Table Of ContentNeurotransmitter Transporters
Contemporary Neuroscience
Neurotransmitter Transporters: Structure, Highly Selective Neurotoxins: Basic and
Function, and Regulation, 2nd edition, Clinical Applications, edited by
edited by Maarten E. A. Reith, 2002 Richard M. Kostrzewa,1998
The Neuronal Environment: Brain Neuroinflammation: Mechanisms and
Homeostasis in Health and Disease, Management, edited by Paul L.
edited by Wolfgang Walz, 2002 Wood,1998
Pathogenesis of Neurodegenerative Dis- Neuroprotective Signal Transduction,
orders,edited by Mark P. Mattson, edited by Mark P. Mattson,1998
2001 Clinical Pharmacology of Cerebral
Stem Cells and CNS Development, Ischemia, edited by Gert J. Ter
edited by Mahendra S. Rao, 2001 Horstand Jakob Korf,1997
Neurobiology of Spinal Cord Injury, Molecular Mechanisms of Dementia,
edited by Robert G. Kalb and edited by Wilma Wasco and
Stephen M. Strittmatter,2000 Rudolph E. Tanzi,1997
Cerebral Signal Transduction: From Neurotransmitter Transporters: Struc-
First to Fourth Messengers, edited ture, Function, and Regulation,
byMaarten E. A. Reith, 2000 edited by Maarten E. A. Reith,
Central Nervous System Diseases: Inno- 1997
vative Animal Models from Lab to Motor Activity and Movement Disorders:
Clinic, edited by Dwaine F. Research Issues and Applications,
Emerich, Reginald L. Dean, III, edited byPaul R. Sanberg, Klaus-
and Paul R. Sanberg,2000 Peter Ossenkopp, and Martin
Mitochondrial Inhibitors and Neurode- Kavaliers,1996
generative Disorders, edited by Neurotherapeutics: Emerging Strate-
Paul R. Sanberg, Hitoo Nishino, gies, edited by Linda M. Pullan
and Cesario V. Borlongan,2000 and Jitendra Patel, 1996
Cerebral Ischemia: Molecular and Cel- Neuron–Glia Interrelations During
lular Pathophysiology, edited by Phylogeny: II. Plasticity and Regen-
Wolfgang Walz, 1999 eration, edited by Antonia
Cell Transplantation for Neurological Vernadakis and Betty I. Roots, 1995
Disorders, edited by Thomas B. Neuron–Glia Interrelations During
Freemanand Håkan Widner,1998 Phylogeny: I. Phylogeny and Ontog-
Gene Therapy for Neurological Disor-
eny of Glial Cells,edited byAntonia
ders and Brain Tumors,edited by E. Vernadakis and Betty I. Roots,
Antonio Chiocca and Xandra O.
1995
Breakefield,1998
Neurotransmitter
Transporters
Structure, Function,
and Regulation
Second Edition
Edited by
Maarten E. A. Reith
College of Medicine, University of Illinois, Peoria, IL
Springer Science+Business
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© 2002 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 2002
Softcover reprint of the hardcover 2nd edition 2002
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Library of Congress Cataloging in Publication Data
Main entry under title:
Neurotransmitter transporters: structure, function, and regulation / edited by Maarten
E. A. Reith.-- 2nd ed.
p. cm. — (Contemporary neuroscience)
Includes bibliographical references and index.
ISBN 978-1-61737-267-4 ISBN 978-1-59259-158-9 (eBook)
DOI 10.1007/978-1-59259-158-9
1. Neurotransmitters. 2. Carrier proteins. I. Reith, Maarten E. A. II. Series.
QP364.7 .N4757 2002
612.8'22—dc21 2001051651
Preface
Neurotransmission is a multicomponent process. Transmitters,
released by neuronal activity, act on pre- and postsynaptic receptors,
and many books detail advances in the receptor field. In addition, after
their release from nerve endings, transmitters are removed from the
neuronal vicinity by uptake into neuronal or glial cells by specific trans-
porter proteins that have been studied intensely over the last 30 years;
this information is scattered throughout numerous publishing
vehicles. Therefore, the primary aim of this second edition of Neu-
rotransmitter Transporters: Structure, Function, and Regulation is to offer
a comprehensive picture of the characterization of neurotransmitter
transporters and their biological roles. The transporter field has moved
forward in stages. In the first phase, progress came from the use of
substrate or blocker ligands selectively targeting transporters, the
application of model systems allowing the study of transmitter trans-
port shielded from storage, and the development of mathematical
models for describing transport phenomena. In the second phase,
roughly covering the last decade, advances in DNA techniques
allowed the cloning of numerous genes coding for different transporter
proteins. In the current, third stage, a wealth of information is being
accumulated in studies relating transporter structure with function,
experiments addressing regulation by posttranslational transforma-
tion, investigations into transport modulation by trafficking processes
and genomic influences, characterization of channel properties of trans-
porters by electrophysiological approaches, and the creation of transgenic
animals under- or overexpressing a given transporter protein.
The first edition of Neurotransmitter Transporters: Structure, Function,
and Regulation was published at the brink of the above 2nd and 3rd phase;
the current, second edition finds the transporter field fully in the 3rd
phase. This second edition of Neurotransmitter Transporters: Structure,
Function, and Regulation has been put together with the goal of retain-
ing most of the original material in describing for each transporter the
cloning history as well as including new progress in characterizing its
structure, function, regulation, and physiological relevance.
v
vi Preface
Interest in neurotransmitter transporters has increased tremen-
dously, along with clearer understanding of their roles in the patho-
physiology of schizophrenia, Tourette’s syndrome, Parkinson’s
disease, affective disorders, attention deficit/hyperactivity disorder,
neurotoxin accumulation and removal, brain ischemia, amyotropic
lateral sclerosis, or in the mechanism of action of drugs of abuse, anti-
depressants, and antiepileptics. Thus, Neurotransmitter Transporters:
Structure, Function, and Regulation, Second Edition will be of interest to
scientists, graduate students, and advanced undergraduates who seek
a comprehensive overview of this active field in neuroscience. Selected
chapters will also be of interest to physicians who are carrying out
imaging and postmortem measurements of neurotransmitter trans-
porters in the human brain, or physicians who study gene linkages and
polymorphisms in relation to psychiatric and other complex diseases.
Each chapter of Neurotransmitter Transporters: Structure, Function,
and Regulation offers a critical summary and synthesis of the progress
in characterizing each transporter in terms of structure–function rela-
tionships and regulation. Chapters 1–9 focus on various neurotrans-
mitter transporters located in neuronal or glial plasma membranes and
in synaptic vesicles. The Na+, Cl–-dependent plasma membrane trans-
porters are described for monoamines (Chapters 1–5) and for a number
of compounds including amino acids (GABA, glycine, proline, betaine,
taurine, and creatine (Chapters 6 and 7). The separate family of Na+-
dependent glutamate transporters is discussed (Chapters 7 and 8) as
well as the family of vesicular transporters for monoamines, acetylcho-
line, and GABA/glycine (Chapter 9). Chapters 10–13 cover a variety
of issues relevant to transporter structure and function. Chapter 10
describes posttranslational modifications with their important impact
on the function of various transporters. Chapter 11 covers the various
classes of blockers for the dopamine transporter with detailed discus-
sion of structural determinants, and Chapter 12 describes the use of
various in vivo imaging techniques and ligands for biogenic amine
transporters, in particular the dopamine transporter in the human
brain. In Chapter 13, the final chapter, the focus is on dopamine trans-
porter changes in human brain as a result of cocaine administration,
with both in vitro and in vivo imaging approaches.
A number of differences between this second edition and the origi-
nal book can be highlighted. First, the more basic cloning and pharma-
cological information on monoamine transporters, previously in
Chapter 1, can now be found in Chapters 3 and 4. The previous topic
of regulation of serotonin transporters (currently Chapter 1, previ-
Preface vii
ously Chapter 2) has been widened to include all three biogenic amine
transporters, and it now emphasizes phosphorylation and trafficking
phenomena. Three new chapters on biogenic amine transporters have
been added: Chapter 3 on chimera and site-directed mutagenesis stud-
ies, Chapter 4 on gene organization and the relationship of polymor-
phisms with psychiatric and other complex human diseases, and
Chapter 5 on transgenic animals carrying altered genes for plasma
membrane monoamine transporters. Current excitement about chan-
nel properties of transporters is covered in Chapters 2 and 8 regarding
electrophysiological studies on cloned monoamine and amino acid
transporters, respectively. The new chapter on transporter imaging,
Chapter 12, entirely focuses on human results including effects of aging
and brain injury, and changes in schizophrenia, phobia, drug abuse,
and other complex human diseases. Chapter 13 covers changes in
dopamine transporters in human brain as a result of cocaine exposure
as previously, with added discussion of in vivo imaging approaches
for the dopamine transporter included in this update. The previous
final chapter detailing the role of biogenic amine transporters in in
vivo and in vitro monoamine release studies has been omitted as more
recent material on in vivo results is now presented in the new Chapter 5.
The authors of the present chapters have been instrumental in
advancing our knowledge of transporters by their experimental and
conceptual contributions to the field, and I feel fortunate to have been
able to join all their forces together in this second edition. I thank
Paul Dolgert, Tom Lanigan, Sr., Elyse O’Grady, Craig Adams, and
Mark Breaugh at Humana Press for allowing the opportunity of a sec-
ond edition, and I hope the book will continue to be used as a popular
resource in the field.
Maarten E. A. Reith
Contents
Preface......................................................................................................... v
Contributors..............................................................................................xi
1 • Regulation of Monoamine Transporters:
Regulated Phosphorylation, Dephosphorylation,
and Trafficking................................................................................ 1
Sammanda Ramamoorthy
2 • Mechanisms of Biogenic Amine
Neurotransmitter Transporters............................................... 25
Gary Rudnick
3 • Structure-Function Relationships
for Biogenic Amine Neurotransmitter Transporters........... 53
Nian-Hang Chen and Maarten E. A. Reith
4 • Gene Organization and Polymorphisms
of Monoamine Transporters: Relationship
to Psychiatric and Other Complex Diseases.............................111
Maureen K. Hahn and Randy D. Blakely
5 • Monoamine Transporters:
Their Role in Maintaining Neuronal Homeostasis ..................171
Raul R. Gainetdinov and Marc G. Caron
6 • Family of Sodium-Coupled Transporters for GABA,
Glycine, Proline, Betaine, Taurine, and Creatine:
Pharmacology, Physiology, and Regulation..............................193
Scott L. Deken, Robert T. Fremeau, Jr.,
and Michael W. Quick
7 • Sodium-Coupled GABA and Glutamate Transporters:
Structure and Function..............................................................235
Baruch I. Kanner
ix
x Contents
8 • The High-Affinity Glutamate and Neutral Amino-Acid
Transporter Family: Structure, Function,
and Physiological Relevance ......................................................255
Yoshikatsu Kanai, Davide Trotti, Urs V. Berger,
and Matthias A. Hediger
9 • Vesicular Neurotransmitter Transporters:
Pharmacology, Biochemistry, and Molecular Analysis............313
Rodrigo Yelin and Shimon Schuldiner
10 • Neurotransmitter-Transporter Proteins:
Post-Translational Modifications..............................................355
Amrat P. Patel and Maarten E. A. Reith
11 • Dopamine-Transporter Uptake Blockers:
Structure-Activity Relationships ..............................................381
F. Ivy Carroll, Anita H. Lewin, and S. Wayne Mascarella
12 • Imaging the Brain Dopamine Transporter
Using PET and SPECT ............................................................433
S. John Gatley, Nora D. Volkow, Joanna S. Fowler,
Yu-Shin Ding, Jean Logan, Gene-Jack Wang,
Christoph Felder, Frank W. Telang,
and Andrew N. Gifford
13 • In Vitro and In Vivo Imaging
of the Human Dopamine Transporter
in Cocaine Abusers..................................................................467
Deborah C. Mash and Julie K. Staley
Index........................................................................................................503
