pharmakol-uni-freiburg.dexviii List of Contributors

Department of Molecular Genetics

German Institute of Human Nutrition Potsdam-Rehbruecke

Germanymonyer@urz-hd.de

GREGB G MOORHEAD

Department of Biological SciencesUniversity of Calgary

Calgary, ABCanadamoorhead@ucalgary.ca

GEORGEMORSTYN

M A Foote Associates, Westlake Village, CA and Department

of MicrobiologyMonash UniversityAustralia

K S MÜHLBERG

III Medical DepartmentUniversity of LeipzigLeipzig

Germanypasr@medizin.uni-leipzig.de

BARBARAMÜLLER

Abteilung VirologieUniversitätsklinikum HeidelbergHeidelberg

Germanybarbara_mueller@med.uni-heidelberg.de

JUDITHM MÜLLER

Universitäts-Frauenklinik und Zentrum für KlinischeForschung, Klinikum der Universität FreiburgFreiburg

Germanyjudith.mueller@uniklinik-freiburg.de

MARTINMÜLLER

Deutsches Krebsforschungszentrum HeidelbergHeidelberg

GermanyMartin.Mueller@dkfz.de

ROLFMÜLLER

Institute for Molecular Biology and Tumor Research (IMT)Philipps-University Marburg

Germanymueller@imt.uni-marburg.de

WERNERMÜLLER-ESTERL

University of Frankfurt Medical SchoolFrankfurt

Germanywme@biochem2.de

List of Contributors xix

Institut für Chemie und Biochemie

Freie Universität Berlin

Institut für Chemie und Biochemie

Freie Universität Berlin

HANS-PETERNOTHACKER

Department of PharmacologyUniversity of CaliforniaIrvine, CA

USAhnothack@uci.edu

ASTRIDNOVOSEL

Children’s University Hospital, Department of PaediatricHaematology & Oncology & Clinical ImmunologyUniversität Düsseldorf

DüsseldorfGermanyAstrid.Novosel@med.uni-duesseldorf.de

BERNDNÜRNBERG

Universitätsklinikum DüsseldorfDüsseldorf

GermanyBernd.Nuernberg@uni-duesseldorf.de

JAMESN OAK

Centre for Addiction & Mental HealthUniversity of Toronto

Toronto, ONTCanadajames.oak@utoronto.ca

STEFANOFFERMANNS

Institute of PharmacologyUniversity of HeidelbergHeidelberg

Germanystefan.offermanns@pharma.uni-heidelberg.de

YASUOOGAWA

Department of PharmacologyJuntendo University School of MedicineTokyo

Japanysogawa@med.juntendo.ac.jp

NATHAND OKERLUND

University of CaliforniaSan Francisco, CAUSA

ALEXANDEROKSCHE

Mundipharma Research GmbHLimburg

GermanyAlexander.oksche@mundipharma-rd.eu

GISELAOLIAS

Department of Molecular GeneticsGerman Institute of Human NutritionPotsdam-Rehbruecke

NuthetalGermanyolias@mail.dife.de

xx List of Contributors

LUKEA J O’NEILL

School of Biochemistry and Immunology

Trinity College Dublin

Sackler Institute of Pulmonary Pharmacology

King’s College London

Institut de Génomique Fonctionnelle

CNRS UMR5203, INSERM U661

Universités de Montpellier 1&2

USAjpinaire@lilly.com

SARAHL PITKIN

Clinical Pharmacology UnitUniversity of CambridgeLevel 6, Centre for Clinical Investigation, Addenbrooke’sHospital

CambridgeUK

ROBINPLEVIN

Strathclyde Institute of Pharmacy and Biomedical SciencesUniversity of Strathclyde

GlasgowUKr.plevin@strath.ac.uk

EREZPODOLY

The Life Sciences InstituteThe Hebrew University of JerusalemIsrael

ANNEMARIEPOLAK

F Hoffmann-La Roche LtdAesch, Basel

Switzerlandannemarie.polak@bluemail.ch

OLAFPONGS

Institut für Neurale Signalverarbeitung, Zentrum fürMolekulare Neurobiologie Hamburg

HamburgGermanypointuri@uke.uni-hamburg.de

BERNDPÖTZSCH

Universitätsklinikum BonnBonn

List of Contributors xxi

DANIELJ RADER

Institute for Translational Medicine and Therapeutics

University of Pennsylvania School of Medicine

Department of Medical Oncology

Beaujon University Hospital

ANNEREIFEL-MILLER

Lilly Research Laboratories

Eli Lilly and Company

GermanyResch.Klaus@MH-Hannover.de

ELKEROEB

GastroenterologyJustus-Liebig-UniversityGießen

Germanyelke.roeb@innere.med.uni-giessen.de

HANSROMMELSPACHER

Department of Clinical NeurobiologyUniversity Hospital Benjamin FranklinFree University Berlin

BerlinGermanyhans.rommelspacher@medizin.fu-berlin.de

THOMASC ROOS

Reha Klinik Neuharlingersiel, Interdisciplinary Center forDermatology, Pneumology and Allergology

NeuharlingersielGermanyroos@rehaklinik-neuharlingersiel-klinik.de

WALTERROSENTHAL

Institut für PharmakologieFreie Universität BerlinBerlin

Germanywalter.rosenthal@charite.de

ANAM ROSSI

Department of PharmacologyUniversity of CambridgeUK

amr50@cam.ac.uk

BERNARDC ROSSIER

Département de Pharmacologie et de Toxicologie de

l’UniversitéLausanneSwitzerlandBernard.Rossier@unil.ch

UWERUDOLPH

Institute of Pharmacology and ToxicologyUniversity of Zürich

ZürichSwitzerlandrudolph@pharma.unizh.ch

GEORGESACHS

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

USAgsachs@ucla.eduxxii List of Contributors

DAVIDB SACKS

Department of Pathology, Brigham and Women’s Hospital

Harvard Medical School

Research Group of Membrane Biology

Hungarian Academy of Sciences

GEORGIOSSCHEINER-BOBIS

Institute of Biochemistry and Endocrinology

Justus Liebig University Giessen

Institut für Experimentelle und Klinische Pharmakologie und

Toxikologie, Albert-Ludwigs-Universität Freiburg

Freiburg

Germany

gudula.schmidt@pharmakol.uni-freiburg.de

ERIKBERGSCHMIDT

Odense University Hospital and Department of Cardiology

TORSTENSCHÖNEBERG

Institut für Biochemie, Medizinische FakultätUniversität Leipzig

LeipzigGermanyTorsten.Schoeneberg@medizin.uni-leipzig.de

WILHELMSCHONER

Institute of Biochemistry and EndocrinologyJustus Liebig University Giessen

GiessenGermany

ROLANDSCHÜLE

Universitäts-Frauenklinik und Zentrum für KlinischeForschung, Klinikum der Universität FreiburgFreiburg

Germanyroland.schuele@uniklinik-freiburg.de

ANNETTESCHÜRMANN

Department of PharmacologyGerman Institute of Human NutritionPotsdam-Rehbruecke

Germanyschuermann@dife.de

CHRISTINASCHWANSTECHER

Molekulare Pharmakologie und ToxikologieTechnische Universität BraunschweigBraunschweig

Germanym.schwanstecher@tu-braunschweig.de

MATHIASSCHWANSTECHER

Molekulare Pharmakologie und ToxikologieTechnische Universität BraunschweigBraunschweig

GermanyM.Schwanstecher@tu-braunschweig.de

DIRKSCHWARZER

Leibniz-Institut für Molekulare Pharmakologie (FMP)Berlin

Germanyschwarzer_biochemie@email.de

List of Contributors xxiii

Bone Research Program

ANZAC Research Institute, The University of Sydney

Concord, NSW

Australia

mjs@anzac.edu.au

ROLANDSEIFERT

Department of Pharmacology and Toxicology

University of Regensburg, Regensburg

CHAR-CHANGSHIEH

Global Pharmaceutical Research and Development, Abbott

David Geffen School of Medicine

University of California at Los Angeles and Veterans

Administration Greater Los Angeles Healthcare System

The Life Sciences Institute

The Hebrew University of Jerusalem

Israel

soreq@cc.huji.ac.il

NOEMISOTO-NIEVES

Albert Einstein college of Medicine

Germanyulrich.speck@charite.de

ANDREASSTAHL

University of CaliforniaDepartment of Nutritional Science and ToxicologyBerkeley, CA 94720, USA

KLAUSSTARKE

Institut für Experimentelle und Klinische Pharmakologie undToxikologie

Universität FreiburgFreiburg

GermanyKlaus.starke@pharmakol.uni-freiburg.de

ALESSANDRASTARLING

Human Genome Research Center, Biosciences InstituteUniversity of São Paulo

São PauloBrazil

WIMA.VAN DERSTEEG

Department of Vascular MedicineAcademic Medical Center, University of AmsterdamAmsterdam

The Netherlandsw.a.vandersteeg@amc.uva.nl

CHRISTOPHSTEIN

Klinik für Anaesthesiologie und Operative IntensivmedizinFreie Universität Berlin

Charité CampusBenjamin FranklinBerlin

Germanychristoph.stein@charite.de

CHRISTIANSTEINKÜHLER

IRBM– Merck Research LaboratoriesPomezia

ItalyChristian_Steinkuhler@Merck.Com

JÖRGSTRIESSNIG

Institut für Pharmazie, Abteilung Pharmakologie undToxikologie

Leopold-Franzens-Universität InsbruckInnsbruck

Austriajoerg.striessnig@uibk.ac.at

xxiv List of Contributors

Department of Molecular Pharmacokinetics, Graduate School

of Pharmaceutical Sciences, The University of Tokyo

Departments of Pharmacology and Toxicology

Medical College of Georgia

Augusta, GA

USA

aterry@mcg.edu

MARIE-CHRISTINTHISSEN

Westfälische Wilhelms-Universität, Institut für

Pharmazeutische und Medizinische Chemie

Department of Cell Biology & Genetics

Erasmus University Medical Center

Rotterdam

The Netherlands

a.vantol@erasmusmc.nl

CHRISTOPHELETOURNEAU

Department of Medical Oncology

Beaujon University Hospital

STEFANUHLIG

Institute of Experimental and Clinical Pharmacology andToxicology

Universitäsklinikum AachenRWTH Aachen

Germanysuhlig@ukaachen.de

HUBERTH M VANTOL

Centre for Addiction & Mental HealthUniversity of Toronto

Toronto, ONTCanadahubert.van.tol@utoronto.ca

PETERVANDENABEELE

Department for Molecular Biomedical ResearchVIB

GhentBelgiumPeter.Vandenabeele@dmbr.ugent.be

UWEVINKEMEIER

Chair of Cell BiologyUniversity of Nottingham Medical SchoolSchool of Biomedical Sciences

Nottingham, NG7 2UHuwe.vinkemeier@nottingham.ac.uk

ANDRÁSVÁRADI

Institute of EnzymologyHungarian Academy of SciencesHungary

List of Contributors xxv

Department of Immunology, Division of Medicine

Imperial College London

Hamilton Regional Laboratory Medicine Program

Hamilton Health Sciences, and Department of Pathology

and Molecular Medicine

Michael G DeGroote School of Medical

School of Biochemistry and Immunology

Trinity College Dublin

HeidelbergGermanyfelix.wieland@bzh.uni-heidelberg.de

THOMASE WILLNOW

Max-Delbrueck-Center for Molecular MedicineBerlin

Germanywillnow@mdc-berlin.de

SUSANWONNACOTT

Department of Biology and BiochemistryUniversity of Bath

UKbsssw@bath.ac.uk

THOMASWORZFELD

Institute of PharmacologyUniversity of HeidelbergHeidelberg

Germany

YOSEFYARDEN

Department of Biological RegulationThe Weizmann Institute of ScienceRehovot

IsraelYosef.Yarden@weizmann.ac.il

MOUSSAB H YOUDIM

Technion-Rappaport Faculty of MedicineEva Topf Center of Excellence for NeurodegenerativeDiseases

Department of PharmacologyHaifa

Israelyoudim@tx.technion.ac.il

ULRICHM ZANGER

Dr Margarete Fischer-Bosch Institute of ClinicalPharmacology

StuttgartGermanyuli.zanger@ikp-stuttgart.de

MAYANAZATZ

Human Genome Research Center, Biosciences InstituteUniversity of São Paulo

São PauloBrazilmayanazatz@uol.com.br

Australiaxxvi List of Contributors

List of Contributors xxvii

The 14-3-3 proteins constitute a family of abundant,

highly conserved and broadly expressed acidic

poly-peptides One member of this family, the 14-3-3σ

isoform {sigma}, is expressed only in epithelial cells

and is frequently down-regulated in a variety of human

cancers and plays a role in the cellular response to DNA

damage The 14-3-3s generally form heterodimers

with other family members, but 14-3-3σ preferentially

forms homodimers in cells Three amino acids that

are completely conserved in all other 14-3-3s, are

not present in 14-3-3σ These amino acids unique to

14-3-3σ confer a second ligand-binding site involved

in 14-3-3σ-specific ligand discrimination

Department of Molecular Pharmacology and Cell

Biology, Charitè-Universitätsmedizin Berlin, Berlin,

Germany

Synonyms

Protein kinase A anchoring proteins

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 Mechanisms

AKAP-dependent Control of cAMP/PKA Signalling

A large variety of extracellular stimuli includinghormones and neurotransmitters elicit the generation

of the second messenger cyclic adenosine 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 Binding

monopho-of four molecules monopho-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] Spatialand 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].AKAP–PKA interactions play a role in a variety ofcellular processes includingβ-adrenoceptor-dependentregulation of cardiac myocyte contraction (Fig 2),vasopressin-mediated water reabsorption, proton secre-tion from gastric parietal cells, modulation of insulinsecretion from pancreatic β cells and T cell receptorsignalling A typical AKAP is AKAP18α, also termedAKAP15 It tethers PKA to▶L-type Ca2+

channelsin

cardiac myocytes and skeletal muscle cells and

facilitates their phosphorylation in response to

β-adrenoceptor activation The phosphorylation increases

the 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 diffuses

throughout the cell Therefore, discrete cAMP/PKA

signalling compartments are only conceivable if this

diffusion is limited.▶Phosphodiesterases(PDE)

estab-lish gradients of cAMP by local hydrolysis of the

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 1 Model of an A kinase anchoring protein

(AKAP) The unifying characteristic of AKAPs is the

presence of a structurally conserved binding domain for

the 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 subunits

each bound to one catalytic subunit (C) Binding of two

molecules of cAMP to each R subunit causes a

conformational change and release of the C subunits,

which in the free form phosphorylate substrate proteins

in close proximity The RBD in all AKAPs with pericentrin

as the only exception forms an amphipathic helix that

docks into a hydrophobic pocket formed by the

dimerization and docking domain of R subunits The

targeting domain, which tethers the AKAP complex to

cellular compartments and docking domains, which bind

further signalling proteins (e.g phosphodiesterases,

phosphatases or other kinases) are specific for

individual AKAPs A few AKAPs possess catalytic

activity such as the RhoGEF-activity in AKAP-Lbc

conferred by a DH domain The proteins within the AKAP

family are without obvious sequence homology

A Kinase Anchoring Proteins (AKAPs)

Figure 2 β-adrenoceptor-induced increases in cardiacmyocyte contractility depend on AKAP–PKA

interactions Stimulation ofβ-adrenoceptors (β1AR) 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 Gsandadenylyl cyclase (AC), and consequent synthesis ofcAMP which binds to regulatory (R) subunits of proteinkinase A (PKA) inducing dissociation of catalytic(C) subunits (see alsoFig 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 cardiac myocytes, Ca2+has to be removed from the cytosol A pivotal role in thisplays sarcoplasmic Ca2+ATPase (SERCA) It pumps

Ca2+back into the SR SERCA is inhibited when bound

to phospholamban (PLB) and activated upondissociation from PLB, which is induced byβ-adrenoceptor-mediated PKA phosphorylation.Collectively, the PKA phosphorylation events increasecardiac myocyte contractility The efficient

phosphorylation of L-type Ca2+channels occurs only ifPKA is anchored to the channel by AKAP18α For thephosphorylation of RyR, PKA anchoring to this channel

by mAKAP is a prerequisite Further AKAPs are likely to

be involved in PKA-dependent phosphorylation events

in response toβ-adrenoceptor stimulation (e.g PLB)

2 A Kinase Anchoring Proteins (AKAPs)

facilitates hydrolysis of cAMP in the vicinity of RyR at

the sarcoplasmic reticulum of cardiac myocytes Local

cAMP hydrolysis keeps mAKAP-associated PKA

activity low An increase in the cAMP level exceeding

the PDE4D3 hydrolyzing capacity activates PKA,

which phosphorylates RyR and increases the open

probability of this Ca2+channel PKA also

phosphor-ylates mAKAP-bound PDE4D3 and thereby enhances

PDE4D3 activity This again increases local cAMP

hydrolysis, switches off PKA, and eventually reduces

RyR phosphorylation This negative feedback loop

regulating RyR phosphorylation is completed by

association of mAKAP with protein phosphatase 2A

(PP2A), dephosphorylating RyR Dephosphorylation

decreases the channel open probability of RyR

AKAP-dependent Integration of Cellular Signalling

In addition to PKA, PDEs and protein phosphatases

involved in cAMP signalling, AKAPs interact with

other signalling proteins whose activation depends

on 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 propro-tein

phosphatases such as calcium/calmodulin-dependent

phosphatase (calcineurin, protein phosphatase 2B,

PP2B) This scaffolding function allows AKAPs to

integrate cellular signalling processes For example, rat

AKAP150 and its human ortholog AKAP79 bind PKA,

PKC and calcineurin In neurons, AKAP150-bound

PKC is activated through a M1 muscarinic

receptor-induced pathway that depends on the G protein Gqand

leads 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 thereby

inhibition of this channel AKAP79 coordinates the

phosphorylation of ▶AMPA channels Cyclic

AMP-activated AKAP79-bound PKA phosphorylates and

thereby activates the channels A raise of cytosolic Ca2+

activates AKAP79-bound calcineurin, which in turn

dephosphorylates the channels The dephosphorylation

mediates the rundown of AMPA channel currents

AKAP-Lbc binds PKA, PKC and PKD and possesses

intrinsic catalytic activity (Rho guanine nucleotide

exchange factor (RhoGEF) activity) Through its

Rho-GEF activity it catalyses the exchange of GDP for GTP on

the▶small GTPase Rho The GTP form of Rho is active

and induces the formation of F-actin-containing stress

fibres Agonists stimulating receptors coupled to the G

protein Gsmay mediate activation of AKAP-Lbc-bound

PKA, which in turn phosphorylates AKAP-Lbc

Subse-quently, a protein of the ▶14–3–3family binds to the

phosphorylated site and inhibits the RhoGEF activity In

contrast, agonists stimulating receptors coupled to the G

protein G12increase the RhoGEF activity

AKAPs Optimise the Limited Repertoire of CellularSignalling Proteins

Intriguingly, the same AKAP may coordinate tion of different target proteins In hippocampalneurons, AKAP150 positions PKA and calcineurin tomodulate AMPA channels and maintains PKC inactive

regula-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 not

in 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 usage

of the limited set of cellular signalling proteins

In summary, the function of AKAPs goes far beyondcontrolling cAMP/PKA signalling by simply tetheringPKA to cellular compartments and confining the access

of 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 targeted

by drugs which are currently applied for the treatment

of 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 protein–protein 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 disruption

of the AKAP18α–PKA interaction that facilitatesL-type Ca2+channel phosphorylation (see above) Thispreventsβ-adrenoceptor-induced increases in cytosolic

Ca2+, an effect resembling that ofβ-blockers In renalcollecting duct principal cells, vasopressin regulateswater reabsorption from primary urine by triggering thePKA phosphorylation and subsequent redistribution ofaquaporin-2 (AQP2) from intracellular vesicles intothe plasma membrane The redistribution depends on

A Kinase Anchoring Proteins (AKAPs) 3

A

the compartmentalization of PKA by AKAPs, one of

which is AKAP18δ The PKA anchoring disruptor

peptides displace PKA from AQP2-bearing vesicles

and inhibit vasopressin-mediated water reabsorption,

i.e have an aquaretic effect These examples suggest

that cell-type specific pharmacological intervention at

selected AKAP–PKA interactions is a feasible concept

for the treatment of human diseases (e.g cardiovascular

disease or diseases associated with water retention)

References

1 Zaccolo M, Pozzan T (2002) Discrete microdomains with

high concentration of cAMP in stimulated rat neonatal

cardiac myocytes Science 295:1711–1715

2 Langeberg LK, Scott JD (2005) A-kinase-anchoring

proteins J Cell Sci 118:3217–3220

3 Tasken K, Aandahl EM (2004) Localized effects of cAMP

mediated by distinct routes of protein kinase A Physiol

Rev 84:137–167

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

focal points in space and time Nat Rev Mol Cell Biol

5:959–970

5 Arkin MR, Wells JA (2004) Small-molecule inhibitors of

protein–protein interactions: progressing towards the

dream Nat Rev Drug Discov 3:301–331

ABC-proteins

▶ABC Transporters

ABC Transporters

Department of Pharmacology, Center of Pharmacology

and Experimental Therapeutics, Ernst-Moritz-Arndt

University Greifswald, Greifswald, Germany

Synonyms

ATP-binding cassette proteins; ABC-proteins

Definition

The ▶ABC-transportersuperfamily represents a large

group of transmembrane proteins Members of this

family are mainly involved in ATP-dependent transport

processes across cellular membranes These proteins

are of special interest from a pharmacological point of

view 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 basis

of homology relationships this superfamily is organized

in several subfamilies named ABCA to ABCF Not all

of 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 asP-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 alsotermed multidrug 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 Cole

et al identified the first member of the so-calledmultidrug resistance related proteins (MRP) The

▶MRP-proteins (MRP1–MRP9) belong to the C-branch

of the ABC-superfamily, which currently consists of atotal of 13 members (ABCC1–ABCC13) In addition

to ABCB1 and the ABCC family, a member of the ABCGfamily 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-gp

or MRP1

Topology and Structure

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

4 ABC-proteins

α-helical, transmembranal segments and two ATP

binding domains linked to the C-terminus of the TMDs

These domains, which are also termed nucleotide

binding folds (NBFs), contain the highly conserved

Walker A and B consensus motifs and the LSGGQ motif

(also called C- or signature motif ) While the Walker A

and B motifs are also found in other ATP-hydrolyzing

ATP proteins, the LSGGQ motif is unique for the

ABC-transporters The ATP hydrolysis catalyzed by the NBFs

is a prerequisite for substrate binding and enables

transport against a substrate gradient In addition to

these general characteristics, several members of

the ABCC-family (e.g., ABCC1–3) contain a further

N-terminal TMD, which, however, is not required

for transport activity In contrast to the other TMDs,

this N-terminal TMD contains five transmembranal

segments and lacks the NBF Besides this structural

variant 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 Expression

Although initially detected in cancer cell lines transporters show a wide tissue distribution Severalmembers of drug transporting ABC-proteins, for exam-ple, are highly expressed in physiological barriers such

ABC-as the apical membrane of gut enterocytes, theendothelial cells of the blood–brain 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 Figure 1 Structure of ABCB1, ABCC1, and ABCG2 (NBF: nucleotide binding fold; TMD:

transmembrane domaine Modified according to▶www.iwaki-kk.co.jp/bio/specialedition/se02.htm)

ABC Transporters 5

A

agents and are therefore expressed both in the

canalicular and sinusoidal membrane The canalicular

expression is a prerequisite for bilary elimination For

example, the bile salt export pump (BSEP/ABCB11) is

transporting bile salts, MRP2 (ABCC2) is involved in

the elimination of organic anions like

bilirubin-glucuronide or glutathione-conjugates and finally,

P-gp (ABCB1) eliminates a wide variety of drugs into the

bile In contrast, other ABC-transporters like MRP1

(ABCC1) and 3 (ABCC3) are mainly located in the

basal membrane of hepatocytes They transport

xeno-biotics and several conjugates back to the blood and

seem to be important under certain pathophysiological

conditions, for example, hepatic expression of both

transporters is enhanced during cholestasis, thereby

protecting the hepatocytes against toxic bile acid

concentrations by transport into the blood followed by

increased 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 is

noteworthy that many of these transporters not only

eliminate xenobiotic and toxic compounds from the

cell, but also endogonous compounds For example,

MRP4, 5, and 8 (ABCC4, 5, and 11), which are

expressed in many tissues and cancer cells, not only

transport xenobiotics like nucleotide-based anticancer

drugs but also the second messenger molecules cAMP

and cGMP Thereby, these transporters may play a role

in regulating intra- and extracellular cyclic nucleotide

concentrations

ABC-Transporters and Disease

Based on their physiological function it is not surprising

that genetic polymorphisms affecting expression and

function of ABC-proteins have been identified asthe underlying mechanisms for some diseases Forexample, mutations in the MRP2 (ABCC2) gene, whichlead to the loss of this protein from the canalicularmembrane of hepatocytes, are the mechanism of the

▶Dubin–Johnson Syndrome Here, the bilary 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 thepathogenesis 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

elimina-Drugs

In 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 expressed

in 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

ABC Transporters Figure 2 ABC-transporter expression in hepatocytes and enterocytes (modified according to

▶www.iwaki-kk.co.jp/bio/specialedition/se02.htm)

6 ABC Transporters

transporter expression and therefore MDR However,

this problem is not restricted to cancer therapy For

example, ABC-transporters are also expressed in the

▶blood–brain barrier; thereby limiting the access of

drugs to the brain While this is useful for drugs like

loperamide, a morphine-based drug against diarrhea, it

might be a problem in the case of antipoychotic and

antiepileptic drugs A list of ABC-transporters and their

substrates is given inTable 1

Second, as already shown for P450 enzymes before,

there is also a drug-interaction potential on the

transporter level The promoter regions of some

ABC-transporter genes (e.g., P-gp) contain transcription

factor binding sites like the pregnane X receptor

(PXR), the constitutive androstane receptor (CAR),

the farnesoid X receptor (FXR), the steroid and

xenobiotic receptor (SXR) or the peroxisome

prolif-erator-activated receptor (PPAR) Therefore, these

proteins are not only regulated by endogenous

compounds like bile acids or steroid hormones but also

by therapeutic agents like phenobarbital, rifampicin, or

dexamethasone This regulation might be accompanied

by an altered bioavailability of transporter substrates,

when coadministered with these compounds For

example, the decreased bioavailability of digoxin, a

P-gp substrate, after coadministration of rifampicin is

due to an enhanced intestinal P-gp expression On the

other 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

plasma levels after coadministration of substrates forthese transporters

In addition, ABC-transporters demonstrate vidual variability caused by genetic polymorphisms

interindi-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 with

an 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 show

a 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 suggestthat 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 largefamily 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

ABC Transporters Table 1 Substrates of ABC-transporters involved in multidrug resistance (MDR)

P-gp (ABCB1) Verapamil, digoxin, mitoxantrone, vinblastine, doxorubicin, losartan, talinolol, cortisol,

dexamethasone, colchicine, loperamide, domperidone, indinavir, erythromycin, tetracycline, itraconazole, cyclosporine, methotrexate, amitryptyline, phenobarbital, morphine, cimetidine, and others

MRP1 (ABCC1) Glucuronides and sulfate conjugates of steroid hormones and bile salts, colchicine,

doxorubicin, daunorubicin, epirubicin, folate, irinotecan, methotrexate, pacitaxel, vinblastine, vincristine, and others

MRP2 (ABCC2) LTC4, bilirubin-glucuronide, estradiol 17 β-glucuronide, dianionic bile salts, anionic

conjugates, glutathione disulfide, and others MRP3 (ABCC3) Organic anions including bile salts

MRP4 (ABCC4) PMEA, PMEG, ganciclovir, AZT, 6-mercaptopurin, thioguanine, methotrexate, cAMP,

cGMP, estradiol 17 β-glucuronide, DHEAS, sulphated bile acids, glutathione, PGE1, PGE2, and others

MRP5 (ABCC5) PMEA, PMEG, cladribine, gemcitabine, cytarabine, 5-FU, 6-mercaptopurine, thioguanine,

cAMP, cGMP, glutathione, DNP-SG, CdCl 2 , and others BCRP (ABCG2) Cisplatin, folate, methotrexate, mitoxantrone, topotecan, irinotecan, steroids (cholesterol,

testosterone, progesterone), certain chlorophyll metabolites, and others

ABC Transporters 7

A

fashion with other detoxification systems like P450

enzymes and ▶uptake transporters In particular,

P-glycoprotein and Cytochrome P450 3A4 are closely

intertwined in terms of regulation and function Thus,

further reviews have to address the combined action of

1 Borst P, Elferink RO (2002) Mammalian ABC transporters

in health and disease Annu Rev Biochem 71:537–592

2 Brinkmann U, Eichelbaum M (2001) Polymorphisms in the

ABC drug transporter gene MDR1 Pharmacogenomics J

1:59–64

3 Chan LM, Lowes S, Hirst BH (2004) The ABCs of drug

transport in intestine and liver: efflux proteins limiting drug

absorption and bioavailability Eur J Pharm Sci 21:25–51

4 Gottesman MM, Ling V (2006) The Molecular basis

of multidrug resistance in cancer: the early years of

P-glycoprotein research FEBS Lett 580:998–1009

5 Holland IB, Kuchler K, Higgins CF (2003) ABC-proteins–

from bacteria to man Academic press

ABPs

▶Actin Binding Proteins

Absence Epilepsy

Absence Epilepsies are a group of epileptic syndromes

typically starting in childhood or adolescence and

characterized by a sudden lack of attention and mild

automatic movements for some seconds to minutes

Absence epilepsies are generalized, i.e the whole

neocortex shifts into a state of sleep-like oscillations

▶Antiepileptic Drugs

Absorption

Absorption is defined as the disappearance of a drug

from the site of administration and its appearance in the

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 site

of absorption is the small intestine In this case, only aportion of drug reaches the blood and arrives at its site

5-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 ZMP

is an analogue of AMP that activates the activated protein kinase (AMPK), for which acade-sine or AICAR can be used as a pharmacologicalactivator

AMP-▶AMP-activated Protein Kinase

8 ABPs

Angiotensin converting enzyme (ACE) plays a central

role in cardiovascular hemostasis Its major function is

the generation of angiotensin (ANG) II from ANG I and

the degradation of bradykinin Both peptides have

profound impact on the cardiovascular system and

beyond ACE inhibitors are used to decrease blood

pressure in hypertensive patients, to improve cardiac

function, and to reduce work load of the heart in patients

with cardiac failure

Mechanism of Action

ACE inhibitors inhibit the enzymatic activity of

▶angiotensin converting enzyme(ACE) This enzyme

cleaves a variety of pairs of amino acids from the

carboxy-terminal part of several peptide substrates The

conversion of ANG I to ANG II and the degradation of

bradykinin to inactive fragments are considered the

most important functions of ACE [1–3] ACE inhibitors

are nonpeptide analogues of ANG I They bind tightly

to the active sites of ACE, where they complex with a

zinc ion and interact with a positively charged group as

well as with a hydrophibic pocket They competitively

inhibit ACE with Ki values in the range between 10–10

and 10–11[3]

Effects of ACE Inhibitors Mediated by the Inhibition of

ANG II Generation

ANG II is the effector peptide of the renin–angiotensin

system [1, 2] ANG II is one of the most potent

vasoconstrictors, fascilitates norepinephrine release,

stimulates aldosterone production, and increases renal

sodium retention In addition, ANG II is considered to

be a growth factor, stimulating proliferation of various

cell types The actions of ANG II are mediated through

two▶angiotensin receptors, termed AT1and AT2 Most

of the cardiovascular functions of ANG II are mediated

through the AT1receptor

In some patients with hypertension and in all patients

with cardiac failure, the renin–angiotensin system is

activated to an undesired degree, burdening the heart

The consequences of diminished ANG II

genera-tion by ACE inhibitors are multiple In patients with

hypertension, blood pressure is reduced as a result

of (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 appears

to be another desired effect of ACE inhibitors It

is 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 increasescontraction of smooth muscle cells, but is also able toinduce vascular injury This can be prevented byblocking ▶NFκB activation [3] suggesting a linkbetween ANG II and inflammation processes involved

in 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 andconstricts 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 appears

to 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

▶aldosteroneproduction 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 recently

it 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 failureexhibit high aldosterone levels even when taking ACEinhibitors

ACE Inhibitors 9

A

In this context, it is important to note that circulating

ANG II levels do not remain reduced during long-term

treatment with ACE inhibitors This is likely the result

of activation of alternative, ACE-independent pathways

of ANG II generation The protective effects of ACE

inhibitors on a long-term scale, therefore, are not

explained by a reduction of circulating ANG II levels

They are either unrelated to inhibition of ANG II

generation, or a result of the inhibition of local

generation of ANG II Indeed, due to the ubiquitous

presence of ACE in endothelial cells, large amounts of

ANG II are generated locally within tissues such as

kidney, blood vessels, adrenal gland, heart, and brain,

and exert local functions without appearing in the

circulation [2] Membrane-bound endothelial ACE, and

consequently local ANG II generation, has been proved

to be of greater significance than ANG II generated in

plasma by the circulating enzyme Experimental

evidence also indicates that plasma ACE may infact

not be relevant to blood pressure control at all

Effects of ACE Inhibitors Mediated by the Inhibition of

Bradykinin Degradation

Kinins are involved in blood pressure control,

regula-tion of local blood flow, vascular permeability, sodium

balance, pain, inflammation, platelet aggregation and

coagulation Bradykinin also exerts antiproliferative

effects [4] In plasma, bradykinin is generated from high

molecular weight (HMW) kininogen, while in tissues

lys-bradykinin is generated from HMW and low

molecular weight (LMW) kininogen Several effects

of bradykinin are explained by the fact that the peptide

potently stimulates the NO-pathway and increases

prostaglandin synthesis in endothelial cells In smooth

muscle cells and platelets, NO stimulates the soluble

guanylate cyclase, which increases cyclic GMP that in

turn activates protein kinase G As a consequence,

vascular tone and subsequently systemic blood pressure

is decreased, local blood flow is improved, and platelet

aggregation is prevented

ACE inhibitors inhibit the degradation of bradykinin

and potentiate the effects of bradykinin by about

50–100-fold The prevention of bradykinin degradation

by ACE inhibitors is particularly protective for the

heart Increased bradykinin levels prevent postischemic

reperfusion arrhythmia, delays manifestations of

cardi-ac ischemia, prevents platelet aggregation, and

proba-bly also reduces the degree of arteriosclerosis and the

development of cardiac hypertrophy The role of

bradykinin and bradykinin-induced NO release for the

improvement of cardiac functions by converting

enzyme inhibitors has been demonstrated convincingly

with use of a specific bradykinin receptor antagonist

and inhibitors of NO-synthase

In the kidney, bradykinin increases renal blood flow,

whereas glomerular filtration rate remains unaffected

Bradykinin stimulates natriuresis and, through tion of prostaglandin synthesis, inhibits the actions ofantidiuretic hormone (ADH), thereby inhibiting waterretention Bradykinin further improves insulin sensitiv-ity and cellular glucose utilization of skeletal musclecells in experimental models This, however, appearsnot to be relevant in the clinical context

stimula-Bradykinin exerts its effects via B1and B2receptors.The inhibition of bradykinin degradation by ACEinhibitors compensatory leads to increased conversion

of bradykinin to des Arg-9-bradykinin by kininase I.This peptide still has strong vasodilatatory propertiesand a high affinity to the B1 receptor The clinicalrelevance of this aspect is not clear The cardioprotec-tive effects of bradykinin are mediated via B2receptors,since they can be blocked by a specific B2 receptorantagonist [4] On the other hand, kinins increasevascular permeability with the consequence of edema,exhibit chemotactic properties with the risk of localinflammation and they are involved in the manifestation

of endotoxic schock Increased bradykinin levels arethus thought to cause some of the undesired effectsobserved with ACE inhibitors, such as cough, allergicreactions, and anaphylactic responses, for instanceangioneurotic edema [5]

Clinical Use (Including Side Effects)ACE inhibitors are approved for the treatment ofhypertension and cardiac failure [5] For cardiac failure,many studies have demonstrated increased survivalrates independently of the initial degree of failure Theyeffectively decrease work load of the heart as well ascardiac hypertrophy and relieve the patients symptoms

In contrast to previous assumptions, ACE inhibitors donot inhibit aldosterone production on a long-term scalesufficiently Correspondingly, additional inhibition ofaldosterone effects significantly reduces cardiac failureand increases survival even further in patients alreadyreceiving diuretics and ACE inhibitors This can beachieved by coadministration of spironolactone, whichinhibits binding of aldosterone to its receptor

In the treatment of hypertension, ACE inhibitors are

as effective as diuretics,β-adrenoceptor antagonists, orcalcium channel blockers in lowering blood pressure.However, increased survival rates have only beendemonstrated for diuretics and β-adrenoceptor antago-nists ACE inhibitors are approved for monotherapy aswell as for combinational regimes ACE inhibitors are thedrugs of choice for the treatment of hypertension withrenal diseases, particularly diabetic nephropathy, becausethey prevent the progression of renal failure and improveproteinuria more efficiently than the other drugs.More than 15 ACE inhibitors are presently available.They belong to three different chemical classes: sul-fhydryl compounds such as captopril, carboxyl com-pounds such as enalapril, and phopshorus compounds

10 ACE Inhibitors

such as fosinopril Sulfhydryl compounds exert more

undesired, but also desired effects, since they

addition-ally interact with endogenous SH groups For instance,

these compounts may potentiate NO-actions or act as

scavengers for oxygen-derived free radicals Carboxyl

compounds are in general more potent than captopril

Phosporous compounds are usually characterized by

the longest duration of action

Most ACE inhibitors are prodrugs, with the

excep-tions of captopril, lisinopril, and ceranapril Prodrugs

exert improved oral bioavailability, but need to be

con-verted to active compounds in the liver, kidney, and/or

intestinal tract In effect, converting enzyme inhibitors

have quite different kinetic profiles with regard to half

time, onset and duration of action, or tissue penetration

In general, ACE inhibitors at the doses used to date

are safe drugs In contrast to many antihypertensive

drugs, ACE inhibitors do not elicit a reflectory

tachycardia and do not influence lipid or glucose

metabolism in an undesired manner Glucose tolerance

is even increased Most undesired effects are

class-specific and related to the inhibition of ACE Less

dangerous, but often bothersome, are dry cough, related

to increased bradykinin levels and loss of taste or

impaired taste The more severe undesired effects are

hypotension, hyperkaliemia, and renal failure, but those

can be easily monitored and appropriately considered

The risk for hypotension increases in combination with

diuretics, particularly when ACE inhibitors are initiated

in patients who already receive diuretics The risk of

hyperkaliemia increases with coadministration of

spironolactone and the risk of renal failure is higher in

volume-depleted patients or those already exhibiting

impaired renal function Seldom (0.05%) the

develop-ment of angioneurotic edema occurs (usually) during

the first days of treatment and is life threatening

Allergic responses and angioneurotic edema are related

to bradykinin Recently, specific AT1receptor

antago-nists have become available and are used in the

management of hypertension and are presently tested

for use in cardiac failure They are believed not to

exhibit the bradykinin-related undesired effects Indeed,

undesired effects of AT1receptor antagonists are lower

than seen with ACE inhibitors On the other hand, AT1

receptor antagonists are probably less effective since

the patients do not profit from the cardioprotective

effects of bradykinin Studies comparing the effects of

ACE inhibitiors with AT1 receptor antagonists are

presently underway ACE inhibitors are contraindicated

in pregnancy (risk of abortion, acute renal failure of the

newborn) and patients with bilateral stenosis of the

renal artery Special caution should be taken if patients

have autoimmunolocial systemic diseases

▶Blood Pressure Control

▶Renin–Angiotensin–Aldosteron System

References

1 Bader M, Paul M, Fernandesz-Alfonso M et al (1994)Molecular biology and biochemistry of the renin-angio-tensin system, Chap 11 In: Swales JD (ed) Textbook ofhypertension Blackwell Scientific Publications, Oxford,London, Edinburgh, pp 214–232

2 Bader M, Peters J, Baltatu O et al (2001)Tissue angiotensin systems: new insights from experimentalanimal models in hypertension research J Mol Med79:76–102

renin-3 Gohlke P, Unger T (1994) Angiotensin converting enzymeinhibitors, Chap 65 In: Swales JD (ed) Textbook ofhypertension Blackwell Scientific Publications, Oxford,London, Edinburgh, pp 1115–1127

4 Linz W, Martorana PA, Schölkens B (1990) Localinhibition of bradykinin degradation in ischemic hearts JCardiovasc Parmacol 15:S99–S109

5 Brogden RN, Todd PA, Sorkin EM (1988) Drugs36:540–600

6 Wong J, Patel RA, Kowey PR (2004) The clinical use ofangiotensin-converting enzyme inhibitors Prog Cardio-vasc Dis 47, 116-130

cho-▶Cholinesterases

▶Emesis

Acetylcholine 11

A

Acetylcholine serves as a neurotransmitter Removal of

acetylcholine within the time limits of the synaptic

transmission is accomplished by acetylcholinesterase

(AChE) The time required for hydrolysis of

acetylcho-line at the neuromuscular junction is less than a

millisecond (turnover time is 150 μs) such that one

molecule of AChE can hydrolyze 6 × 105acetylcholine

molecules per minute The Kmof AChE for

acetylcho-line is approximately 50–100 μM AChE is one of

the most efficient enzymes known It works at a rate

close to catalytic perfection where substrate diffusion

becomes rate limiting AChE is expressed in

choliner-gic neurons and muscle cells where it is found attached

to the outer surface of the cell membrane

Acetyltransferase is an enzyme that catalyses the transfer

of an acetyl group from one substance to another

▶Histon Acetylation

N -Acetyltransferases

N-Acetyltransferases (NATs) catalyze the conjugation

of an acetyl group from acetyl-CoA on to an amine,hydrazine or hydroxylamine moiety of an aromaticcompound NATs are involved in a variety of phaseII-drug metabolizing processes There are two isozymesNAT I and NAT II, which possess different substratespecificity profiles The genes encoding NAT I andNAT II are both multi-allelic Especially for NAT II,genetic polymorphisms have been shown to result indifferent phenotypes (e.g., fast and slow acetylators)

▶Proton-Sensing GPCRs

ACPD

ACPD (1-aminocyclopentane-1,3-dicarboxylic acid) is

a selective agonist for metabotropic glutamate (mGlu)

12 Acetylcholine Hydrolase

receptors Within the 4 stereoisomers, 1S,3R-ACPD

activates group-I and group-II mGlu receptors as well as

some group-III receptors (mGlu8) at higher

concentra-tions The 1S,3S-ACPD isomer is one of the first

selective group-II mGlu receptor agonists described

These molecules have been widely used to identify the

possible physiological functions of mGlu receptors

▶Metabotropic Glutamate Receptors

Actin Binding Proteins

By binding to F-actin, actin binding proteins (ABPs)

stabilize F-actin or regulate its turnover Known ABPs

are proteins such as α-actinin, talin, tensin, filamin,

nexilin, fimbrin, and vinculin

▶Cytoskeleton

Actin Filaments

▶Cytoskeleton

Action Potential

An Action Potential is a stereotyped (within a given

cell) change of the membrane potential from a resting

(intracellular negative) value to a depolarized lular positive) value and then back to the resting value

(intracel-The durations of Action Potentials range from a couple

of milliseconds in nerve cells to hundreds of seconds in cardiac cells Action Potentials may bepropagated along very elongated cells (skeletal mus-cles, axons of neurons, etc) or from one cell to anothervia electrical gap junctions (e.g in cardiac tissue)

Activated Partial Thromboplastin Time

Activated partial thromboplastin time (aPTT) is acoagulation assay, which measures the time for plasma

to clot upon activation by a particulate substance (e.g.,kaolin) in the presence of negatively charged phospho-lipids

▶Anticoagulants

Activator Protein-1

Activator Protein-1 (AP1) comprises transcriptional plexes formed by dimers of members of the Fos, Jun, andATF family of transcription factors These proteins containbasic leucine zipper domains that mediate DNA bindingand dimerization They regulate many aspects of cellphysiology in response to environmental changes

com-▶NFAT Family of Transcription Factors

Active Site

Active site of an enzyme is the binding site wherecatalysis occurs The structure and chemical properties ofthe active site allow the recognition and binding of thesubstrate The active site is usually a small pocket at thesurface of the enzyme that contains residues responsible

Active Site 13

A

for the substrate specificity (charge, hydrophobicity, and

steric hindrance) and catalytic residues which often act as

proton donors or acceptors or are responsible for binding

a cofactor such as pyridoxal, thiamine, or NAD The

active site is also the site of inhibition of enzymes

Active Transport

Permeation of a drug through biological membranes

against the electrochemical gradient This type of drug

transport requires energy produced by intracellular

Active Transporters use the energy of ATP for vectorial

transport through a biological membrane against

concentration gradient of the transported substrate

▶ABC Transporters

▶MDR-ABC Transporters

Activins

Activins are growth and differentiation factors

belong-ing to the transformbelong-ing growth factor-β superfamily

They are dimeric proteins, consisting of two inhibin-β

subunits The structure of activins is highly conserved

during vertebrate evolution Activins signal through

type I and type II receptor serine/threonine receptor

kinases Subsequently downstream signals such as

Smad proteins are phosphorylated Activins are present

in many tissues of the mammalian organism, where

they function as autocrine and/or paracrine regulators

of various physiological processes, including

repro-duction In the hypothalamus, activins are thought

to stimulate the release of gonadotropin-releasing

hormone In the pituitary, activins increase

follicle-stimulating hormone secretion and up-regulate

gon-adotropin-releasing hormon receptor expression In

the ovaries, activins regulate processes such asfolliculogenesis, steroid hormone production andoocyte maturation During pregnancy, activin-A is alsoinvolved in the regulation of placental functions

▶Receptor Serine/Threonine Receptor Kinase

▶Transforming Growth Factor-β Superfamily

Acute Phase Reactants

Acute phase reactants (e.g., C-reactive protein) are teins that increase during inflammation and are deposited

pro-in damaged tissues They were first discovered pro-in theserum, but are now known to be involved in inflammatoryprocesses in the brain (e.g., found in the brain ofAlzheimer patients and associated with amyloid plaques)

▶Fatty Acid Transporters

B-cells carry antigen receptors that are generated

by random genetic rearrangement during the ontogeny

of lymphocytes in the bone marrow (B cells) or the

thymus (T-cells) The hallmarks of adaptive immunity are

the improved and specific defenses by T and B memory

cells and antibodies after repeated exposure

(immuno-logical memory) to the eliciting antigen

▶Immune Defense

Adaptor Proteins

Department of Pathology, Brigham and Women’s

Hospital, Harvard Medical School, Boston, MA, USA

Synonyms

Scaffold; Docking protein; Anchoring protein

Definition

Adaptor proteins are multi-domain proteins (Fig 1) that

interact with components of signaling pathways [1] As

a consequence of these interactions, adaptor proteins

are able to regulate signaling events within the cell,

providing spatiotemporal control and specificity, and

influencing how a cell responds to a particular stimulus

Basic MechanismsAdaptor proteins function by simultaneously interact-ing with multiple components of a signaling pathway(Fig 2) In order to be able to bind to more than onetarget protein at the same time, adaptor proteins contain

at least two specific protein-protein interaction mains These domains recognize specific motifs in thetarget proteins and can act completely independently,like beads on a string, or interact with another domainwithin the same molecule Such intramolecular inter-actions can regulate the ability of each domain to bind toits target

do-Adaptor Protein Function

In their simplest form, adaptor proteins perform astraightforward function: the formation of multi-proteincomplexes However, they often provide more than astatic scaffold support for signaling components,instead enabling dynamic regulation to control propa-gation of pathways and networks Consequently,adaptor proteins can act as signaling modules, directingpropagation of the pathway, influencing downstreamevents and even modifying the cellular response to aspecific stimulus Some of the different roles played byadaptor proteins are described below These functionsare not mutually exclusive and more than one of theseroles can be performed by a particular adaptor protein atone time

Assembly of Signaling Complexes

This is perhaps the simplest function provided byadaptor proteins and involves bringing together

Adaptor Proteins Figure 1 Adaptor protein domains A scheme of the domain structures of some

well-characterized adaptor proteins is shown Descriptions of domain characteristics are in main text except: C2,

binds to phospholipids; GTPase activating protein (GAP) domain, inactivates small GTPases such as Ras; Hect

domain, enzymatic domain of ubiquitin ligases and GUK domain, guanylate kinase domain For clarity, not all

domains contained within these proteins are shown

Adaptor Proteins 15

A