Table Of ContentThe GABA Receptors
The Receptors
Series Editor
David B. Bylund
University ofNebraska Medical Center, Omaha, NE
Board of Editors
S. J. Enna Bruce S. McEwen
University of Kansas RockefeIler University
Kansas City, Kansas New York, New York
Morley D. Hollenberg Solomon H. Snyder
University of Calgary lohns Hopkins University
Calgary, Alberta, Canada Baltimore, Maryland
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-l Adrenergic Receptors,
edited by Robert R. Ruffolo, Jr., 1987
The GABA Receptors,
edited by S. J. Enna, 1983
The
GABA
Receptors
SECOND EDITION
Edited by
s. J.
Enna
University of Kansas Medical School, Kansas City, KS
Norman G. Bowery
The Medical School Edgbaston, University of Birmingham, UK
Springer Science+Business
Media, LLC
© 1997 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 1997
Softcover reprint of the hardcover 2nd edition 1997
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Cover illustration: Fig. 1 from Chapter 4, "Pharmacology ofMammalian GABA Receptors," by
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Neil Upton and Thomas Blackburn.
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10 9 8 7 6 5 4 3 2 1
ISBN 978-1-4757-2599-5 ISBN 978-1-4757-2597-1 (eBook)
DOI 10.1007/978-1-4757-2597-1
Preface
Thirteen years have passed since publication of the first edition of The
GA BA Receptors. During that time dramatic advances have been made in
defining further the properties of this neurotransmitter system. Thus, in 1983
evidence indicating pharmacologically distinct subtypes of GABA receptors
was just emerging and work had commenced on the purification and isolation
ofthese sites. Two broad categories ofreceptors were proposed, GABA and
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GABAB' based primarily on differential sensitivities to antagonists and their
distinctive electrophysiological properties. Though only a few classes ofd rugs
known to interact with the GABA system were marketed, preclinical and
clinical studies were underway to identify additional agents. Given the growing
appreciation ofthe importance ofthe GABAergic system as a target for drugs,
it was predicted that the area was ripe for exploitation. The present monograph
is a testament to the accuracy of that prophecy.
Detailed in this second edition of The GABA Receptors are the wealth of
recent data accumulated on the fundamental properties of GABA receptors.
With respect to the GABA site, molecular cloning experiments have demon
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strated unequivocally the multiplicity of these receptors, all of which form
neuronal membrane-bound chloride ion channels. Given the number of differ
ent subunits that can join to form the heteropentameric construct, there is a
potential for several thousand molecularly distinct GABA receptors, although
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only a few are thought to be present in mammalian brain. Elegant genetic
engineering studies have produced animal models used to examine the biologi
cal and pharmacological importance ofindividual GABA receptor subunits.
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It has also been discovered that the sensitivity of the GABA receptor is
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modulated by certain steroids, revealing yet another approach to the manipu
lation ofthis system. Such information has provided a more precise character
ization of the mechanism of action of established drugs and has been used to
design novel and more selective therapeutics.
As for the GABAB receptor, the synthesis of highly potent and specific
antagonists has provided tools to define its properties. Although the genes
responsible for expressing GABABr eceptors have yet to be isolated, it appears
certain there are multiple, pharmacologically distinct subtypes of this
G-protein coupled site.
v
vi Preface
The discovery of a third broad category of GABA receptors, the GABAc
site, suggests that the classification of this receptor system is far from
complete, indicating further the therapeutic potential that remains in devel
oping additional agents capable of regulating GABA receptor function.
The past decade has also witnessed the cloning and expression of the
GABA transporter. Inasmuch as this protein plays a crucial role in regulating
the synaptic activity ofGABA, it is a prime target for modifying GABAergic
function.
Included among the newagents developed during the past decade are
agonists, antagonists, and partial agonists for the benzodiazepine component
ofthe GABA site, as wen as drugs that modify GABA reuptake or metabo
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lism. Some of these are already available for human use, while others are
awaiting approval, or are still in clinical trials. Thus, as anticipated, the
accumulating data on the molecular, biochemical, and physiological properties
of GABA receptors and related proteins have, since the first edition of this
volume, expanded significantly the list of drugs that interact with this neu
rotransmitter system and have spurred the synthesis of additional agents.
These and related issues are detailed in the various chapters of The GABA
Receptors. Besides providing an overview of the topic, this timely volume
should serve as a guide to the direction of future research in the area. The
information provided will be of interest to nuerobiologists in general, and to
pharmacologists, medicinal chemists, and neurophysiologists in particular.
s.
J. Enna
Norman G. Bowery
Contents
Preface ........................................................................................................... v
Contributors ................................................................................................ ix
1 • Structure and Function of GABA Reuptake Systems ...................... 1
Baruch I. Kanner
2 • Diversity in Structure, Pharmacology, and Regulation of GABA
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Receptors ....................................................................................... 11
H. Möhler, D. Benke, J. Benson, B. Lüscher, U. Rudolph,
and J. M. Fritschy
3 • GABA Receptor Agonists, Partial Agonists, and Antagonists ..... 37
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Povl Krogsgaard-Larsen, Bente FreIund, and Bjarke Ebert
4 • Pharmacology of Mammalian GABA Receptors ........................... 83
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Neil Upton and Thomas Blackburn
5 • The Interaction of Intravenous Anesthetic Agents with Native
and Recombinant GABA Receptors: An Electrophysiological
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Study ............................................................................................ 121
Jeremy J. Lambert, Delia Belelli, Marco Pistis,
Claire Hill-Venning, and John A. Peters
6 • Electrophysiology of GABAB Receptors ...................................... 157
RudolfA . Deisz
7 • Pharmacology of Mammalian GABAB Receptors ......................... 209
Norman G. Bowery
8 • Cellular and Biochemical Responses to GAB AB Receptor
Activation .................................................................................... 237
Martin Cunningham and S. J. Enna
9 • Biochemical and Molecular Properties of GABAB Receptors ..... 259
Kinya Kuriyama and Masaaki Hirouchi
Vll
viii Contents
10 • Chemistry ofGABAs Modulators .................................................. 271
Wolfgang Froestl and Stuart J. Miekel
11 • Molecular Biology, Pharmacology, and Physiology ofGABAc
Receptors ..................................................................................... 297
Graham A. R. Johnston
Index ......................................................................................................... 325
Contributors
DELIA BELELLI • Neurosciences Institute, Department ofP harmacology
and Clinical Pharmacology, Ninwells Hospital and Medical School,
University ofD undee, Scotland
D. BENKE· Institute ofPharmacology, University ofZurich, Switzerland
J. BENSON • Institute ofP harmacology, University ofZ urich, Switzerland
THOMAS BLACKBURN· SmithKline Beecham, Harlow, UK
NORMAN G. BOWERY • Department ofP harmacology, The Medical School
Edgbaston, University ofB irmingham, UK
MARTIN CUNNINGHAM • Molecular Devices Corporation, Sunnyvale, CA
RUDOLF A. DEISZ • Max-Planck Institute ofP sychiatry, Munich, Germany
BJARKE EBERT • Department ofM edicinal Chemistry, PharmaBiotec Research
Center, The Royal Danish School ofP harmacy, Copenhagen, Denmark
S. J. ENNA • Department ofP harmacology, Toxicology, and Therapeutics,
University ofK ansas Medical School, Kansas City, KS
J. M. FRITSCHY • Institute ofP harmacology, University ofZurich, Switzerland
WOLFGANG FROESTL • Research and Development Department, Pharmaceuticals
Division, CIBA-GEIGY, Basel, Switzerland
BENTE FR0LUND • Department ofM edicinal Chemistry, PharmaBiotec
Research Center, The Royal Danish School ofP harmacy, Copenhagen,
Denmark
CLAIRE HILL-V ENNING • Neurosciences Institute, Department ofP harmacology
and Clinical Pharmacology, Ninwells Hospital and Medical School,
University ofD undee, Scotland
MASAAKI HIROUCHI • Department ofP harmacology, Kyoto Prefectural
University ofM edicine, Kyoto, Japan
GRAHAM A. R. JOHNSTON • Adrien Albert Laboratory ofM edicinal Chemistry,
Department ofPharmacology, University ofSydney, Australia
BARUCH I. KANNER· Department ofBiochemistry, Hadassah Medical
School, The Hebrew University, Jerusalem, Israel
POVL KROGSGAARD-LARSEN • Department ofM edicinal Chemistry,
PharmaBiotec Research Center, The Royal Danish School ofP harmacy,
Copenhagen, Denmark
KINY A KURIYA MA • Department ofP harmacology, Kyoto Prefectural
University ofM edicine, Kyoto, Japan
IX
x Contributors
JEREMY LAMBERT • Neurosciences Institute, Department ofP harmacology
and Clinical Pharmacology, Ninwells Hospital and Medical School,
University ofD undee, Scotland
B. LÜSCHER • Institute ofP harmacology, University ofZ urich, Switzerland
STUART J. MICKEL • Research and Development Department, Pharmaceuticals
Division, CIBA-GEIGY. Basel, Switzerland
H. MÖHLER • Institute ofPharmacology, University ofZurich, Switzerland
JOHN A. PETERS • Neurosciences Institute, Department ofP harmacology
and Clinical Pharmacology, Ninwells Hospital and Medical School,
University ofD undee, Scotland
MARCO PISTlS • Neurosciences Institute, Department ofP harmacology
and Clinical Pharmacology, Ninwells Hospital and Medical School,
University ofD undee, Scotland
U. RUDOLPH • Institute ofP harmacology, University ofZ urich, Switzerland
NEIL UPTON • SmithKline Beecham, Harlow, UK
