Molecular Neurobiology

399 Pages·1988·31.061 MB·English

by  Nicolas G. Bazan, David C. U’Prichard (auth.), Nicolas G. Bazan, David U’Prichard (eds.)

MOLECULAR
NEUROBIOLOGY
MOLECULAR
NEUROBIOLOGY
Edited by
G.
NICOLAS BAZAN
LSU Eye Center
Louisiana State University Medical Center
New Orleans, Louisiana
and
DAVID U'PRICHARD
ICI Pharmaceuticals Group
and
Department of Neurosciences
Johns Hopkins University School of Medicine
Baltimore, Maryland
HumanaPress • Clifton,NewJersey
ISBN-13: 978-1-4612-8946-3 e-1SBN-13: 978-1-4612-4604-6
001: 10.1007/978-1-4612-4604-6
Copyright © 1988 The Humana Press Inc.
Softcover reprint of the hardcover 1st edition 1988
POBox 2148
Clifton, NJ 07015
All Rights Reserved.
No part of this publication may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopy, recording, or any information
storage and retrieval system, without permission in writing from the copyright owner.
This book contains the complete contents of Volume 1 of Molecular Neurobiology.
Table of Contents
Volume 1, Nos. 1/2, Spring/Summer 1987
1 Nicolas Bazan and David U'Prichard
Editorial
3 Solomon H. Snyder (Johns Hopkins University, Baltimore, MD)
Molecular Neurobiology: Past, Present, and Future
9 Colin J. Barnstable (Rockefeller University, NY)
A Molecular View of Vertebrate Retinal Development
47 Hermona Soreq and Averell Gnatt
(Hebrew University, Jerusalem, Israel)
Molecular Biological Search for Human Genes Encoding
Cholinesterases
81 Paul Greengard (Rockefeller University, NY)
Neuronal Phosphop roteins: Mediators of Signal Transduction
121 David R. Sibley and Robert J. Lefkowitz (Duke University, Durham, NC)
j3-Adrenergic Receptor-Coupled Adenylate Cyclase:
Biochemical Mechanisms of Regulation
155 Ronald S. Duman, Paul M. Sweetnam, Peter A. Gallombardo,
and John F. Tallman (Yale University, New Haven, CT)
Molecular Biology of Inhibitory Amino Acid Receptors
Volume 1, No.3, Fall 1987
191 Patricia Contreras, Joseph B. Monahan, Thomas H. Lanthorn, Linda
M. Pullan, Debora A. DiMaggio, Gail E. Hundelmann, Nancy M. Gray,
and Thomas L. O'Donahue (G. D. Searle & Co.)
Phencyclidine: Physiological Actions, Interactions with Amino Acids
and Endogenous Ligands
213 Arthur D. Lander (Massachusetts Institute of Technology)
Molecules That Make Axons Grow
247 Paul M. Salvaterra (Beckman Research Institute of the City of Hope)
Molecular Biology and Neurobiology of Choline Acctyltransferase
Volume 1, No.4, Winter 1987
281 Jon Lindstrom, Ralf Schoepfer, and Paul Whiting
(Salk Institute for Biological Studies)
Molecular Studies of the Neuronal Nicotinic Acetylcholine
Receptor Family
339 Xandra O. Breakefield and Alfred I. Geller
(Eunice Kennedy Shriver Center)
Gene Transfer into the Nervous System
373 Olivier Civelli, Curtis Machida, James Bunzow, Paul Albert, Eric
Hanneman, Jolm Salon, David Grandy, and Jean Bidlack
(Vollum Institute for Advanced Biomedical Research)
The Next Frontier in the Molecular Biology of the Opioid System:
The Opioid Receptors
393 Edward Herbert
395 Indices
Molecular Neurobiology
Volume 1, Nos. 1/2, Spring/Summer 1987
Copyright © 1987 The Humana Press Inc.
All Rights of Any Nature Whatsoever Reserved.
No part of this publication may be reproduced or transmitted in any form or by
any means, electronic or mechanical, including photocopy, recording, or any infor
mation storage and retrieval system, without permission in writing from the copy
right owner.
Molecular Neurobiology is made available for abstracting or indexing regularly
in Chemical Abstracts, Biological Abstracts, Current Contents, Science Citation Index,
Excerpta Medica, Index Medicus, and appropriate related. compendia.
Editorial
In recent years, bibliographic vehicles have more or less kept pace with the explosive increase in
information in the field of Neurobiology, with the introduction of many new "primary" journals
covering all major aspects of Neurobiology in an increasingly specific manner. To have the temerity
to launch yet another journal thus requires explanation and justification by the editors. It is our hope
and belief that you, our scientific colleagues in the field, will endorse our rationale for bringing
Molecular Neurobiology into the world, and work closely with us to sustain its growth and develop
ment into the leading intensive review journal in the field.
An attempt to define the scientific content of the term molecular neurobiology is a precondition for
expounding the journal's philosophy. "Neurobiology" has been around for many years and is a
portmanteau word that summarizes the many disciplines associated with study of the central and
peripheral nervous systems, viz.: Neurochemistry, Neurophysiology, Neuropharmacology, Neuro
pathology, etc. It is our intent to maintain this broadly encompassing definition of Neurobiology in
the editorial content of this journal. "Molecular" is an increasingly vague word, though of course,
Molecular Biology is an established discipline with its own extensive bibliographic world. The scope
of this journal will deliberately not be limited to "Molecular Neurobiology" defined as the application
of molecular biological techniques to the study of the nervous system. Rather, Molecular Neurobiol
ogy will be oriented toward prOviding up-to-date understanding-at the molecular level-of all
biochemical and physiological processes relevant to nervous system function and disease. This will
include of course the analysis of the structural and functional expression of neuroproteins, as per mol
ecular biology, but in additon, Molecular Neurobiology will cover studies of integrated functions in the
nervous system, whether intraneuronal, synaptic, neuronal circuits, neuron-glia interactions, or
behaviors.
Certain major areas the journal plans to cover can be more completely specified.. Thus, the molec
ular basis of neurotransmitter function is now approachable, and not merely through the simple
identification of membrane receptor proteins and the study of the kinetics of ligand-receptor inter
actions. We will also be treating recent advances in receptor biochemistry from the viewpoints of
receptor protein structure and coding, the placement and mobility of receptor proteins in the plasma
membrane, the structural and functional expression and regulation of receptors in neurons, and the
biochemistry of receptor coupling to membrane effector proteins (enzymes, ion channels) and to
intracellular second messengers. An allied area of interest is the role of membrane lipids in receptor
function and neuronal signal transduction. The structure and coding of receptors and other proteins
important for neuronal function-such as potential-dependent ion channels, transport proteins,
neurotransmitter-related enzymes, effector enzymes, intraneuronal "second messenger receptors",
etc.-will, as data accumulates, allow us to identify and understand the occurrence of heterology and
Molecular Neurobiology Volume 1, 1987
2 Editorial
polymorphism in these proteins, and place this information in evolutionary and genetic contexts.
These advances will be covered by Molecular Neurobiology, as well as their implications for pathogen
esis and therapeutics.
The scope of Molecular Neurobiology will include advances in the understanding of synaptic func
tion, which will arise from new electrophysiological techniques such as patch clamping, and new
information on neurotransmitter production and disposition (especially for peptide neurotransmit
ters), the role of "neuromodulators", and the coexistence and concurrent functionality of two or more
transmitters within the same neuron, combined with the likelihood of allosteric interactions between
receptors for cotransmitters occurring on the same membrane. Recent data in this area suggests that
trans-synaptic signaling is far more finely integrated than heretofore recognized. A major aim of the
journal will be to promote the convergence of new biochemical and molecular biological knowledge
of the brain attained increasingly through techniques of specific protein and gene labeling in situ
(autoradiography, immunocytochemistry, in situ hybridization). Molecular Neurobiology will encour
age realization of the admittedly distant goal of a functional neuroanatomy of the brain that is in step
with biochemical and molecular biological advances using brain isolates.
The emphasis on molecular and synaptic expression, function, and regulation leads naturally to
another major focus of the journal: the understanding, at the molecular level, of neuronal plasticity,
of the mechanisms of learning and memory, and of the cellular and organotypic processes related to
ontogenesis, development, and aging of neural and brain function. Lastly, Molecular Neurobiology will
emphasize coverage of studies on the molecular and genetic basis of diseases of the nervous system,
whether neurological or psychiatriC. Indeed, this is a field in which very significant breakthroughs
are now occurring, especially in the area of neurodegenerative diseases.
The field of molecular neurobiology, thus defined, is undergoing a very rapid expansion of knowl
edge that is sure to continue. The aim and philosophy of Molecular Neurobiology is to act as a forum
for intensive, in-depth, and critical review of the field. The journal will solicit such review articles
from distinguished scientists who are actively contributing to each of the specialty areas outlined
above. Our aim is to review each area with sufficient frequency to keep pace with the expected rapid
advances. To assist in the task of identifying emerging information, contributors, and editing articles
for scientific content, we have been extremely fortunate to assemble an outstanding Editorial Advi
sory Board, and we thank each Board Member for a genuine willingness to contribute time and effort
to help establish the highest possible standard of quality for papers appearing in the journal. We are
prepared to accept unsolicited manuscripts after thorough editorial review. It is axiomatic that any
rapidly moving scientific discipline breeds controversy, and we will not shy away from publishing
controversial viewpoints that may ultimately help to clarify an emerging base of knowledge.
Molecular Neurobiology will be published on a quarterly basis initially, with the first four issues
appearing before the end of 1987. Because of the extraordinary early response of our initial panel of
invited authors, we are especially pleased to be beginning with this truly excellent double issue. We
are grateful for the help of the community of Neurobiologists in getting the journal off to such a re
sounding start and solicit our colleagues' ongoing help in maintaining the journal at the forefront of
quality, respected scientific publications. We thank you in advance for your support of Molecular
Neurobiology.
Nicolas G. Bazan
David C. U'Prichard
Molecular Neurobiology Volume 7, 7987
Molecular Neurobiology
Past, Present, and Future
S%mo n H. Snyder
Departments of Neuroscience, Pharmacology, and Molecular Sciences,
and Psychiatry and Behavioral Sciences
The Johns Hopkins University School of Medicine
725 North Wolfe Street, Baltimore, MD 21205
Introduction theoretical incidence may be as high as 25%.
Several workers now feel that a diathesis for
Alzheimer's disease is transmitted in a genetic
In providing a perspective of molecular neu
ally dominant pattern. Evidence for genetic
robiology, one need not tarry overly long in re
propensity toward schizophrenia and affective
viewing past history, since, depending on one's
disease is overwhelming. Thus, if one ap
perspective, the past is only a handful of years
proaches molecular neurobiology as the study
ago. In medical school and throughout my sub
of the nervous system, with a view to under
sequent medical training, genetics was sorely
standing the causes and possible therapies of
neglected. There seemed no need to devote
human disease, then there is ample justification
much attention to medical genetics, since gen
to focus particularly on molecular genetics.
etic diseases seemed restricted to a few very un
common conditions that were usually not treat
able. Along with the rapid advances in molecu
Neurotransmitter Receptors
lar biology has corne an appreciation that many
of the most common diseases possess major
genetic detenninants. For instance, Alzheimer's Molecular genetics is rapidly pervading all of
disease is probably the most common brain dis neurobiology. Drug and neurotransmitter re
order in the world. All sorts of etiologies have ceptors have not escaped. When we first inves
been propounded, ranging from viruses that tigated neurotransmitter receptors by ligand
enter the brain through the nose to toxic metals, binding techniques, a number of colleagues ad
such as aluminum. Genetic studies now indi vocated that we move rapidly toward solubili
cate a pronounced genetic predisposition to zation and purification of these membrane pro
ward Alzheimer's disease. When one considers teins. The reasoning was that one could thereby
that the incidence of this disorder increases at a clone the genes for the receptor. At that time it
rapid rate with advancing age, its age-corrected was not clear just what one could learn from
Molecular Neurobiology 3 Volume 1, 1987
4 Snyder
such an enterprise. Recent receptor characteri tion of light by the eye and of neurotransmitters
zation by numerous laboratories has revealed by synaptic receptors. Of course, both beta re
many surprises. The most extensive work has ceptors and rhodopsin interact with GTP-bind
emerged from investigations of the nicotinic ing proteins. Indeed, one would antici pa te close
acetylcholine receptor of fish electric organs. similarities between the intracellular portion of
The work of several groups, but most especially all G-protein-associated receptors. Surprising
that of Numa, has shown that the acetylcholine ly, the two distinct beta receptors that have been
recognition site and the associated sodium cloned and rhodopsin display the greatest hom
channel are part of the same protein molecule. ology in the membrane-spanning region and
This finding was somewhat unexpected, since not in the intracellular domain where interac
one would have thought that Nature would tions presumbly take place with G proteins.
prefer to sculpt acetylcholine-recognition sites Even more unexpected are the extracellular
and ion channels separately for different pur domains of the two beta receptors. To recognize
poses and then allow the distinct proteins to catecholamines, presumably, they should be
work together in some sort of allosteric fashion. very similar. Yet, they resemble each other less
By eliciting molecular mutations of the recep than do the membrane-spanning regions.
tor in precisely defined sequences, researchers The very recent cloning of genes for muscar
are now clarifying exactly which portions of the inic cholinergic receptors reveals an extremely
molecule mediate specific synaptic actions. close resemblance to the structure of beta recep
There are many questions to be asked, such as tors. Indeed, muscarinic and beta receptors are
where local anesthetics act to alter synaptic about as similar as the two subtypes of beta re
function. Similarly, investigations of receptor ceptors. Acetylcholine and the catecholamines
phosphorylation have provided insights into are thought of as very different neurotransmit
cholinergic receptor desensitization. Strikingly, ters so that the close Similarity of their receptors
in the electric organ receptor one can detect is perhaps counterintuitive. On the other hand,
endogenous tyrosine kinases that phosphoryl both are associated with G proteins. Moreover,
ate the acetylcholine receptor,linking this recep norepinephrine and acetylcholine are the major
tor protein with the many other targets of onco transmitters of the autonomic nervous system.
gene-coded tyrosine kinases. The receptor similarities suggest that the entire
The nicotinic acetylcholine receptor is so a autonomic nervous system evolved in a unitary
bundant, thousands of times more concentrated fashion and that muscarinic and cholinergic
in the electric organ than are most neurotrans functions separated later in evolution. This no
mitter receptors in the brain, that one worries tion would accord with the numerous demon
whether precedents established with the acetyl strations that cholinergiC and adrenergic prop
choline receptor can be translated to other sys eries are interchangeable in developing autono
tems. Very recently it has been possible to clone mic neurons. Such a concept also predicts that
genes for other neurotransmitter receptors. Par alpha-adrenergic receptors will turn out to re
ticular success has come with studies of beta semble beta and muscarinic receptors.
adrenergic receptors, based on the work of Lef Elegant studies from the laboratory of Bar
kowitz at Duke University and a variety of re nard have resulted in the isolation of the GABA
searchers at the Merck and Genentech Compan benzodiazepine receptor complex and quite
ies. Properties of the cloned beta recepters pro recently in the cloning of the genes for this re
vide a number of novel insights. The structure ceptor complex (Burt, personal communi
of beta receptors closely resembles that of rho cation). One might anticipate valuable insights.
dopsin, indicating a link between the recogni- Conventional ligand-binding techniques have
Molecular Neurobiology Volume 7, 7987
Molecular Neurobiology: Past Present and Future 5
I I
revealed a number of distinct recognition sites ceptors. In ligand-binding studies, differences
on this receptor. Benzodiazepines, barbiturates, in the drug selectivity of the various receptor
and GABA all bind to distinct but allosterically sites are also sufficiently minor that for several
interacting sites. This explains the pharmacol years a number of researchers, including my
ogic evidence that barbiturates and benzodiaze self, felt that one could account for these differ
pines act to facilitate the synaptic effects of ences on the basis of a single receptor with sev
GABA. Yet another site on this receptor presum eral binding sites. A given drug or enkephalin
ably interacts with ethyl alcohol. Recent re related peptide might interact with all or only
search reveals that one of the benzodiazepines some of the attachment points, thereby produc
developed by the Roche Drug Company, Ro15- ing a distinctive binding profile. The elegant
4513, blocks the effects of alcohol. These actions studies of Kosterlitz, combining binding and
involve a subtype of a benzodiazepine receptor bioassay, established definitively the existence
at which Ro15-4513 must act as some sort of of distinct mu-, delta-, and kappa-receptor sub
"partial" inverse agonist. Thus, pure benzodiaz types. In addition to these three, well-estab
epine antagonists, such as Ro15-1788, reverse lished receptors, several other receptor sub
the alcohol blocking effects ofRo15-4513. Other types have been characterized and may also
drugs, usually of a carboline structure, are said represent separate molecular entities. As of this
to be inverse agonists at benzodiazepine recep writing (early 1987), several laboratories have
tors because they cause profound anxiety re corne close to completing the cloning of genes
sponses in humans and animals that are antoag for some subtypes of opiate receptors. It may be
onized by Ro 15-1788. The term 'inverse agonist' hoped that a full characterization of opiate re
refers to the fact that the anxiety-relieving ef ceptor genes will reveal the molecular basis for
fects of drugs such as diazepam represent "con receptor subtypes as well as sites of intererac
ventional agonist" effects at the receptor and are tions with G proteins.
blocked by Ro15-1788. The molecular genetics
of a GABA-benzodiazepine receptor should
considerably enhance our understanding of the Molecular Neuroanatomy
relationship of the various drug recognition
sites and the nature of agonism, antagonism,
Ligand-binding techniques used first with
and inverse agonism.
tissue homogenates to characterize neurotrans
One of the principal puzzles of opiate recep
mitter receptors have been employed to image
tors that might be clarified by molecular genetic
receptors by light microscopic autoradiog
approaches relates to receptor subtypes. The
raphy. The resultant localization of many recep
differences in opiate structures that gave rise to
tors for neurotransmitters and drugs has assis
varying types of opiate effects are quite subtle.
ted greatly in our understanding of how drugs
Indeed, on the basis of drug effects in intact
exert particular pharmacologic effects. For in
animals and humans, many investigators were
stance, the localization of opiate receptors to
skeptical that there really exist different recep
areas of the brain involved in emotional regula
tor subtypes. Instead, one might postulate only
tion, pain perception, pupillary diameter regu
a single opiate receptor, with differences in clini
lation, and respiratory centers, can explain most
cal effects of certain opiates involving sites other
of the major pharmacologic actions of opiate
than opiate receptors, Indeed, this appears to be
drugs.
the case for the psychotomimetic effects of opi
Techniques that were employed successfully
ates that involve sigma receptors, presumably
for neurotransmitter-receptor autoradiography
unrelated in a fundamental sense to opiate re-
have been extended to other types of ligands
Molecular Neurobiology Volume 7, 7987