Table Of ContentThe P2 Nucleotide Receptors
The Receptors
Series Editor
David B. Bylund
University of Nebraska Medical Center, Omaha, NE
Board of Editors
S. J. Enna Bruce S. McEwen
University of Kansas Rockefeller University
Kansas City, Kansas New York, New York
Morley D. Hollenberg Solomon H. Snyder
University of Calgary Johns Hopkins University
Calgary, Alberta, Canada Baltimore, Maryland
The P2 Nucleotide Receptors
edited by John T. Turner, Gary A. Weisman, and Jeffrey S. Fedan, 1998
The GABA Receptors, Second Edition
edited by S. J. Enna and Norman G. Bowery, 1997
The Ionotropic Glutamate Receptors
edited by Daniel T. Monaghan and Robert Wenthold, 1997
The Dopamine Receptors,
edited by Kim A. Neve and Rachael L. Neve, 1997
The Metabotropic Glutamate Receptors,
edited by P. Jeffrey Conn and Jitendra Patel, 1994
The Tachykinin Receptors,
edited by Stephen H. Buck, 1994
The Beta-Adrenergic Receptors,
edited by John P. Perkins, 1991
Adenosine and Adenosine Receptors,
edited by Michael Williams, 1990
The Muscarinic Receptors,
edited by Joan Heller Brown, 1989
The Serotonin Receptors,
edited by Elaine Sanders-Bush, 1988
The Alpha-2 Adrenergic Receptors,
edited by Lee Limbird, 1988
The Opiate Receptors,
edited by Gavril W. Pasternak, 1988
The Alpha-t Adrenergic Receptors,
edited by Robert R. Ruffolo, Jr., 1987
The GABA Receptors,
edited by S. J. Enna, 1983
TheP2
Nucleotide
Receptors
Edited by
J
ohn T. Turner
Department of Pharmacology
University of Missouri-Columbia, MO
Gary A. Weisman
Department of Biochemistry
University of Missouri-Columbia, MO
Jeffrey S. Fedan
Physiology Section
National Institute for Occupational Safety and Health
Morgantown, WV
*
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© 1998 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 1998
Softcover reprint of the hardcover 1s t edition 1998
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Library of Congress Cataloging in Publication Data
The P2 nucleotide receptors/edited by John T. Tumer, Gary A. Wiesman, Jeffrey S. Fedan.
p. cm.-(The Receptors)
Includes index.
ISBN 978-1-4612-7289-2 ISBN 978-1-4612-1800-5 (eBook)
DOI 10.1007/978-1-4612-1800-5
1. Purine nucleotides-Receptors. 1. Tumer, John T., Professor. II. Weisman, Gary A.
III. Fedan, Jeffrey S. IV.Series.
[DNLM: 1. Receptors, Purinergic P2. QU 58 P9891998]
QP625.P87p2 1998
572.8'5-dc21
DNLM/OLC
for Library of Congress
Preface
The publication of The P2 Nucleotide Receptors occurs during a period
of rapid expansion of the knowledge concerning receptors for extracellular
nucleotides. The evidence obtained primarily from physiological and pharma
cological experiments for the existence of multiple P2 receptors has, since
1993, been complemented by molecular cloning approaches, resulting in
documentation of the existence of a surprisingly large number of P2 receptor
subtypes belonging to two major families: the ligand-gated ion channel P2X
receptors and the G protein-coupled P2Y receptors. The combined functional
and molecular approach to studying P2 receptors and the physiological roles
they subserve has permitted progress previously hampered by the lack of
experimental tools (e.g., high-affinity, subtype-selective antagonists and reli
able radioligand binding assays) that are available to researchers investigating
receptors for other extracellular signaling molecules.
One of the current challenges in the P2 receptor field is to establish
conclusively the identity of the cloned P2 receptor subtype(s) involved in the
various physiological effects ofe xtracellular nucleotides. This is a particularly
challenging goal for the P2X receptors, since the cloned receptors, at least in
some cases, may be subunits ofheteromultimeric complexes that give rise to
the native A TP-regulated ion channels. Efforts also must be made to verify that
all of the putative P2 receptors that have been cloned are indeed members of
this receptor family. Conversely, there are strong physiological and biochemi
cal data indicating the existence ofP2 receptors yet to be cloned, including an
adenylate cyclase-inhibitory receptor.
A consequence ofthe rapid increase in the number ofc loned P2 receptors,
and the concurrent increase in the variety of observed effects of extracellular
nucleotides in multiple organ systems, has been the appreciation of the
inadequacy of the original nomenclature system for nucleotide receptors. The
IUPHAR-recommended scheme (Pharmacol. Rev. 46, p. 143), as summarized
in Chapter 2 for P2X receptors and in Chapter 3 for P2Y receptors, allows for
the systematic naming of cloned, expressed, and validated P2 receptor sub
types. Although not without its shortcomings, the IUPHAR scheme has
obvious advantages over the earlier, rather haphazard approach and has been
used in this volume as much as practicable. In some cases when insufficient
evidence exists for identifying a P2 receptor subtype defined in functional
v
Preface
Vl
assays as one of the cloned receptor subtypes, one must revert to the older
nomenclature for pharmacologically-defined subtypes. As work continues in
this field, many of these issues will be resolved.
The editors are most grateful to the chapter authors, who have provided
an up-to-date synopsis of the exciting research in the P2 receptor field. We
would also like to note the constructive support we have received from the
Series Editor for The Receptors, David Bylund, and from the publisher,
Humana Press.
John T. Turner
Gary A. Weisman
JeffreyS. Fedan
Contents
Preface ........................................................................................................... v
Contributors ................................................................................................ ix
PART I. HISTORICAL PERSPECTIVES OF P2 NUCLEOTIDE RECEPTORS
1 • History of Extracellular Nucleotides and Their Receptors ............... 3
Geoffrey Burnstock
II.
PART PHARMACOLOGICAL AND MOLECULAR CHARACTERIZATION
OF P2 NUCLEOTIDE RECEPTORS
2 • P2X Receptors: Cloned and Expressed .......................................... 43
Richard J. Evans, Annmarie Surprenant, and R. Alan North
3 • The Cloning and Expression of G Protein-Coupled
P2Y Nucleotide Receptors ........................................................... 63
Gary A. Weisman, Fernando A. Gonzalez, Laurie Erb,
Richard C. Garrad, and John T. Turner
4 • Structure Activity Relationships of P2 Receptor Agonists
and Antagonists ............................................................................ 81
Kenneth A. Jacobson, Yong-Chul Kim, Emidio Camaioni,
and A. Michiel van Rhee
5 • Pharmacological Selectivities of Molecularly Defined
Subtypes of P2Y Receptors ....................................................... 109
T. Kendall Harden, Robert A. Nicholas, Joel R. Schachter,
Eduardo R. Lazarowski, and Jose L. Boyer
6 • P2 Receptor Modeling and Identification of Ligand Binding Sites ... 135
A. Michiel van Rhee, Kenneth A. Jacobson,
Richard C. Garrad, Gary A. Weisman, and Laurie Erb
III.
PART MECHANISMS OF P2 NUCLEOTIDE RECEPTOR ACTION
7 • Nucleotide Receptors Coupling to the Phospholipase C
Signaling Pathway ...................................................................... 169
Jean-Marie Boeynaems, Didier Communi, Rodolphe Janssens,
Serge Motte, Bernard Robaye, and Sabine Pirotton
Vll
Vlll Contents
8 • Cyclic AMP and Tyrosine Kinase Cascades in the Regulation
of Cellular Function by P2Y Nucleotide Receptors .................. 185
Michael R. Boarder
9 • Characteristics of Ligand-Gated Ion Channel P2 Nucleotide
Receptors ..................................................................................... 211
Charles Kennedy, Suzanne E. Hickman,
and Samuel C. Silverstein
10 • Cell Responses Initiated by Ecto-Kinases ..................................... 231
s.
Jeffrey Fedan
PART IV. PHYSIOLOGICAL ROLES FOR P2 NUCLEOTIDE RECEPTORS
11 • Functions of Extracellular Nucleotides in Peripheral
and Central Neuronal Tissues .................................................... 259
Eugene M. Silinsky, Ivar von Kiigelgen, Andrew D. Smith,
and David P. Westfall
12 • Role of Purinoceptors in the Regulation of Lung Surfactant
Secretion ...................................................................................... 291
Seamus A. Rooney
13 • The Role of Nucleotide Receptors in the Cardiovascular System .... 319
Sabine Pirotton, Claude Desgranges, Guy Vassort,
and Jean-Marie Boeynaems
14 • Physiological Roles for P2 Receptors in Platelets,Visceral
Smooth Muscle, and the Immune and Endocrine Systems ....... 361
Susanna Hourani, Francesco DiVirgilio,
and Marie-Madeleine Loubatieres-Mariani
15 • Therapeutic Applications for Nucleotides in Lung Disease ......... 413
Scott H. Donaldson and Richard C. Boucher
PART V. FUTURE VISTAS
16 • Future Directions in P2 Receptor Research ................................... 427
s.
Jeffrey Fedan, Gary A. Weisman, and John T. Turner
Index ......................................................................................................... 429
Contributors
MICHAEL R. BOARDER • Department of Cell Physiology and Pharmacology,
University ofL eicester, UK
J EAN-MARIE Boeynaems • Institute ofI nterdisciplinary Research, School
ofM edicine, and Department ofM edical Chemistry, Erasme Hospital,
Universite Libre de Bruxelles, Brussels, Belgium
RICHARD C. BOUCHER • Division ofP ulmonary and Critical Care, University
of North Carolina at Chapel Hill, NC
JOSE L. BOYER • Department ofP harmacology, School ofM edicine,
University ofN orth Carolina at Chapel Hill, NC
GEOFFREY BURNSTOCK • Department ofA natomy and Developmental
Biology, University College London, UK
EMIDIO CAMAIONI • Molecular Recognition Section, Laboratory
ofB ioorganiC Chemistry. NIDDK, National Institutes ofH ealth,
Bethesda. MD
DIDIER COMMUNI • Institute ofI nterdisciplinary Research, School
ofM edicine. Universite Libre de Bruxelles. Brussels, Belgium
CLAUDE DESGRANGES • Unite d 'atherosc!erose de I 'Institut National de la
Sante et de la Recherche Medicale, INSERM U-441, Pessac, France
FRANCESCO DIVIRGILIO· Institute of General Pathology, University
ofF errara, Italy
SCOTT A. DONALDSON· University ofN orth Carolina Hospitals,
Chapel Hill, NC
LAURIE ERB • Department ofB iochemistry, University ofM issouri
Columbia, MO
RICHARD J. EVANS· Department of Cell Physiology and Pharmacology,
University ofL eicester, UK
JEFFREY S. FEDAN • Physiology Section, National Institute for Occupational
Safety and Health, Morgantown, WV
RICHARD C. GARRAD • Department ofB iochemistry, University ofM issouri
Columbia, MO
FERNANDO A. GONZALEZ • Department ofC hemistry, University ofP uerto
Rico, Rio Piedras, PR
T. KENDALL HARDEN • Department ofP harmacology, School ofM edicine,
University ofN orth Carolina at Chapel Hill, NC
IX
x Con tribu tors
SUZANNE E. HICKMAN· Department ofP hysiology and Cellular Biophysics,
College ofP hysicians and Surgeons, Columbia University,
New York, NY
SUSANNA HOURANI· School ofB iological Sciences, University of Surrey,
Guilford, Surrey, UK
KENNETH A. JACOBSON • Molecular Recognition Section, Laboratory
ofB ioorganic Chemistry, NIDDK, National Institutes ofH ealth,
Bethesda, MD
RODOLPHE JANSSENS· Institute ofI nterdisciplinary Research, School
ofM edicine, Universite Libre de Bruxelles, Department of Vascular
Pathology, Erasme Hospital, Brussels, Belgium
CHARLES KENNEDY • Department ofP hysiology and Pharmacology,
University ofS trathclyde, Royal College, Glasgow, UK
Y ONG-CHUL KIM • Molecular Recognition Section, Laboratory
ofB ioorganic Chemistry, NIDDK, National Institutes of Health,
Bethesda, MD
EDUARDO R. LAZAROWSKI • Department of Pharmacology, School
ofM edicine, University of North Carolina at Chapel Hill, NC
MARIE-MADELEINE LOUBATIERES-MARIANI • Laboratoire de Pharmacologie
Institut de Biologie, Montpellier Cedex, France
SERGE MOTTE· Institute ofI nterdisciplinary Research, School of Medicine,
Universite Libre de Bruxelles, Department of Vascular Pathology,
Erasme Hospital, Brussels, Belgium
ROBERT A. NICHOLAS • Department ofP harmacology, School ofM edicine,
University ofN orth Carolina at Chapel Hill, NC
R. ALAN NORTH • Geneva Biomedical Research Institute, Glaxo Wellcome
Research and Development, Geneva, Switzerland
SABINE PIROTTON • Institute ofI nterdisciplinary Research, School
ofM edicine, Universite Libre de Bruxelles, Brussels, Belgium
BERNARD ROBA YE • Institute of Interdisciplinary Research, School
ofM edicine, Universite Libre de Bruxelles, Brussels, Belgium
SEAMUS A. ROONEY • Division ofP erinatal Medicine, Department
ofP ediatrics, Yale University School ofM edicine, New Haven, CT
JOEL R. SCHACHTER • Department of Pharmacology, School ofM edicine,
University ofN orth Carolina at Chapel Hill, NC
EUGENE M. SILINSKY • Department ofM olecular Pharmacology,
Northwestern University Medical School, Chicago, IL
