The Nicotinic Acetylcholine Receptor: Current Views and Future Trends

233 Pages·1998·6.997 MB·English

by  Francisco J. Barrantes (auth.), Francisco J. Barrantes (eds.)

Springer-Verlag Berlin Heidelberg GmbH
J.
Francisco Barrantes (Ed.)
The Nicotinic
Acetylcholine Receptor:
Current Views
and Future Trends
Springer
Francisco J. Barrantes
Instituto de Investigaciones
Bioqufmicas de Bahfa Blanca
Un iversidad N acional del Sur
Bahfa Blanca, Argentina
ISBN 978-3-662-39256-0 ISBN 978-3-662-40279-5 (eBook)
DOI 10.1007/978-3-662-40279-5
Biotechnology Intelligence Unit
Library of Congress Cataloging-in-Publication data
The nicotinic acetylcholine receptor: current views and future trends 1
[edited by] Francisco Jose Barrantes.
p. cm.--(Biotechno1ogy intelligence unit)
Includes bibliographical references and index.
ISBN 978-3-662-39256-0
1. Nicotinic receptors. 2. Acetylcholine--Receptors.
I. Barrantes, Francisco Jose, 1944- . II. Series.
[DNLM: 1. Receptors, Nicotinic--physiology. 2. Receptors. Cholinergic--physiology. WL
102.8 N6618 1997]
QP364·7.N541997
612.8'14--dc21
DNLM/DLC
for Library of Congress
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=====FOREWORD=====
O
ver the last two decades a convergence of techniques from various
scientific disciplines has contributed to our comprehension of the
structure, evolutionary trends and the multiplicity of functions per
formed by ligand-and voltage-gated ion channels and receptors. This
book puts together in a well organized, comprehensive and yet suc
cinct manner one of the fastest growing fields in the Molecular Neuro
sciences, that of the ligand-gated ion channels (LGIC). Several neu
rotransmitter receptors constitute this superfamily, the nicotinic ace
tylcholine receptor still being the prototype.
The study of central nervous system (neuronal) acetylcholine re
ceptors is generating growing interest owing to their likely involvement
in nicotine addiction and other pathological conditions, and the pos
sibility of developing pharmacological compounds exploiting the posi
tive effects of nicotine (anxiolysis, anti-depression, cognitive enhance
ment) without the negative health consequences of tobacco usage. Fu
ture trends are analyzed in each chapter; they encompass the likely
strategies to be employed in decoding structure-function relationships
of the receptor molecule, in establishing the differences in ionic selec
tivity and establishing the mechanisms of permeability through the
pore, and the possible use of genetic kindredness between acetylcho
line receptors of different species for the diagnosis of new genetic
diseases.
CONTENTS
1. Introduction: Structure Meets Function
at the Acetylcholine Receptor ...................................................... 1
Francisco]. Barrantes
2. Evolution of the AChR and Other Ligand-Gated
Ion Channels ................................................................................. 11
Marcelo 0. Ortells
Introduction ................................................................................ n
Evolutionary Trees of the LGIC Superfamily .......................... 12
Origin of the LGIC Superfamily ............................................... 18
Evolution of Cationic Receptors .............................................. 22
Evolution of Anionic Receptors ............................................... 25
Why So Many Receptors? ......................................................... 26
3· The Ligand Binding Domains
of the Nicotinic Acetylcholine Receptor ................................... 31
Richard]. Prince and Steven M. Sine
Historical Overview ................................................................... 32
Overall Structure ....................................................................... 33
AChR Ligands ............................................................................ 35
Receptor Activation and Ligand Binding ............................... 38
Contributions of the a-Subunits .............................................. 39
Contributions of the Non-a Subunits ..................................... 46
Summary .................................................................................... 52
4· Adding up the Energies in the Acetylcholine Receptor
Channel: Relevance to Allosteric Theory ................................. 61
Meyer B. Jackson
The Assumptions of Allosteric Theory ................................... 62
Allosteric Theory in Terms
of Macromolecular Additivity .............................................. 66
Contacts in Allosteric Proteins:
Micromolecular Additivity ................................................... 67
Are Interactions Additive? ....................................................... 70
Nonadditivity at Binding Sites ................................................. 74
Additivity in the M2 Region ..................................................... 78
Conclusions ............................................................................... 81
;. Molecular Modeling of the Nicotinic
Acetylcholine Receptor ............................................................... 8S
Marcelo 0. Ortells, Georgina E. Barrantes
and Francisco]. Barrantes
Introduction ............................................................................... 85
Molecular Models for the AChR Structure ............................. 88
6. Ion Conduction Through the Acetylcholine
Receptor Channel ...................................................................... 109
Alfredo Villarroel
Introduction ............................................................................. 109
Permeation of Organic Ions ..................................................... 111
Alkali Cations ........................................................................... 117
Anion Permeability .................................................................. 127
Divalent Cations ...................................................................... 130
7· Neuronal Nicotinic Acetylcholine Receptors ........................ 145
Ronald]. Lukas
Introduction .............................................................................. 145
Distributions and Functions of Nicotinic Receptors
in Neurons ............................................................................. 152
Nicotinic Receptors and Molecular Bases
for Nicotine Dependence ..................................................... 159
Prospects ................................................................................... 161
8. Molecular Pathology of the Nicotinic
Acetylcholine Receptor .............................................................. 17.5
Francisco]. Barrantes
Introduction .............................................................................. 175
Myasthenia Gravis ................................................................... 179
Congenital Myasthenic Syndromes (CMS) and Other
"Molecular Dyskinesias" of the AChR Channel ................ 185
Fast Channel Syndrome ........................................................... 191
AChR Pathological Findings and Some Therapeutic
Prospects in Aging, Alzheimer's and Parkinson's
Diseases ................................................................................. 191
Neurotoxic Substances and Loss of Neuronal AChR
in Dementia and Other Neurological Disorders .............. 194
Anxiety, Schizophrenia and Neuronal AChR ....................... 194
Involvement of the a4 Neuronal AChR Subunit
in Some Forms of Epilepsies ............................................... 195
Gilles de Ia Tourette's Syndrome ........................................... 198
Pain ........................................................................................... 199
Stress ......................................................................................... 199
Onchocerciasis ......................................................................... 199
Future Perspectives ................................................................. 200
Concluding Remarks .............................................................. 205
Color Figures ........................................................................................ 213
Index ...................................................................................................... 2.17
EDITOR
rr===================
Francisco J, Barrantes
lnstituto de Investigaciones Bioqufmicas de Bahia Blanca
Universidad Nacional del Sur
Bahia Blanca, Argentina
s,
Chapters 1, 8
CONTRIBUTORS
I=========== =============I
Georgina E. Barrantes Richard J. Prince
Instituto de Neurociencias Receptor Biology Laboratory
Departamento de Biologia Department of Physiology
Buenos Aires, Argentina and and Biophysics
Instituto de Investigaciones Mayo Foundation
Bioquimicas de Bahia Blanca Rochester, Minnesota, U.S.A.
Bahia Blanca, Argentina Chapter3
Chapters
Steven M. Sine
Meyer B. Jackson Receptor Biology Laboratory
Department of Physiology Department of Physiology
University of Wisconsin- and Biophysics
Madison Mayo Foundation
Madison, Wisconsin, U.S.A. Rochester, Minnesota, U.S.A.
Chapter4 Chapter3
Ronald J. Lukas Alfredo Villarroel
Division of Neurobiology Department of Physiology
Barrow Neurological Institute and Biophysics
Phoenix, Arizona, U.S.A. Dalhousie University School
Chapter7 of Medicine
Halifax, Nova Scotia, Canada
Marcelo 0. Ortells Chapter6
Instituto de Neurociencia
Facultad de Ciencias Exactas
yNaturales
Universidad de Buenos Aires,
Buenos Aires Argentina and
Instituto de Investigaciones
Bioquimicas de Bahia Blanca
Bahia Blanca, Argentina
Chapters 2, 5
1
CHAPTER
Introduction:
Structure Meets Function
at the Acetylcholine Receptor
Francisco J. Barrantes
W
hen is a topic mature for critical analysis? Has the field of the
nicotinic acetylcholine receptor (AChR) reached the necessary
stage of "ripeness" to warrant such an exercise? Any nonspecialized
readers following its development by browsing through reviews on
the subject over the last two decades may have gotten the impres
sion that the topic has" ... always been almost finished; only the de
tailed high-resolution structure is still lacking ... :' But as a Spanish
philosopher put it, "there are no exhausted subjects, but men ex
hausted in the pursuance of such subjects ... :' The more we learn
about the AChR, the more questions that can be formulated, and the
more complex the subject becomes.
What has made the AChR field unique for almost two decades
is that it has provided us with a perfect object to contemplate a single
molecule in action, thanks to its inherent ability to amplify the sig
nal stemming from the passage of thousands of ions through its in
trinsic pore, the channel. Before this was experimentally feasible
using the technique we know as patch-damp recording, biochem
ists had already taken a first glance at the AChR through isolation,
purification and characterization procedures. In this reductionist ap
proach-biochemistry is, after all, a form of molecular dissection
(or molecular"anatomy" from the Greek ava' =up; 1op =cut; Caelius
Aurelianus ca. 420)-pounding the appropriate tissue and having
the right pharmacological tools were essential. As often happens, the
The Nicotinic Acetylcholine Receptor: Current Views and Future Trends,
edited by Francisco J. Barrantes. © 1998 Springer-Verlag and R.G. Landes Company.