Main Molecular and Cellular Signaling

# Molecular and Cellular Signaling

0 / 0
How much do you like this book?
What’s the quality of the file?

Makes connections between diseases, drugs and signaling in those chapters not specifically devoted to pathogens.

Reviews background in first 5 chapters then offers chapters on cancers and apoptosis and on bacteria and viruses.

Signaling in the immune, endocrine (hormonal) and nervous systems covered along with cancer, apoptosis and gene regulation.

Each chapter ends with a problem section to facilitate discussion.

Year:
2005
Edition:
1
Publisher:
Springer
Language:
english
Pages:
616 / 592
ISBN 10:
0387221301
ISBN 13:
9780387260150
Series:
Biological and Medical Physics, Biomedical Engineering
File:
PDF, 5.64 MB

## Most frequently terms

You can write a book review and share your experiences. Other readers will always be interested in your opinion of the books you've read. Whether you've loved the book or not, if you give your honest and detailed thoughts then people will find new books that are right for them.
1

Year:
2010
Language:
english
File:
EPUB, 343 KB
5.0 / 5.0
2

### Critical Perspectives on Activity: Explorations Across Education, Work, and Everyday Life

Year:
2006
Language:
english
File:
PDF, 2.36 MB
0 / 0
BIOLOGICAL AND MEDICAL
PHYSICS
BIOMEDICAL ENGINEERING

Martin Beckerman

Molecular and
Cellular Signaling
With 227 Figures

Martin Beckerman
Y12 National Security Complex
Oak Ridge, TN 37831-7615
USA
beckermanm@y12.doe.gov

Beckerman, Martin.
Molecular and cellular signaling/Martin Beckerman.
p. cm.—(Biological and medical physics, biomedical engineering, ISSN 1618-7210)
Includes bibliographical references and index.
ISBN 0-387-22130-1 (alk. paper)
1. Cellular signal transduction. I. Title. II. Series.
QP517.C45B43 2005
571.7¢4—dc22
2004052556
ISBN-10: 0-387-22130-1
ISBN-13: 978-0387-22130-4

Printed on acid-free paper.

AIP Press is an imprint of Springer Science+Business Media, Inc.
All rights reserved. This work may not be translated or copied in whole or in part without the
written permission of the publisher (Springer Science+Business Media, Inc., 233 Spring Street,
New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly
analysis. Use in connection with any form of information storage and retrieval, electronic
adaptation, computer software, or by similar or dissimilar methodology now know or hereafter developed is forbidden.
The use in this publication of trade names, trademarks, service marks, and similar terms, even
if they are not identiﬁed as such, is not to be taken as an expression of opinion as to whether
or not they are subject to proprietary rights.
Printed in the United States of America.
9 8 7 6 5 4 3 2 1
springeronline.com

SPIN 10948309

(BS/EB)

Series Preface

The ﬁelds of biological and medical physics and biomedical engineering are
research in physics, biology, chemistry, and medicine. The Biological and
Medical Physics/Biomedical Engineering series is intended to be comprehensive, covering a broad range of topics important to the study of the
physical, chemical, and biologic; al sciences. Its goal is to provide scientists
and engineers with textbooks, monographs, and reference works to address
the growing need for information.
Books in the series emphasize established and emergent areas of science
including molecular, membrane, and mathematical biophysics; photosynthetic energy harvesting and conversion; information processing; physical
principles of genetics; sensory communications; and automata networks,
neural networks, and cellular automata. Equally important will be coverage
of applied aspects of biological and medical physics and biomedical engineering, such as molecular electronic components and devices, biosensors,
medicine, imaging, physical principles of renewable energy production,
advanced prostheses, and environmental control and engineering.
Oak Ridge, Tennessee

Elias Greenbaum
Series Editor-in-Chief

v

Preface

This text provides an introduction to molecular and cellular signaling in
biological systems. Cells partition their core cellular processes into a ﬁxed
infrastructure and a control layer. Proteins in the control layer, the subject
of this textbook, function as signals, as receptors of the signals, as transcription factors that turn genes on and off, and as signaling transducers and
intermediaries. The signaling and regulatory proteins and associated small
molecules make contact with the ﬁxed infrastructure responsible for metabolism, growth, replication, and reproduction at well-deﬁned control points,
where the signals are converted into cellular responses.
The text is aimed at a broad audience of students and other individuals
interested in furthering their understanding of how cells regulate and coordinate their core activities. Malfunction in the control layer is responsible
for a host of human disorders ranging from neurological disorders to
cancers. Most drugs target components in the control layer, and difﬁculties
in drug design are intimately related to the architecture of the control layer.
The text will assist students and individuals in medicine and pharmacology
interested in broadening their understanding of how the control layer
works. To further that goal, there are chapters on cancers and apoptosis,
and on bacteria and viruses. In those chapters not speciﬁcally devoted to
pathogens, connections between diseases, drugs, and signaling are made.
The target audience for this text includes students in chemistry, physics,
and computer science who intend to work in biological and medical physics,
and bioinformatics and systems biology.To assist them, the textbook includes
a fair amount of background information on the main points of these areas.
The ﬁrst ﬁve chapters of the book are mainly background and review
chapters. Signaling in the immune, endocrine (hormonal), and nervous
systems is covered, along with cancer, apoptosis, and gene regulation.
Biological systems are stunningly well engineered. Proof of this is all
around us. It can be seen in the sheer variety of life on Earth, all built pretty
much from the same building blocks and according to the same assembly
rules, but arranged in myriad different ways. It can be seen in the relatively
modest sizes of the genomes of even the most complex organisms, such as
vii

viii

Preface

ourselves. The genomes of worms, ﬂies, mice, and humans are roughly
comparable, and only a factor of two or three larger than those of some
bacteria. The good engineering of biological systems is exempliﬁed by the
above-mentioned partition of cellular processes into the ﬁxed infrastructure and the control layer. This makes possible machinery that always works
the same way in any cell at any time, and whose interactions can be exactly
known, while allowing for the machinery’s regulation by the variable
control layer at well-deﬁned control points.
Another example of good engineering design is that of modularity of
design. Proteins, especially signaling proteins, are modular in design and
their components can be transferred, arranged, and rearranged to make
many different proteins. The protein components interact with one another
through their interfaces. There are interfaces for interactions with other
proteins and with lipids DNA and RNA. Modularity is encountered not
only in the largely independent components, but also in the DNA regulatory sequences. These sequences serve as control points for the networks
that regulate gene expression. The DNA regulatory sequences can also
be rearranged in a multitude of ways along the chromosomes, and these
rearrangements, rather than the genes themselves, are largely responsible
for the richness of life on Earth. Two of the key objectives of the text are
to examine how modularity in design is used and how interfaces are
exploited. X-ray crystal structures and nuclear magnetic resonance (NMR)
solution structures provide insights at the atomic level of how the interfaces
between modules operate, and these will be looked at throughout the text.
One of the great conceptual breakthroughs in explorations of the control
layer was the idea that signaling proteins involved in cell-to-cell communication are organized into signaling pathways. In a signaling pathway, there
is a starting point, usually a receptor at the plasma membrane, and an endpoint (control point), more often than not a transcription regulatory site
in the nucleus, and there is a linear route leading from one to the other.
In spite of the enormous complexity of metazoans, there are only about a
dozen or so such pathways. These will be explored in the context of where
they are most strongly associated. For example, some pathways are prominent during development and are best understood in that context. Other
pathways are associated with stress responses and are best understood
within that framework, and still others are associated with immune
responses.
Signaling and the cellular responses to signals are complex.The responses
are controlled by a plethora of positive and negative feedback loops. The
presence of feedback complicates the simple picture of a linear pathway,
but this aspect is an essential part of the signaling process. Positive feedback ensures that once the appropriate thresholds are passed there will be
a ﬁrm commitment to a speciﬁc action and the system will not jump back
and forth between alternative responses. Negative feedback generates the
thresholds that ensure random excursions and perturbations do not unnec-

Preface

ix

essarily commit the cell to some irreversible response when it ought not to,
and it permits the cells to turn off the signaling once it has served its
purpose. These feedback loops will be examined along with the discussions
of the linear signaling pathways.
The goal of this textbook is to provide an introduction to the molecular
and cellular signaling processing comprising the control layer. The topic is
a vast one, and it is not possible to cover every possible aspect and still keep
the text concise and readable. To achieve the stated goal, material of a historical nature has been omitted, as have lengthy descriptions of all proteins
identiﬁed as being involved in the particular aspect of signaling being considered. In place of such an encyclopedic approach, selected processes are
presented step-by-step from start to end. These examples serve as simple
models of how the control process is carried out.
Oak Ridge, Tennessee

Martin Beckerman

Contents

Series Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Guide to Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.

2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1
Prokaryotes and Eukaryotes . . . . . . . . . . . . . .
1.2
The Cytoskeleton and Extracellular Matrix . . . . .
1.3
Core Cellular Functions in Organelles . . . . . . . .
1.4
Metabolic Processes in Mitochondria and
Chloroplasts . . . . . . . . . . . . . . . . . . . . . . .
1.5
Cellular DNA to Chromatin . . . . . . . . . . . . . .
1.6
Protein Activities in the Endoplasmic Reticulum and
Golgi Apparatus . . . . . . . . . . . . . . . . . . . . .
1.7
Digestion and Recycling of Macromolecules . . . . .
1.8
Genomes of Bacteria Reveal Importance of
Signaling . . . . . . . . . . . . . . . . . . . . . . . . .
1.9
Organization and Signaling of Eukaryotic Cell . . .
1.10 Fixed Infrastructure and the Control Layer . . . . .
1.11 Eukaryotic Gene and Protein Regulation . . . . . .
1.12 Signaling Malfunction Central to Human
Disease . . . . . . . . . . . . . . . . . . . . . . . . . .
1.13
Organization of Text . . . . . . . . . . . . . . . . . .
The Control Layer . . . . . . . . . . . . . . . . . . . . . . .
2.1
Eukaryotic Chromosomes Are Built from
Nucleosomes . . . . . . . . . . . . . . . . . . . . . .
2.2
The Highly Organized Interphase Nucleus . . . . .
2.3
Covalent Bonds Deﬁne the Primary Structure of a
Protein . . . . . . . . . . . . . . . . . . . . . . . . .
2.4
Hydrogen Bonds Shape the Secondary Structure .
2.5
Structural Motifs and Domain Folds:
Semi-Independent Protein Modules . . . . . . . .

v
vii
xxv

.
.
.
.

1
1
2
3

.
.

4
5

.
.

6
8

.
.
.
.

9
10
12
13

.
.

15
16

. .

21

. .
. .

22
23

. .
. .

26
27

. .

29
xi

xii

Contents

2.6
2.7
2.8
2.9
2.10
2.11
2.12
2.13
2.14
2.15
2.16

Arrangement of Protein Secondary Structure
Elements and Chain Topology . . . . . . . . . . .
Tertiary Structure of a Protein: Motifs and
Domains . . . . . . . . . . . . . . . . . . . . . . .
Quaternary Structure: The Arrangement of
Subunits . . . . . . . . . . . . . . . . . . . . . . .
Many Signaling Proteins Undergo Covalent
Modiﬁcations . . . . . . . . . . . . . . . . . . . .
Anchors Enable Proteins to Attach to
Membranes . . . . . . . . . . . . . . . . . . . . .
Glycosylation Produces Mature Glycoproteins .
Proteolytic Processing Is Widely Used in
Signaling . . . . . . . . . . . . . . . . . . . . . . .
Reversible Addition and Removal of Phosphoryl
Groups . . . . . . . . . . . . . . . . . . . . . . . .
Reversible Addition and Removal of Methyl and
Acetyl Groups . . . . . . . . . . . . . . . . . . . .
Reversible Addition and Removal of SUMO
Groups . . . . . . . . . . . . . . . . . . . . . . . .
Post-Translational Modiﬁcations to Histones . .

. . .

29

. . .

30

. . .

32

. . .

33

. . .
. . .

34
36

. . .

36

. . .

37

. . .

38

. . .
. . .

39
40

3. Exploring Protein Structure and Function . . . . . . . . .
3.1
Matter . . . . . . . . . . . . . . . . . . . . . . . . .
3.2
Biomolecule Absorption and Emission Spectra . .
3.3
Protein Structure via X-Ray Crystallography . . .
3.4
Membrane Protein 3-D Structure via Electron and
Cryoelectron Crystallography . . . . . . . . . . . .
3.5
Determining Protein Structure Through NMR . .
3.6
Intrinsic Magnetic Dipole Moment of Protons and
Neutrons . . . . . . . . . . . . . . . . . . . . . . . .
3.7
Using Protein Fluorescence to Probe Control
Layer . . . . . . . . . . . . . . . . . . . . . . . . . .
3.8
Exploring Signaling with FRET . . . . . . . . . . .
3.9
Exploring Protein Structure with Circular
Dichroism . . . . . . . . . . . . . . . . . . . . . . .
3.10 Infrared and Raman Spectroscopy to Probe
Vibrational States . . . . . . . . . . . . . . . . . . .
3.11 A Genetic Method for Detecting Protein
Interactions . . . . . . . . . . . . . . . . . . . . . .
3.12 DNA and Oligonucleotide Arrays Provide
Information on Genes . . . . . . . . . . . . . . . .
3.13 Gel Electrophoresis of Proteins . . . . . . . . . . .
3.14
Mass Spectroscopy of Proteins . . . . . . . . . . . .

. .

45

. .
. .
. .

46
49
49

. .
. .

53
53

. .

56

. .
. .

57
58

. .

60

. .

61

. .

61

. .
. .
. .

62
63
64

Contents

4.

5.

Macromolecular Forces . . . . . . . . . . . . . . . . . . .
4.1
Amino Acids Vary in Size and Shape . . . . . . .
4.2
Amino Acids Behavior in Aqueous
Environments . . . . . . . . . . . . . . . . . . . .
4.3
Formation of H-Bonded Atom Networks . . . .
4.4
Forces that Stabilize Proteins . . . . . . . . . . .
4.5
Atomic Radii of Macromolecular Forces . . . . .
4.6
Osmophobic Forces Stabilize Stressed Cells . . .
4.7
Protein Interfaces Aid Intra- and Intermolecular
Communication . . . . . . . . . . . . . . . . . . .
4.8
Interfaces Utilize Shape and Electrostatic
Complementarity . . . . . . . . . . . . . . . . . .
4.9
Macromolecular Forces Hold Macromolecules
Together . . . . . . . . . . . . . . . . . . . . . . .
4.10 Motion Models of Covalently Bonded Atoms . .
4.11
Modeling van der Waals Forces . . . . . . . . . .
4.12 Molecular Dynamics in the Study of System
Evolution . . . . . . . . . . . . . . . . . . . . . . .
4.13 Importance of Water Molecules in Cellular
Function . . . . . . . . . . . . . . . . . . . . . . .
4.14 Essential Nature of Protein Dynamics . . . . . .

xiii

. . .
. . .

71
71

.
.
.
.
.

.
.
.
.
.

72
74
74
75
76

. . .

77

. . .

78

. . .
. . .
. . .

79
79
81

. . .

83

. . .
. . .

84
85

Protein Folding and Binding . . . . . . . . . . . . . . . . .
5.1
The First Law of Thermodynamics: Energy Is
Conserved . . . . . . . . . . . . . . . . . . . . . . .
5.2
Heat Flows from a Hotter to a Cooler Body . . . .
5.3
Direction of Heat Flow: Second Law of
Thermodynamics . . . . . . . . . . . . . . . . . . .
5.4
Order-Creating Processes Occur Spontaneously as
Gibbs Free Energy Decreases . . . . . . . . . . . .
5.5
Spontaneous Folding of New Proteins . . . . . . .
5.6
The Folding Process: An Energy Landscape
Picture . . . . . . . . . . . . . . . . . . . . . . . . .
5.7
Misfolded Proteins Can Cause Disease . . . . . . .
5.8
Protein Problems and Alzheimer’s Disease . . . .
5.9
Amyloid Buildup in Neurological Disorders . . . .
5.10 Molecular Chaperones Assist in Protein Folding
in the Crowded Cell . . . . . . . . . . . . . . . . .
5.11 Role of Chaperonins in Protein Folding . . . . . .
5.12 Hsp 90 Chaperones Help Maintain Signal
Transduction Pathways . . . . . . . . . . . . . . . .
5.13 Proteins: Dynamic, Flexible, and Ready to
Change . . . . . . . . . . . . . . . . . . . . . . . . .

.
.
.
.
.

. .

89

. .
. .

90
91

. .

92

. .
. .

93
94

.
.
.
.

.
.
.
.

96
98
99
100

. .
. .

101
102

. .

103

. .

104

xiv

Contents

6. Stress and Pheromone Responses in Yeast . . . . . . . . . .
6.1
How Signaling Begins . . . . . . . . . . . . . . . . .
6.2
Signaling Complexes Form in Response to
Receptor-Ligand Binding . . . . . . . . . . . . . . . .
6.3
Role of Protein Kinases, Phosphatases, and
GTPases . . . . . . . . . . . . . . . . . . . . . . . . .
6.4
Role of Proteolytic Enzymes . . . . . . . . . . . . . .
6.5
End Points Are Contact Points to Fixed
Infrastructure . . . . . . . . . . . . . . . . . . . . . .
6.6
Transcription Factors Combine to Alter Genes . . .
6.7
Protein Kinases Are Key Signal Transducers . . . . .
6.8
Kinases Often Require Second Messenger
Costimulation . . . . . . . . . . . . . . . . . . . . . .
6.9
Flanking Residues Direct Phosphorylation of
Target Residues . . . . . . . . . . . . . . . . . . . . .
6.10 Docking Sites and Substrate Speciﬁcity . . . . . . . .
6.11 Protein Phosphatases Are Prominent Components of
Signaling Pathways . . . . . . . . . . . . . . . . . . .
6.12 Scaffold and Anchor Protein Role in Signaling and
Speciﬁcity . . . . . . . . . . . . . . . . . . . . . . . .
6.13 GTPases Regulate Protein Trafﬁcking in the Cell . .
6.14 Pheromone Response Pathway Is Activated by
Pheromones . . . . . . . . . . . . . . . . . . . . . . .
6.15 Osmotic Stresses Activate Glycerol Response
Pathway . . . . . . . . . . . . . . . . . . . . . . . . .
6.16 Yeasts Have a General Stress Response . . . . . . .
6.17 Target of Rapamycin (TOR) Adjusts Protein
Synthesis . . . . . . . . . . . . . . . . . . . . . . . . .
6.18 TOR Adjusts Gene Transcription . . . . . . . . . . .
6.19 Signaling Proteins Move by Diffusion . . . . . . . .

7.

Two-Component Signaling Systems . . . . . . . . . .
7.1
Prokaryotic Signaling Pathways . . . . . . . .
7.2
Catalytic Action by Histidine Kinases . . . .
7.3
The Catalytic Activity of HK Occurs at the
Active Site . . . . . . . . . . . . . . . . . . . .
7.4
The GHKL Superfamily . . . . . . . . . . . .
7.5
Activation of Response Regulators by
Phosphorylation . . . . . . . . . . . . . . . . .
7.6
Response Regulators Are Switches Thrown at
Transcriptional Control Points . . . . . . . . .
7.7
Structure and Domain Organization of
Bacterial Receptors . . . . . . . . . . . . . . .
7.8
Bacterial Receptors Form Signaling Clusters

.
.

111
112

.

113

.
.

115
116

.
.
.

117
118
119

.

121

.
.

122
123

.

123

.
.

124
125

.

125

.
.

128
129

.
.
.

131
133
134

. . . . .
. . . . .
. . . . .

139
140
141

. . . . .
. . . . .

143
144

. . . . .

145

. . . . .

146

. . . . .
. . . . .

147
148

Contents

7.9
7.10
7.11
7.12
7.13
7.14

Bacteria with High Sensitivity and Mobility .
Feedback Loop in the Chemotactic Pathway
How Plants Sense and Respond to Hormones
Role of Growth Plasticity in Plants . . . . . .
Role of Phytochromes in Plant Cell Growth .
Rhythms . . . . . . . . . . . . . . . . . . . . .

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

.
.
.
.
.

149
150
152
154
154

. . . . .

156

8. Organization of Signal Complexes by Lipids, Calcium, and
Cyclic AMP . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1
Composition of Biological Membranes . . . . . . . .
8.2
Microdomains and Caveolae in Membranes . . . . .
8.3
Lipid Kinases Phosphorylate Plasma Membrane
Phosphoglycerides . . . . . . . . . . . . . . . . . . . .
8.4
Generation of Lipid Second Messengers from
PIP2 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5
Regulation of Cellular Processes by PI3K . . . . . .
8.6
PIPs Regulate Lipid Signaling . . . . . . . . . . . . .
8.7
Role of Lipid-Binding Domains . . . . . . . . . . . .
8.8
Role of Intracellular Calcium Level Elevations . . .
8.9
Role of Calmodulin in Signaling . . . . . . . . . . . .
8.10 Adenylyl Cyclases and Phosphodiesterases Produce
and Regulate cAMP Second Messengers . . . . . . .
8.11 Second Messengers Activate Certain Serine/
Threonine Kinases . . . . . . . . . . . . . . . . . . .
8.12 Lipids and Upstream Kinases Activate PKB . . . . .
8.13 PKB Supplies a Signal Necessary for Cell
Survival . . . . . . . . . . . . . . . . . . . . . . . . . .
8.14 Phospholipids and Ca2+ Activate Protein
Kinase C . . . . . . . . . . . . . . . . . . . . . . . . .
8.15 Anchoring Proteins Help Localize PKA and PKC
Near Substrates . . . . . . . . . . . . . . . . . . . . .
8.16 PKC Regulates Response of Cardiac Cells to
Oxygen Deprivation . . . . . . . . . . . . . . . . . .
8.17 cAMP Activates PKA, Which Regulates Ion
Channel Activities . . . . . . . . . . . . . . . . . . . .
8.18 PKs Facilitate the Transfer of Phosphoryl Groups
from ATPs to Substrates . . . . . . . . . . . . . . . .
9. Signaling by Cells of the Immune System . . . .
9.1
Leukocytes Mediate Immune Responses
9.2
Leukocytes Signal One Another Using
Cytokines . . . . . . . . . . . . . . . . . .
9.3
APC and Naïve T Cell Signals Guide
Differentiation into Helper T Cells . . .

xv

.
.
.

161
162
163

.

165

.
.
.
.
.
.

165
167
168
169
170
171

.

172

.
.

173
174

.

176

.

177

.

178

.

179

.

180

.

182

. . . . . . . .
. . . . . . . .

187
188

. . . . . . . .

190

. . . . . . . .

192

xvi

Contents

9.4
9.5
9.6
9.7
9.8
9.9
9.10
9.11
9.12
9.13
9.14
9.15
9.16
9.17
9.18
9.19
9.20

10.

Five Families of Cytokines and Cytokine
Receptors . . . . . . . . . . . . . . . . . . . . . .
Role of NF-kB/Rel in Adaptive Immune
Responses . . . . . . . . . . . . . . . . . . . . . .
Role of MAP Kinase Modules in Immune
Responses . . . . . . . . . . . . . . . . . . . . . .
Role of TRAF and DD Adapters . . . . . . . . .
Toll/IL-1R Pathway Mediates Innate Immune
Responses . . . . . . . . . . . . . . . . . . . . . .
TNF Family Mediates Homeostasis, Death, and
Survival . . . . . . . . . . . . . . . . . . . . . . . .
Role of Hematopoietin and Related Receptors .
Role of Human Growth Hormone Cytokine . . .
Signal-Transducing Jaks and STATs . . . . . . . .
Interferon System: First Line of Host Defense in
Mammals Against Virus Attacks . . . . . . . . . .
Leukocytes . . . . . . . . . . . . . . . . . . . . . .
B and T Cell Receptors Recognize Antigens . .
MHCs Present Antigens on the Cell Surface . .
Antigen-Recognizing Receptors Form Signaling
Complexes with Coreceptors . . . . . . . . . . .
Costimulatory Signals Between APCs and
T Cells . . . . . . . . . . . . . . . . . . . . . . . .
Role of Lymphocyte-Signaling Molecules . . . .
Kinetic Proofreading and Serial Triggering of
TCRs . . . . . . . . . . . . . . . . . . . . . . . . .

Cell Adhesion and Motility . . . . . . . . . . . . . . . .
10.1 Cell Adhesion Receptors: Long Highly Modular
Glycoproteins . . . . . . . . . . . . . . . . . . .
10.2 Integrins as Bidirectional Signaling Receptors .
10.3 Role of Leukocyte-Speciﬁc Integrin . . . . . .
10.4 Most Integrins Bind to Proteins Belonging to
the ECM . . . . . . . . . . . . . . . . . . . . . .
10.5 Cadherins Are Present in Most Cells of the
Body . . . . . . . . . . . . . . . . . . . . . . . .
10.6 IgCAMs Mediate Cell–Cell and Cell–ECM
Adhesion . . . . . . . . . . . . . . . . . . . . . .
10.7 Selectins Are CAMs Involved in Leukocyte
Motility . . . . . . . . . . . . . . . . . . . . . . .
10.8 Leukocytes Roll, Adhere, and Crawl to Reach
the Site of an Infection . . . . . . . . . . . . . .
10.9 Bonds Form and Break During Leukocyte
Rolling . . . . . . . . . . . . . . . . . . . . . . .

. . .

193

. . .

194

. . .
. . .

196
196

. . .

198

.
.
.
.

.
.
.
.

199
200
202
203

. . .

205

. . .
. . .
. . .

206
207
208

. . .

209

. . .
. . .

211
212

. . .

213

. . . .

221

. . . .
. . . .
. . . .

221
223
224

. . . .

225

. . . .

226

. . . .

228

. . . .

229

. . . .

230

. . . .

231

.
.
.
.

Contents

10.10 Bond Dissociation of Rolling Leukocyte as Seen in
Microscopy . . . . . . . . . . . . . . . . . . . . . . .
10.11 Slip and Catch Bonds Between Selectins and
Their Carbohydrate Ligands . . . . . . . . . . . . .
10.12 Development in Central Nervous System . . . . .
10.13 Diffusible, Anchored, and Membrane-Bound
Glycoproteins in Neurite Outgrowth . . . . . . . .
10.14 Growth Cone Navigation Mechanisms . . . . . . .
10.15 Molecular Marking by Concentration Gradients of
Netrins and Slits . . . . . . . . . . . . . . . . . . . .
10.16 How Semaphorins, Scatter Factors, and Their
Receptors Control Invasive Growth . . . . . . . .
10.17 Ephrins and Their Eph Receptors Mediate
Contact-Dependent Repulsion . . . . . . . . . . .
11.

xvii

. .

232

. .
. .

233
234

. .
. .

235
236

. .

237

. .

239

. .

239

Signaling in the Endocrine System . . . . . . . . . . . . . . . .
11.1 Five Modes of Cell-to-Cell Signaling . . . . . . . . . .
11.2 Role of Growth Factors in Angiogenesis . . . . . . . .
11.3 Role of EGF Family in Wound Healing . . . . . . . .
11.4 Neurotrophins Control Neuron Growth,
Differentiation, and Survival . . . . . . . . . . . . . . .
11.5 Role of Receptor Tyrosine Kinases in Signal
Transduction . . . . . . . . . . . . . . . . . . . . . . . .
11.6 Phosphoprotein Recognition Modules Utilized Widely
in Signaling Pathways . . . . . . . . . . . . . . . . . . .
11.7 Modules that Recognize Proline-Rich Sequences
Utilized Widely in Signaling Pathways . . . . . . . . .
11.8 Protein–Protein Interaction Domains Utilized Widely
in Signaling Pathways . . . . . . . . . . . . . . . . . . .
11.9 Non-RTKs Central in Metazoan Signaling Processes
and Appear in Many Pathways . . . . . . . . . . . . .
11.10 Src Is a Representative NRTK . . . . . . . . . . . . .
11.11 Roles of Focal Adhesion Kinase Family of
NRTKs . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.12 GTPases Are Essential Regulators of Cellular
Functions . . . . . . . . . . . . . . . . . . . . . . . . . .
11.13 Signaling by Ras GTPases from Plasma Membrane
and Golgi . . . . . . . . . . . . . . . . . . . . . . . . . .
11.14 GTPases Cycle Between GTP- and GDP-Bound
States . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.15 Role of Rho, Rac, and Cdc42, and Their Isoforms . . .
11.16 Ran Family Coordinates Trafﬁc In and Out of the
Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.17 Rab and ARF Families Mediate the Transport of
Cargo . . . . . . . . . . . . . . . . . . . . . . . . . . . .

247
248
249
250
251
252
254
256
256
258
259
261
262
263
264
266
267
268

xviii

Contents

12. Signaling in the Endocrine and Nervous Systems
Through GPCRs . . . . . . . . . . . . . . . . . . . . . . . .
12.1
GPCRs Classiﬁcation Criteria . . . . . . . . . . . .
12.2 Study of Rhodopsin GPCR with Cryoelectron
Microscopy and X-Ray Crystallography . . . . . .
12.3 Subunits of Heterotrimeric G Proteins . . . . . . .
12.4 The Four Families of Ga Subunits . . . . . . . . . .
12.5 Adenylyl Cyclases and Phosphodiesterases Key to
Second Messenger Signaling . . . . . . . . . . . . .
12.6 Desensitization Strategy of G Proteins to Maintain
Responsiveness to Environment . . . . . . . . . . .
12.7 GPCRs Are Internalized, and Then Recycled or
Degraded . . . . . . . . . . . . . . . . . . . . . . . .
12.8 Hormone-Sending and Receiving Glands . . . . .
12.9 Functions of Signaling Molecules . . . . . . . . . .
12.10 Neuromodulators Inﬂuence Emotions, Cognition,
Pain, and Feeling Well . . . . . . . . . . . . . . . .
12.11 Ill Effects of Improper Dopamine Levels . . . . .
12.12 Inadequate Serotonin Levels Underlie Mood
Disorders . . . . . . . . . . . . . . . . . . . . . . . .
12.13 GPCRs’ Role in the Somatosensory System
Responsible for Sense of Touch and
Nociception . . . . . . . . . . . . . . . . . . . . . .
12.14 Substances that Regulate Pain and Fever
Responses . . . . . . . . . . . . . . . . . . . . . . .
12.15 Composition of Rhodopsin Photoreceptor . . . . .
12.16 How G Proteins Regulate Ion Channels . . . . . .
12.17 GPCRs Transduce Signals Conveyed by
Odorants . . . . . . . . . . . . . . . . . . . . . . . .
12.18 GPCRs and Ion Channels Respond to
Tastants . . . . . . . . . . . . . . . . . . . . . . . . .
13.

. .
. .

275
276

. .
. .
. .

278
279
280

. .

281

. .

282

. .
. .
. .

284
285
288

. .
. .

289
291

. .

292

. .

292

. .
. .
. .

293
295
297

. .

297

. .

299

Cell Fate and Polarity . . . . . . . . . . . . . . . . . . . . . .
13.1 Notch Signaling Mediates Cell Fate Decision . . . .
13.2 How Cell Fate Decisions Are Mediated . . . . . . .
13.3 Proteolytic Processing of Key Signaling
Elements . . . . . . . . . . . . . . . . . . . . . . . . .
13.4 Three Components of TGF-b Signaling . . . . . . .
13.5 Smad Proteins Convey TGF-b Signals into the
Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . .
13.6 Multiple Wnt Signaling Pathways Guide Embryonic
Development . . . . . . . . . . . . . . . . . . . . . .
13.7 Role of Noncanonical Wnt Pathway . . . . . . . . .
13.8 Hedgehog Signaling Role During Development . . .
13.9
Gli Receives Hh Signals . . . . . . . . . . . . . . . .

.
.
.

305
306
307

.
.

308
311

.

313

.
.
.
.

314
317
317
318

Contents

13.10 Stages of Embryonic Development Use
Morphogens . . . . . . . . . . . . . . . . . . . . . . .
13.11 Gene Family Hierarchy of Cell Fate Determinants in
Drosophila . . . . . . . . . . . . . . . . . . . . . . . .
13.12 Egg Development in D. Melanogaster . . . . . . . .
13.13 Gap Genes Help Partition the Body into
Bands . . . . . . . . . . . . . . . . . . . . . . . . . . .
13.14 Pair-Rule Genes Partition the Body into
Segments . . . . . . . . . . . . . . . . . . . . . . . . .
13.15 Segment Polarity Genes Guide Parasegment
Development . . . . . . . . . . . . . . . . . . . . . .
13.16 Hox Genes Guide Patterning in Axially Symmetric
Animals . . . . . . . . . . . . . . . . . . . . . . . . .
14.

Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.1 Several Critical Mutations Generate a
Transformed Cell . . . . . . . . . . . . . . . . . . . .
14.2 Ras Switch Sticks to “On” Under Certain
Mutations . . . . . . . . . . . . . . . . . . . . . . . .
14.3 Crucial Regulatory Sequence Missing in Oncogenic
Forms of Src . . . . . . . . . . . . . . . . . . . . . . .
14.4 Overexpressed GFRs Spontaneously Dimerize in
Many Cancers . . . . . . . . . . . . . . . . . . . . . .
14.5 GFRs and Adhesion Molecules Cooperate to
Promote Tumor Growth . . . . . . . . . . . . . . . .
14.6 Role of Mutated Forms of Proteins in Cancer
Development . . . . . . . . . . . . . . . . . . . . . .
14.7 Translocated and Fused Genes Are Present in
Leukemias . . . . . . . . . . . . . . . . . . . . . . . .
14.8
Repair of DNA Damage . . . . . . . . . . . . . . . .
14.9 Double-Strand-Break Repair Machinery . . . . . . .
14.10 How Breast Cancer (BRCA) Proteins Interact with
DNA . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.11 PI3K Superfamily Members that Recognize
Double-Strand Breaks . . . . . . . . . . . . . . . . .
14.12 Checkpoints Regulate Transition Events in a
Network . . . . . . . . . . . . . . . . . . . . . . . . .
14.13 Cyclin-Dependent Kinases Form the Core of
Cell-Cycle Control System . . . . . . . . . . . . . . .
14.14 pRb Regulates Cell Cycle in Response to
Mitogenic Signals . . . . . . . . . . . . . . . . . . . .
14.15 p53 Halts Cell Cycle While DNA Repairs Are
Made . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.16 p53 and pRb Controllers Central to Metazoan
Cancer Prevention Program . . . . . . . . . . . . . .

xix

.

320

.
.

321
322

.

323

.

324

.

325

.

326

.

331

.

332

.

334

.

336

.

336

.

337

.

338

.
.
.

339
340
342

.

344

.

345

.

346

.

347

.

347

.

349

.

350

xx

Contents

14.17 p53 Structure Supports Its Role as a Central
Controller . . . . . . . . . . . . . . . . . . . . . . . . .
14.18 Telomerase Production in Cancer Cells . . . . . . . . .
15.

16.

Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15.1 Caspases and Bcl-2 Proteins Are Key Mediators of
Apoptosis . . . . . . . . . . . . . . . . . . . . . . . .
15.2 Caspases Are Proteolytic Enzymes Synthesized as
Inactive Zymogens . . . . . . . . . . . . . . . . . . .
15.3 Caspases Are Initiators and Executioners of
Apoptosis Programs . . . . . . . . . . . . . . . . . .
15.4 There Are Three Kinds of Bcl-2 Proteins . . . . . . .
15.5
How Caspases Are Activated . . . . . . . . . . . . .
15.6 Cell-to-Cell Signals Stimulate Formation of the
DISC . . . . . . . . . . . . . . . . . . . . . . . . . . .
15.7
Death Signals Are Conveyed by the Caspase 8
Pathway . . . . . . . . . . . . . . . . . . . . . . . . .
15.8 How Pro- and Antiapoptotic Signals Are
Relayed . . . . . . . . . . . . . . . . . . . . . . . . . .
15.9 Bcl-2 Proteins Regulate Mitochondrial Membrane
Permeability . . . . . . . . . . . . . . . . . . . . . . .
15.10 Mitochondria Release Cytochrome c in Response to
Oxidative Stresses . . . . . . . . . . . . . . . . . . . .
15.11 Mitochondria Release Apoptosis-Promoting
Agents . . . . . . . . . . . . . . . . . . . . . . . . . .
15.12 Role of Apoptosome in (Mitochondrial Pathway to)
Apoptosis . . . . . . . . . . . . . . . . . . . . . . . .
15.13 Inhibitors of Apoptosis Proteins Regulate Caspase
Activity . . . . . . . . . . . . . . . . . . . . . . . . . .
15.14 Smac/DIABLO and Omi/HtrA2 Regulate IAPs . .
15.15 Feedback Loops Coordinate Actions at Various
Control Points . . . . . . . . . . . . . . . . . . . . . .
15.16 Cells Can Produce Several Different Kinds of
Calcium Signals . . . . . . . . . . . . . . . . . . . . .
15.17 Excessive [Ca2+] in Mitochondria Can Trigger
Apoptosis . . . . . . . . . . . . . . . . . . . . . . . .
15.18 p53 Promotes Cell Death in Response to Irreparable
DNA Damage . . . . . . . . . . . . . . . . . . . . . .
15.19 Anti-Cancer Drugs Target the Cell’s Apoptosis
Machinery . . . . . . . . . . . . . . . . . . . . . . . .
Gene
16.1
16.2
16.3

Regulation in Eukaryotes . . . . . . . . . . . .
Organization of the Gene Regulatory Region
How Promoters Regulate Genes . . . . . . .
TFs Bind DNA Through Their DNA-Binding
Domains . . . . . . . . . . . . . . . . . . . . .

352
354

.

359

.

360

.

361

.
.
.

362
363
365

.

366

.

367

.

368

.

369

.

371

.

372

.

373

.
.

374
375

.

375

.

376

.

377

.

378

.

379

. . . . .
. . . . .
. . . . .

385
386
387

. . . . .

389

Contents

16.4
16.5
16.6
16.7
16.8
16.9
16.10
16.11
16.12
16.13
16.14
16.15
16.16
16.17
17.

Transcriptional Activation Domains Initiate
Transcription . . . . . . . . . . . . . . . . . . . . .
Nuclear Hormone Receptors Are Transcription
Factors . . . . . . . . . . . . . . . . . . . . . . . .
Composition and Structure of the Basal
Transcription Machinery . . . . . . . . . . . . . .
RNAP II Is Core Module of the Transcription
Machinery . . . . . . . . . . . . . . . . . . . . . .
Regulation by Chromatin-Modifying
Enzymes . . . . . . . . . . . . . . . . . . . . . . .
Multiprotein Complex Use of Energy of ATP
Hydrolysis . . . . . . . . . . . . . . . . . . . . . .
Protein Complexes Act as Interfaces Between
TFs and RNAP II . . . . . . . . . . . . . . . . . .
Alternative Splicing to Generate Multiple
Proteins . . . . . . . . . . . . . . . . . . . . . . . .
Pre-Messenger RNA Molecules Contain Splice
Sites . . . . . . . . . . . . . . . . . . . . . . . . . .
Small Nuclear RNAs (snRNAs) . . . . . . . . . .
How Exon Splices Are Determined . . . . . . . .
Translation Initiation Factors Regulate Start of
Translation . . . . . . . . . . . . . . . . . . . . . .
eIF2 Interfaces Upstream Regulatory Signals and
the Ribosomal Machinery . . . . . . . . . . . . .
Critical Control Points for Protein Synthesis . . .

xxi

. . .

392

. . .

393

. . .

393

. . .

394

. . .

395

. . .

397

. . .

398

. . .

399

. . .
. . .
. . .

400
401
403

. . .

404

. . .
. . .

406
407

Cell Regulation in Bacteria . . . . . . . . . . . . . . . . . .
17.1 Cell Regulation in Bacteria Occurs Primarily at
Transcription Level . . . . . . . . . . . . . . . . . .
17.2 Transcription Is Initiated by RNAP
Holoenzymes . . . . . . . . . . . . . . . . . . . . .
17.3 Sigma Factors Bind to Regulatory Sequences in
Promoters . . . . . . . . . . . . . . . . . . . . . . .
17.4 Bacteria Utilize Sigma Factors to Make Major
Changes in Gene Expression . . . . . . . . . . . .
17.5 Mechanism of Bacterial Transcription Factors . . .
17.6 Many TFs Function as Response Regulators . . . .
17.7 Organization of Protein-Encoding Regions and
Their Regulatory Sequences . . . . . . . . . . . . .
17.8 The Lac Operon Helps Control Metabolism in
E. coli . . . . . . . . . . . . . . . . . . . . . . . . . .
17.9 Flagellar Motors Are Erected in Several Stages . .
17.10 Under Starvation Conditions, B. subtilis Undergoes
Sporulation . . . . . . . . . . . . . . . . . . . . . . .
17.11 Cell-Cycle Progression and Differentiation in
C. crescentus . . . . . . . . . . . . . . . . . . . . . .

. .

411

. .

412

. .

412

. .

414

. .
. .
. .

414
416
417

. .

418

. .
. .

419
421

. .

422

. .

424

xxii

Contents

17.12 Antigenic Variation Counters Adaptive Immune
Responses . . . . . . . . . . . . . . . . . . . . . . . .
17.13 Bacteria Organize into Communities When Nutrient
Conditions Are Favorable . . . . . . . . . . . . . . .
17.14 Quorum Sensing Plays a Key Role in Establishing a
Colony . . . . . . . . . . . . . . . . . . . . . . . . . .
17.15 Bacteria Form Associations with Other Bacteria on
Exposed Surfaces . . . . . . . . . . . . . . . . . . . .
17.16 Horizontal Gene Transfer (HGT) . . . . . . . . . . .
17.17 Pathogenic Species Possess Virulence Cassettes . . .
17.18 Bacterial Death Modules . . . . . . . . . . . . . . . .
17.19 Myxobacteria Exhibit Two Distinct Forms of
Social Behavior . . . . . . . . . . . . . . . . . . . . .
17.20 Structure Formation by Heterocystous
Cyanobacteria . . . . . . . . . . . . . . . . . . . . . .
17.21 Rhizobia Communicate and Form Symbiotic
Associations with Legumes . . . . . . . . . . . . . .
18.

Regulation by Viruses . . . . . . . . . . . . . . . . . . . . . .
18.1 How Viruses Enter Their Host Cells . . . . . . . . .
18.2 Viruses Enter and Exit the Nucleus in
Several Ways . . . . . . . . . . . . . . . . . . . . . . .
18.3
Ways that Viruses Exit a Cell . . . . . . . . . . . . .
18.4 Viruses Produce a Variety of Disorders in
Humans . . . . . . . . . . . . . . . . . . . . . . . . .
18.5 Virus–Host Interactions Underlie Virus Survival and
Proliferation . . . . . . . . . . . . . . . . . . . . . . .
18.6 Multilayered Defenses Are Balanced by
Multilayered Attacks . . . . . . . . . . . . . . . . . .
18.7 Viruses Target TNF Family of Cytokines . . . . . . .
18.8 Hepatitis C Virus Disables Host Cell’s Interferon
System . . . . . . . . . . . . . . . . . . . . . . . . . .
18.9 Human T Lymphotropic Virus Type 1 Can Cause
Cancer . . . . . . . . . . . . . . . . . . . . . . . . . .
18.10 DNA and RNA Viruses that Can Cause Cancer . .
18.11 HIV Is a Retrovirus . . . . . . . . . . . . . . . . . . .
18.12 Role of gp120 Envelope Protein in HIV . . . . . . .
18.13 Early-Acting tat, rev, and nef Regulatory
Genes . . . . . . . . . . . . . . . . . . . . . . . . . . .
18.14 Late-Acting vpr, vif, vpu, and vpx Regulatory
Genes . . . . . . . . . . . . . . . . . . . . . . . . . . .
18.15 Bacteriophages’ Two Lifestyles: Lytic and
Lysogenic . . . . . . . . . . . . . . . . . . . . . . . . .
18.16 Deciding Between Lytic and Lysogenic Lifestyles . .
18.17 Encoding of Shiga Toxin in E. coli . . . . . . . . . .

.

426

.

426

.

428

.
.
.
.

430
430
431
433

.

434

.

435

.

436

.
.

441
442

.
.

442
443

.

444

.

445

.
.

446
447

.

447

.
.
.
.

449
450
452
453

.

454

.

456

.
.
.

457
458
459

Contents

19.

20.

21.

xxiii

Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19.1
How Membrane Potentials Arise . . . . . . . . . . . .
19.2 Membrane and Action Potentials Have Regenerative
Properties . . . . . . . . . . . . . . . . . . . . . . . . .
19.3 Hodgkin–Huxley Equations Describe How Action
Potentials Arise . . . . . . . . . . . . . . . . . . . . . .
19.4 Ion Channels Have Gates that Open and Close . . . .
19.5 Families of Ion Channels Expressed in Plasma
Membrane of Neurons . . . . . . . . . . . . . . . . . .
19.6
Assembly of Ion Channels . . . . . . . . . . . . . . . .
19.7 Design and Function of Ion Channels . . . . . . . . .
19.8 Gates and Filters in Potassium Channels . . . . . . . .
19.9 Voltage-Gated Chloride Channels Form a
Double-Barreled Pore . . . . . . . . . . . . . . . . . .
19.10 Nicotinic Acetylcholine Receptors Are Ligand-Gated
Ion Channels . . . . . . . . . . . . . . . . . . . . . . . .
19.11 Operation of Glutamate Receptor Ion Channels . . .

465
466

Neural Rhythms . . . . . . . . . . . . . . . . . . . . . . . . . .
20.1 Heartbeat Is Generated by Pacemaker Cells . . . . .
20.2 HCN Channels’ Role in Pacemaker Activities . . . . .
20.3 Synchronous Activity in the Central Nervous
System . . . . . . . . . . . . . . . . . . . . . . . . . . .
20.4
Role of Low Voltage-Activated Calcium Channels . . . .
20.5 Neuromodulators Modify the Activities of
Voltage-Gated Ion Channels . . . . . . . . . . . . . . .
20.6 Gap Junctions Formed by Connexins Mediate
Rapid Signaling Between Cells . . . . . . . . . . . . .
20.7 Synchronization of Neural Firing . . . . . . . . . . . .
20.8 How Spindling Patterns Are Generated . . . . . . . .
20.9 Epileptic Seizures and Abnormal Brain Rhythms . . .
20.10 Swimming and Digestive Rhythms in Lower
Vertebrates . . . . . . . . . . . . . . . . . . . . . . . . .
20.11 CPGs Have a Number of Common Features . . . . .
20.12 Neural Circuits Are Connected to Other Circuits and
Form Systems . . . . . . . . . . . . . . . . . . . . . . .
20.13 A Variety of Neuromodulators Regulate Operation
of the Crustacean STG . . . . . . . . . . . . . . . . . .
20.14 Motor Systems Adapt to Their Environment and
Learn . . . . . . . . . . . . . . . . . . . . . . . . . . . .

487
487
489

Learning and Memory . . . . . . . . . . . . . . . . . . . . . . .
21.1 Architecture of Brain Neurons by Function . . . . . .
21.2 Protein Complexes’ Structural and Signaling Bridges
Across Synaptic Cleft . . . . . . . . . . . . . . . . . . .

468
470
472
474
476
478
478
479
480
483

492
492
494
495
497
498
498
499
502
504
505
506
511
512
514

xxiv

Contents

21.3

The Presynaptic Terminal and the Secretion of
Signaling Molecules . . . . . . . . . . . . . . . . . . .
PSD Region Is Highly Enriched in Signaling
Molecules . . . . . . . . . . . . . . . . . . . . . . . .
The Several Different Forms of Learning and
Memory . . . . . . . . . . . . . . . . . . . . . . . . .
Signal Integration in Learning and Memory
Formation . . . . . . . . . . . . . . . . . . . . . . . .
Hippocampal LTP Is an Experimental Model of
Learning and Memory . . . . . . . . . . . . . . . . .
Initiation and Consolidation Phases of LTP . . . . .
CREB Is the Control Point at the Terminus of the
Learning Pathway . . . . . . . . . . . . . . . . . . . .
Synapses Respond to Use by Strengthening and
Weakening . . . . . . . . . . . . . . . . . . . . . . . .
Neurons Must Maintain Synaptic Homeostasis . . .
Fear Circuits Detect and Respond to Danger . . . .
Areas of the Brain Relating to Drug Addiction . . .
Responses . . . . . . . . . . . . . . . . . . . . . . . .
Drug Addiction May Be an Aberrant Form of
Synaptic Plasticity . . . . . . . . . . . . . . . . . . . .
In Reward-Seeking Behavior, the Organism Predicts
Future Events . . . . . . . . . . . . . . . . . . . . . .

.

515

.

518

.

520

.

521

.
.

523
524

.

525

.
.
.
.

526
528
529
529

.

531

.

532

.

533

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

539

Index

553

21.4
21.5
21.6
21.7
21.8
21.9
21.10
21.11
21.12
21.13
21.14
21.15
21.16

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Guide to Acronyms

This Guide to Acronyms contains a list arranged alphabetically of commonly
encountered acronyms all of which are discussed in the text. There are a
number of instances where the same acronym has more than one usage. In
some cases, the correct meaning can be discerned from the way the acronym
is denoted, but in other cases, the correct usage must be deduced from the
context. In the text, proteins are written starting with a capital letter, while
the genes encoding the proteins are written all in lowercase letters. Protein
names are, for the most part, not included in the list of acronyms. Proteins
appearing in the list with names ending in numerals such as Ste2 are entered
once; names of proteins of the same spelling with different numerals (e.g.,
Ste7, Ste11 in the case of Ste2) can be readily deduced.
5-HT

5-hydroxytryptamine (serotonin)

AA
AC
ACE
ACF
ACh
ACTH
AFM
AGC
AHL
AIDS
AIF
AIP
AKAP
ALK
ALS

arachidonic acid
angiotensin-converting enzyme
ATP-dependent chromatin assembly and remodeling factor
acetylcholine
a disintegrin and metalloprotease
attention-deﬁcit hyperactivity disorder
atomic force microscopy
PKA, PKG, PKC family
acetyl homoserine lactase
acquired immunodeﬁciency syndrome
apoptosis inducing factor
autoinducing peptides
A-kinase anchoring protein
activin receptor-like kinase
amytrophic lateral sclerosis
xxv

xxvi

Guide to Acronyms

AMP
AMPA
AMPK
ANT
APC
APC
APP
ARC-L
Arf
ARF
ARR
ATM
ATP
ATR
AVN
AVP

a-amino-3-hydroxyl-5-methyl-4-isoxazole propionate acid
AMP-dependent protein kinase
antigen-presenting cell
amyloid b protein precursor
activation-recruited coactivator-large
alternative reading frame (of exon 2)
Arabidopsis response regulator
ataxia-telangeictasia mutated
atrioventricular node
vasopressin

Bcl-2
BCR
BDNF
BER
BFGF
BIR
BLV
BMP
BRCA1
BRCT
BRE
bZIP

B cell leukemia 2
B-cell receptor
brain-derived neurotrophic factor
base excision repair
basic ﬁbroblast growth factor
baculoviral IAP repeat
bovine leukemia virus
bone morphogenetic protein
breast cancer 1
BRCA1 C-terminal
TFIIB recognition element
basic region leucine zipper

C1
CaM
CaMKII
cAMP
CAP
CAPRI
CaR
CARD
CB
CBP
CBP
CD
Cdc25
Cdk

protein kinase C homology-1
caspase-activated deoxyribonuclease
calmodulin
calcium/calmodulin-dependent protein kinase II
cyclic AMP
catabolite activator protein
calcium-promoted Ras inactivator
extracellular calcium receptor
caspase recruitment domain
CaMK/SH3/guanylate kinase domain protein
Cajal body
complement binding protein
CREB binding protein
cluster of differentiation
cell division cycle (protein) 25
cyclin-dependent kinase

Guide to Acronyms

cDNA
CFP
CFTR
cGMP
CHRAC
Chromo
Ci
Ck2
ClC
Clk
CMGC
CNG
CNS
CNTF
CoA
COX
CPG
CR
CRD
CRE
CREB
CRF
CRH
CRSP
CSF
cSMAC
CST

complementary DNA
cyan ﬂuorescent protein
cystic ﬁbrosis transmembrane conductance regulator
cyclic guanosine monophosphate
chromatin accessibility complex
chromatin organization modiﬁer
cubitus interruptus
casein kinase-2
chloride channel of the CLC family
cyclin-dependent kinase-like kinase
CDK, MAPK, GSK-3 CLK, CK2
cyclic nucleotide-gated
central nervous system
ciliary neurotrophic factor
acetyl coenzyme A
cyclo-oxygenase
central pattern generator
consensus repeat
cysteine-rich domain
cAMP response element
cAMP response element-binding protein
corticotropin-releasing factor
corticotropin-releasing hormone
coactivator required for Sp1 activation
cerebrospinal ﬂuid
central supramolecular activation cluster
cortistatin

DA
DAG
DAT
dATP
DC
DCC
DD
DED
DEP
DFF
Dhh
DIABLO
DISC
DIX
DLG
DNA
DNA-PK
DPE

dopamine
diacylglycerol
dopamine transporter
dendritic cell
deleted in colorectal cancer
death domain
death effector domain
disheveled, egl-10, and pleckstrin
DNA fragmentation factor
desert hedgehog
direct IAP binding protein with low pI
death-inducing signaling complex
disheveled and axin
discs large
deoxyribonucleic acid
DNA-dependent protein kinase
downstream promoter element

xxvii

xxviii

Guide to Acronyms

DR
DSB
DSL
dsRNA

death receptor
double-strand break
delta/serrate/lin
double-stranded RNA

E
ECF
ECM
EEG
EGF
EGFR
eIF
EPEC
ER
ERK
ESCRT
ESE
ESI
ESS
EVH1

extracytoplasmic function
extracellular matrix
electroencephalographic
epidermal growth factor
epidermal growth factor receptor
eukaryotic initiation factors
enteropathogenic E. coli
endoplasmic reticulum
extracellular signal-regulated kinase
endosomal-sorting complexes required for transport
exonic splice enhancer
electrospray ionization
exonic splice silencer
enabled/vasodilator-stimulated phosphoprotein homology-1

FA
FAK
FAT
FH
FHA
FNIII
FRAP
FSH
FYVE

Fas-associated death domain
ﬁbronectin type III
ﬂuorescence recovery following photobleaching
follicle-stimulating hormone
Fab1p, YOTB, Vac1p, Eea1

GABA
GAP
GAS
GAS
GDI
GDNF
GDP
GEF
GFP
GFR
GH
GHIH
GHRH

g-aminobutyric acid
GTPase-activating protein
group A streptococcus
interferon-gamma activated site
GDP dissociation inhibitors
glial-derived neurotrophic factor
guanosine diphosphate
guanine nucleotide exchange factor
green ﬂuorescent protein
growth factor receptor
growth hormone
growth hormone-inhibiting hormone
growth hormone-releasing hormone

Guide to Acronyms

GIRK
GKAP
GPCR
GPI
GRH
GRIP
GRK
GSK-3
GTP

G protein-linked inward rectiﬁed K+ channels
guanylate kinase-associated protein
G protein-coupled receptor
glycosyl phosphatidyl inositol
glutamate receptor interacting protein
G protein-coupled receptor kinase
glycogen synthase kinase-3
guanosine triphosphate

HA
HAT
HDAC
hGH
HGT
Hh
HHV
HIV
HK
HLH
HNC
hnRNP
HOG
HPt
HR
Hsp
HSV-1
hTERT
HTH
HTLV-1
hTR
HtrA2

histamine
histone acetyltransferase
histone deacetylase
human growth hormone
horizontal gene transfer
hedgehog
human herpesvirus
human immunodeﬁciency virus
histidine kinase
helix-loop-helix
hyperpolarization-activated cyclic nucleotide gated
heterogeneous nuclear RNP
high osmolarity glycerol
histidine phosphotransfer
homologous recombination
heat shock protein
herpes simplex virus type 1
human telomerase reverse transcriptase
helix-turn-helix
human T lymphotropic virus type 1
human telomerase RNA
high temperature requirement factor A2

IAP
ICAM
ICE
IEG
IFN
Ig
IGC
IgCAM
IGluR
IGluR
Ihh

inhibitor of apoptosis
interleukin-1b converting enzyme
immediate early gene
interferon
immunoglobulin
interchromatin granule clusters
inhibitory glutamate receptor ion channel
ionotropic glutamate receptor
Indian hedgehog

xxix

xxx

Guide to Acronyms

IL
ILP
IN
Inr
InsP3R
IP
IPSP
IRAK
IRES
IRF
IS
IS
ISE
ISRE
ISS
ISWI
ITAM

interleukin
IAP-like protein
integrase
initiator
inositol (1,4,5) triphosphate receptor
Ischemic preconditioning
inhibitory postsynaptic potential
IL-1R-associated kinase
internal ribosomal entry site
interferon regulatory factor
immunological synapse
intracellular stores
intronic splice enhancer
interferon stimulated response element
intronic splice silencer
imitation SWI
immunoreceptor tyrosine-based activation motif

Jak
JNK

Janus kinase
c-Jun N-terminal kinase

KSHV

Kaposi’s sarcoma-associated herpesvirus

L
LAMP
LANA-1
LH
LNR
LNS
LPS
LRR
LTD
LTP
LTR
LZ

late (domain)
latency-associated membrane protein
latency-associated nuclear antigen type 1
luteinizing hormone
lin/notch repeat
laminin, neurexin, sex hormone-binding globulin
lipopolysaccharides
leucine-rich repeat
long-term depression
long-term potentiation
long terminal repeat
leucine zipper

MA
MAGE
MALDI
MAOI
MAP
MAPK
MCP
MD
MH1
MHC

matrix
melanoma-associated antigen
matrix-assisted laser desorption ionization
monoamine oxidase inhibitor
mitogen-activated protein
mitogen-activated protein kinase
methyl-accepting chemotaxis protein
molecular dynamics
major histocompatibility complex

Guide to Acronyms

MIP
MM
MMP
MMR
MRI
mRNA
MSH
MVB

macrophage inﬂammatory protein
molecular mechanics
matrix metalloproteinase
mismatch repair
magnetic resonance imaging
messenger RNA
melanocyte-stimulating hormone
multivesicular body

NAc
nAChR
NAIP
NBS
NC
NCAM
NE
NER
NES
NFAT
NF-kB
NGF
NH
NHEJ
NICD
NKA
NKB
NLS
NMDA
NMR
NPC
NRAGE
NRIF
NSAID
NSF
NURF

nucleus accumbens
nicotinic acetylcholine receptor
p75-associated cell death executioner
neuronal inhibitory apoptosis protein
Nijmegem breakage syndrome
nucleocapsid
nucleotide excision repair
nuclear export signal (sequence)
nuclear factor of activated T cells
nuclear factor kappa B
nerve growth factor
amide (molecule)
nonhomologous end joining
notch intracellular domain
neurokinin A
neurokinin B
nuclear localization signal (sequence)
N-methyl-d-aspartate
nuclear magnetic resonance
nuclear pore complex
neurotrophin receptor-interacting MAGE homolog
neurotrophin receptor-interacting factor
nonsteroidal anti-inﬂammatory drug
N-ethylmaleimide-sensitive fusion protein
nucleosome remodeling factor

OCT
OPR
OT

octopamine
octicopeptide repeat
oxytocin

PACAP
PAGE
PBP
PCP
PCR

polyacrylamide gel electrophoresis
periplasmic binding protein
planar cell polarity
polymerase chain reaction

xxxi

xxxii

Guide to Acronyms

PDB
PDE
PDGF
PDK
PDZ
PGHS
PH
PIC
PIH
PIKK
PIP
PKA
PKB
PKC
PKG
PKR
PLA2
PLC
PMCA
PNS
POMC
PP-II
PRH
PRL
PS
PSD
PSD-95
pSMAC
PTB
PTH
PTHrH
PTPC
PYD

protein data bank
phosphodiesterase
platelet-derived growth factor
phosphoinositide-dependent protein kinase
PSD-95, DLG, ZO-1
endoperoxide H synthase
pleckstrin homology
pre-initiation complex
prolactin-inhibiting hormone
phosphoinositide 3-kinase related kinase
phosphatidylinositol phosphatase
protein kinase A
protein kinase B
protein kinase C
protein kinase G
protein kinase R
phospholipase A2
phospholipase C
plasma membrane calcium ATPase
peripheral nervous system
pro-opiomelanocortin
polyproline (helix)
prolactin-releasing hormone
prolactin
pseudosubstrate
postsynaptic density
postsynaptic density protein of 95 kDa
peripheral supramolecular activation cluster
phosphotyrosine binding
parathyroid hormone
parathyroid hormone related protein
permeability transition pore complex
pyrin domain

QM

quantum mechanics

RACK
RAIP
RE
REM
RF
RGS
RH
RHD
RIP

receptor for activated C-kinase
Arg-Ala-Ile-Pro (motif)
responsive (response) element
rapid eye movement
regulator-of-G-protein signaling
RGS homology
rel homology domain
receptor-interacting protein

Guide to Acronyms

RNA
RNP
ROS
RPA
RR
RRE
RRM
rRNA
RSC
RT
RTK
RyR

ribonucleic acid
ribonucleoprotein
reactive oxygen species
replication protein A
response regulator
rev response region
RNA recognition motif
ribosomal RNA
remodels the structure of chromatin
reverse transcriptase
receptor tyrosine kinase
ryanodine receptor

S/T
S6K
SAGA
SAM
SAM
SAN
SARA
SC1
SCR
SDS
SE
SERCA
SH2
Shh
SIV
Ski
Smac
SMCC
SN
SNAP
SNARE
SNF
SnoN
snRNA
snRNP
SODI
Sos
SP
SSRI
SST
STAT
Ste2

serine/threonine
ribosomal S6 kinase
sterile a motif
sinoatrial node
Schwann cell factor-1
short consensus repeat
sodium dodecyl sulfate
spongiform encephalopathies
sarco-endoplasmic reticulum calcium ATPase
Src homology-2
sonic hedgehog
simian immunodeﬁciency virus
Sloan–Kettering Institute proto-oncogene
second mitochondrial activator of caspases
SRD- and MED-containing cofactor complex
sunstantia nigra
soluble NSF-attachment protein
soluble NSF-attachment protein receptor
sucrose nonfermenting
ski-related novel gene N
small nuclear RNA
small nuclear ribonucleoprotein particle
superoxide dismutase
Son-of-sevenless
substance P
selective serotonin reuptake inhibitor
somatostatin
signal transducer and activator of transcription
sterile 2

xxxiii

xxxiv

Guide to Acronyms

STG
STRE
STTK
SUMO
SWI

stomatogastric ganglion
stress responsive element
serine/threonine and tyrosine kinase
small ubiquitin-related modiﬁer
(mating type) switch

TACE
TAF
TAR
TBP
TCA
TCR
TF
TGF-b
TGIF
TM
TNF
TOF
TOP
TOR
TOS
TRAF
TRAIL
TRAP
TRF1
tRNA
TSH

tumor necrosis factor-a converting enzyme
TBP-associated factor
transactivating response (region)
TATA box binding protein
tricyclic antidepressants
T-cell receptor
transcription factor
transforming growth factor-b
TG3-interacting factor
transmembrane
tumor necrosis factor
time-of-ﬂight
terminal oligopyrimidine
target of rapamycin
Phe-Glu-Met-Asp-Ile (motif)
TNF-R-associated death domain
TNF receptor-associated factor
TNF-related apoptosis-inducing ligand
thyroid hormone receptor-associated protein
telomeric repeat binding factor 1
transfer RNA
thyroid-stimulating hormone

UP
UPEC
UTR

upstream (sequence)
uropathogenic E. coli
untranslated region

VAMP
VDAC
VEGF
VIP
Vps
VTA

vesicle-associated membrane protein
voltage-dependent anion channels
vascular endothelial growth factor
vasoactive intestinal peptide
vascular protein sorting
ventral tegmental area

Wg

wingless

XIAP

YFP

yellow ﬂuorescent protein

ZO-1

zona occludens 1

1
Introduction

Life on Earth is remarkably diverse and robust. There are organisms that
live in the deep sea and far underground, around hot midocean volcanic
vents and in cold arctic seas, and in salt brines and hot acidic springs. Some
of these creatures are methanogens that synthesize all their essential biomolecules out of H2, CO2 and salts; others are hyperthermophiles that use
H2S as a source of hydrogen and electrons, and still others are halophiles
that carry out a form of photosynthesis without chlorophyll. Some of these
extremeophiles are animallike, while others are plantlike or funguslike or
like none of these.
from organism to organism, all carry out the same core functions of metabolism, cell division and signaling in roughly the same manner. The underlying unity extends from tiny parasitic bacteria containing minimal
complements of genes to large differentiated multicellular plants and
animals. Each organism has a similar set of basic building blocks and
utilizes similar assembly principles. The myriad forms of life arise mostly
through rearrangements and expansions of a basic set of units rather than
different biochemistries or vastly different parts or assembly rules.

1.1 Prokaryotes and Eukaryotes
There are two basic forms of cellular organization, prokaryotic and eukaryotic. Prokaryotes—bacteria and archaeons—are highly streamlined unicellular organisms. Prokaryotes such as bacteria are small, typically 1 to 10
microns in length and about 1 micron in diameter. They may be spherical
(coccus), or rod shaped (bacillus), or corkscrew shaped (spirochette).
Regardless of their shape, prokaryotic cells consist of a single compartment
surrounded by a plasma membrane that encloses the cytoplasm and separates outside from inside. The genetic material is contained in a small
number, usually one, of double-stranded, deoxyribonucleic acid (DNA)
molecules, the chromosomes that reside in the intracellular ﬂuid medium
1

2

1. Introduction

(cytosol). Bacterial chromosomes are typically circular and are compacted
into a nucleoid region of the cytosol. Many bacterial species contain
additional (extra-chromosomal) shorter, circular pieces of DNA called
plasmids.
The bacterial plasma membrane contains the molecular machinery
responsible for metabolism and the sensory apparatus needed to locate
nutrients. When nutrients are plentiful the bacterial cell organization is
ideally suited for rapid growth and proliferation. There are two kinds of
bacterial cell envelopes. The envelopes of gram-positive bacteria consist of
a thick outer cell wall and an inner plasma membrane. Those of gramnegative bacteria consist of an outer membrane and an inner plasma membrane. A thin cell wall and a periplasmic space are situated between the two
membranes.The plasma membrane is an important locus of activity. In addition to being sites for metabolism and signaling, the plasma membrane and
cell wall are sites of morphological structures extending out from the cell
surface of the bacteria. These include ﬂagellar motors and several different
kinds of secretion systems.
Eukaryotic cells are an order of magnitude larger in their linear dimensions than prokaryotic cells. Cells of eukaryotes—protists, plants, fungi, and
animals—differ from prokaryotes in two important ways. First, eukaryotic
cells have a cytoskeleton, a highly dynamic meshwork of protein girders that
crisscross these larger cells and lend them mechanical support. Second,
eukaryotic cells contain up to ten or more organelles, internal compartments, each surrounded by a distinct membrane and each containing their
own complement of enzymes. In contrast to prokaryotes, core cellular functions such as metabolism are sequestered in these compartments.

1.2 The Cytoskeleton and Extracellular Matrix
The cytoskeleton and extracellular matrix perform multiple functions. The
cytoskeleton provides structural support, and serves as a transportation
highway and communications backbone. Chromosomes, organelles, and
vacuoles are transported along actin ﬁlaments and microtubules of the
cytoskeleton. Actin ﬁlaments are used for short distance transport, while
microtubules serve as a rail system for delivering cargo over long distances.
Signal molecules are anchored at sites along the cytoskeleton, and the
cytoskeleton functions as a communications backbone linking signaling
molecules in the plasma membrane and extracellular matrix (ECM) to
signaling units in the cell nucleus.
The extracellular matrix consists of an extended network of polysaccharides and proteins secreted by cells. The ECM provides structural support
for cells forming organs and tissues in multicellular eukaryotes. In plants,
the ECM is referred to as the cell wall and serves a protective role. Cells of
animals secrete a variety of signaling molecules onto the extracellular

1.3 Core Cellular Functions in Organelles

3

matrix, and these molecules guide cellular migration and adhesion during
development. The ECM is not a simple passive medium. Instead, signaling
between ECM and the cytoskeleton is maintained throughout development
The existence of a transport system in which large numbers of molecules can be moved along the cytoskeleton to and from the plasma membrane is important for signaling between cells in the body. In the immune
system, transport vacuoles move signal molecules called cytokines (antiinﬂammatory agents such as histamines, and antimicrobial agents that
attack pathogens) to the cell surface where they are secreted from the cell.
In the nervous system, neurotransmitters are moved over long distances
down the axon and into the axon terminal via transport vesicles. In addition to outbound trafﬁcking, there is inbound trafﬁcking. Surface components are continually being recycled back to the internal organelles, where
they are then either reused or degraded.

1.3 Core Cellular Functions in Organelles
In prokaryotes, a single outer membrane is sufﬁcient for membranedependent processes such as photosynthesis and oxidative phosphorylation
(respiration), and protein and lipid synthesis. However, a single membrane
is not adequate in eukaryotes because of the large, cubic increase in cell
volume. Nature’s solution to this design problem is a system of organelles
surrounded by membranes that perform membrane-speciﬁc cell functions
and sequester speciﬁc sets of enzymes. There are more than a half dozen
different kinds of organelles in a typical multicellular eukaryote. Organelles
present in typical multicellular eukaryotic cells are listed in Table 1.1, along
with their cellular functions.

Table 1.1. Organelles of the eukaryotic cell: The
principal functions of the proteins sequestered in these
organelles are listed in the second column.
Organelle
Mitochondria
Chloroplasts
Nucleus
Endoplasmic reticulum
Golgi apparatus
Lysosomes
Peroxisomes
Endosomes

Function
Respiration
Photosynthesis (plants)
Stores DNA; transcription and
splicing
Protein synthesis-translation
Processing, packaging, and shipping
Internalization of material

4

1. Introduction

Organelles are characterized by the mix of enzymes they contain and by
the assortment of proteins embedded in their membranes. Three kinds of
proteins—pores, channels, and pumps—embedded in plasma and organelle
membranes allow material to enter and leave a cell or organelle.
• Pores: Pore-forming proteins, or porins, are membrane-spanning proteins
found in the outer membrane of gram-negative bacteria, mitochondria
and chloroplasts. They form water-ﬁlled channels that enable hydrophilic
molecules smaller than about 600 Da to pass through the membrane in
and out of the cell or organelle. For example, bacterial porins allow nutrients to enter and waste products to exit the cell while inhibiting the
passage of toxins and other dangerous materials.
• Ion channels: These are membrane-spanning proteins forming narrow
pores that enable speciﬁc inorganic ions, typically Na+, K+, Ca2+ or Cl-, to
pass through cell membranes. Ion channels are an essential component
of the plasma membranes of nerve cells, where they are responsible for
all electrical signaling. Ion channels regulate muscle contractions and
processes associated with them, such as respiration and heartbeat, and
regulate osmobalance and hormone release.
• Pumps: Pumps are membrane-spanning proteins that transport ions and
molecules across cellular and intracellular membranes. While ion channels allow ions to passively diffuse in or out of cells along electrochemical
gradients, pumps actively transport ions and molecules.Thus, they are able
to act against electrochemical gradients, whereas ion channels cannot,
and maintain homeostatic balances within the cell. The transport involves
the performance of work and must be coupled to an energy source. A
variety of energy sources are utilized by pumps, including adenosine
triphosphate (ATP) hydrolysis, electron transfer, and light absorption.

1.4 Metabolic Processes in Mitochondria
and Chloroplasts
In all cells, energy is stored in the chemical bonds of adenosine triphosphate
(ATP) molecules. In metabolism, enzymes break down large biomolecules
into small basic components, synthesize new biomolecules out of those basic
components, and produce ATP. In catabolic processes such as glycolysis and
oxidative phosphorylation, large polymeric molecules are disassembled into
smaller monomeric units. The intermediates are then further broken down
into cellular building blocks such as CO2, ammonia, and citric acid. Key
goals of the catabolic processes are the production of ATP and reducing
power needed for the converse, anabolic processes—the assembly of cellular building blocks into small biomolecules, the synthesis of components,
and their subsequent assembly into organelles, cytoskeleton, and other cellular structures.

1.5 Cellular DNA to Chromatin

5

Glycolysis takes place in the cytoplasm while the citric acid cycle occurs
in the mitochondrial matrix. Five complexes embedded in the inner mitochondrial membrane carry out oxidative phosphorylation (respiration). The
constituents of the ﬁve respiratory complexes—enzymes of the electron
transport chain—pump protons from the matrix to the cytosol of the mitochondria, then use the free energy released by these actions to produce ATP
photosystems I and II, function in chroloplasts.
Chloroplasts and mitochondria are enclosed in double membranes. The
inner membrane of a mitochondrion is highly convoluted, forming structures called cristae. A similar design strategy is used in chroloplasts. The
inner membrane of a chloroplast encloses a series of folded and stacked
thylakoid structures. These designs give rise to organelles possessing large
surface areas for metabolic processes. The ATP molecules are used not only
for anabolism, but also in other core cellular processes, including signaling,
where work is done and ATP is needed.
The relocation of the machinery for metabolism from the plasma membrane to internal organelles is a momentous event from the viewpoint of
signaling. It not only provides for a far greater energy supply but also frees
up a large portion of the plasma membrane for signaling. In eukaryotic cells,
the plasma membrane is studded with large numbers of signaling proteins
that are either embedded in the plasma membrane, running from the
outside to the inside, or attached to one side or the other by means of a
tether.

1.5 Cellular DNA to Chromatin
Cellular DNA is sequestered in the nucleus where it is packaged into chromatin. As shown in Figure 1.1, all organisms on Earth today use DNA to
encode instructions for making proteins and use RNA as an intermediate
stage. This fundamental aspect of all of biology was ﬁrmly established by
Crick and Watson in their pioneering study in the mid-twentieth century.
In the ﬁrst step—transcription—protein machines copy selected portions
of a DNA molecule onto mRNA templates. In prokaryotes the ribosomal machinery operating concurrently with the transcription apparatus
translates the mRNA molecules into proteins. In eukaryotes there is an

Figure 1.1. Genes and proteins: Depicted is the two-step process in which DNA
nucleotide sequences, or genes, are ﬁrst transcribed onto messenger RNA (mRNA)
nucleotide sequences, and then these templates are used to translate the nucleotide
sequences into amino acid sequences.

6

1. Introduction

intermediate step: Protein machines known as spliceosomes edit the initial
RNA transcripts called pre-mRNA molecules, and produce as their output
mature mRNA molecules. The ribosomal machines then translate the
mature mRNAs into proteins.
In eukaryotes, cellular DNA is sequestered within the nucleus, and this
organelle is the site of transcription and splicing. The nucleus is enclosed in
a concentric double membrane studded with large numbers of aqueous
pores. The pores enable the two-way selective movement of material
between the nucleus and cytoplasm. Since proteins are synthesized in the
cytoplasm, nuclear proteins—proteins that carry out their tasks inside the
nucleus—are imported from the cytoplasm to the nucleus, while messenger
RNAs and ribosomal subunits are exported. A variety of structural and regulatory proteins regularly shuttle back and forth between nucleus and cytoplasm. The pores, referred to as nuclear pore complexes, are composed of
about 100 proteins and are approximately 125 MDa in mass. All particles
entering or exiting the nucleus pass through these large pores. Small particles passively diffuse through the pores while large macromolecules are
actively transported in a regulated fashion.
The sequestering of the DNA within a nucleus is advantageous for
several reasons. It insulates the DNA against oxidative byproducts of
normal cellular processes taking place in the cytoplasm and from mechanical forces and stresses generated by the cytoskeleton. It separates the
transcription apparatus from the translation machinery, thereby allowing
independent control of both, and it makes possible the intermediate ribonucleic RNA editing (splicing) stage.
Eukaryotic DNA is wrapped in proteins called histones and tightly packaged into a number of chromosomes in the nucleus. As a result of sequestering and packaging, far more information can be stored in eukaryotic
DNA than in prokaryotic DNA. The wrapping up of the DNA to form chromatin enables the cells to regulate transcription of its genes in a particularly simple way that is not possible in prokaryotes. When the DNA is
wrapped tightly about the histones the DNA cannot be transcribed since
the sites that need to be accessible to the transcription machinery are
blocked. When the wrapping is loosened, these sites become available and
transcription can be carried out. A large number of eukaryotic regulators
of transcription operate on a chromatin-level of organization, making transcription easier or harder by manipulating chromatin.

1.6 Protein Activities in the Endoplasmic Reticulum
and Golgi Apparatus
The endoplasmic reticulum (ER) encompasses more than half the membrane surface of a eukaryotic cell and about 10% of its volume. It is
the primary site of protein synthesis (translation), fatty acid and lipid

1.6 Protein Activities in the Endoplasmic Reticulum and Golgi Apparatus

7

synthesis, and bilayer assembly. It is divided into a rough ER and a smooth
ER. The rough ER gets its name from the presence of numerous ribosomes
bound to its cytosolic side.The rough ER is the site where membrane-bound
proteins, secreted proteins, and proteins destined for the interior (lumen)
of organelles are synthesized. The smooth ER lacks ribosomes. It is the site
where lipids are synthesized and assembled and where fatty acids such as
steroids are synthesized. It stores intracellular Ca2+ and assists in carbohydrate metabolism and in drug and poison detoxiﬁcation.
Not all ribosomes are bound to the endoplasmic reticulum. Instead, there
are two populations of ribosomes, bound and free. Bound ribosomes are
attached to the rough ER, but free ribosomes are distributed in the cytosol.
The free ribosomes are otherwise identical to their membrane-bound
counterparts, and they synthesize cytosolic proteins.
In order for a protein to carry out its physiological function it must fold
into and maintain its correct three-dimensional shape. Proteins are subject
to several different kinds of stresses. Abnormal conditions, such as elevated
or reduced temperatures and abnormal pH conditions, can result in the
denaturization (unfolding) or misfolding of proteins so that they no longer
have the correct shape and cannot function. Another type of condition that
can affect the shape of the protein is molecular crowding. A group of small
protein-folding machines called heat shock proteins or stress proteins or
molecular chaperones guide nascent polypeptide chains to the correct location and maintain the proteins in folded states that permit rapid activation
and assembly. They also refold partially unfolded proteins. In those cases
where the proteins cannot be returned to a proper state the misfolded proteins are tagged for destruction by another set of small protein machines
called proteases. These proteolytic machines enable a cell to degrade and
recycle proteins that are no longer needed, as well as those that are
damaged and cannot be refolded properly by the stress proteins.
Newly synthesized proteins are processed, subjected to quality control
with respect to their folding, and then shipped to their cellular destinations.
Prosthetic groups—sugars and lipids—are added to proteins destined for
insertion in the membrane to enable them to attach to the membranes.
These modiﬁcations are made subsequent to translation in several stages,
as the proteins are passed through the ER and Golgi apparatus. The overall
process resembles an assembly line that builds up the proteins, folds them,
inserts them into membranes, sorts them, labels them with targeting
sequences, and ships them out to their cellular destinations (Figure 1.2).
The Golgi apparatus consists of a stacked system of membrane-enclosed
sacs called cisternae. Some of the polysaccharide modiﬁcations needed to
make glycoproteins are either made or started in the rough ER. Proteins,
especially signaling proteins destined for export (secretion) from the cell
or for insertion into the plasma membrane, are sent from the rough ER to
the smooth ER where they are encapsulated into transport vesicles pinched
off from the smooth ER. The transport vesicles are then sent to the Golgi

8

1. Introduction

Figure 1.2. Movement of proteins through the endoplasmic reticulum and Golgi
apparatus: Proteins synthesis and processing start with the export of mRNAs from
the nucleus to the ribosome-studded rough endoplasmic reticulum. Nascent proteins synthesized in ribosomes are processed and then shipped in transport vesicles
to the Golgi. They pass through the cis (nearest the ER) and trans (furthest from
the ER) Golgi, and the ﬁnished products are then shipped out to their lysosomal
and the plasma membrane destinations.

for further processing and eventual shipping to their cellular destinations.
The Golgi apparatus takes the carbohydrates and attaches then as oligosaccharide side chains to some of these proteins to form glycoproteins and to
complete modiﬁcations started in the rough ER. Both proteins and lipids
are modiﬁed in the Golgi. Other proteins, synthesized as inactive precursor
molecules, are processed to produce activated forms in the Golgi. Modiﬁed
proteins are enclosed in transport vesicles, pinched off from the Golgi, and
shipped to destinations such as the plasma membrane and the extracellular matrix (Figure 1.2).

1.7 Digestion and Recycling of Macromolecules
Digestion and the recycling of macromolecules take place in a network of
transport and digestive organelles. The last three organelles listed in Table
1.1 are involved in digestion. Peroxisomes and lysosomes contain sets of
enzymes used for digestion of macromolecules. In these highly acidic environments, macromolecules are broken down into smaller molecules. By
sequestering enzymes in these compartments the rest of the cell is protected
from the digestive properties of the enzymes. Lysosomes are small
organelles that degrade ingested bacteria and nonfunctional organelles.

1.8 Genomes of Bacteria Reveal Importance of Signaling

9

Perixosomes are utilized for the sequestering of oxidative enzymes. Their
digestive enzymes degrade fatty acids to small biomolecules. Peroxisomes
are a diverse collection of organelles, each with its own mix of enzymes.
Some peroxisomes detoxify harmful substances. Others, in plants, convert
fatty acids to sugars and carry out photorespiration.
Endosomes, the ﬁnal set of eukaryotic organelles listed in Table 1.1, facilitate the transport of extracellular material and membrane proteins from
the plasma membrane to lysosomes for degradation. Several kinds of
organelles—early endosomes, carrier vesicles, and late endosomes—form a
transport and sorting system that moves ingested foodstuffs, captured
pathogens, dead material, and ligand-bound receptors and lipid plasma
membrane components to the lysosomes and other cellular compartments
In summary, cells are highly dynamic entities; materials are continually
being brought in and out of the cell, and moved back and forth to the
surface. There is a continual ﬂow of outbound trafﬁc of cargo from the ER
and Golgi to organelles and the cell surface, and there is a continual ﬂow
of inbound trafﬁc from the cell surface to lysosomal and peroxisomal compartments. Signal proteins destined for the plasma membrane and for secretion are packaged into vacuoles. These transient structures are formed by
pinching off portions of membrane. The vacuoles are moved over the rail
system and fused with membranes at the destination (exocytosis). Similarly,
materials from the cell surface are captured, packaged into vesicles, and
shipped to digestive compartments for processing (endocytosis).

1.8 Genomes of Bacteria Reveal Importance
of Signaling
Insights into the importance of signaling can be obtained from analyses of
the composition of the genomes of bacteria. Prokaryotes are tiny organisms
that tell us a lot about signaling. Prokaryotic genomes range in size from
0.5 MBp to more than 12 MBp. The Mycoplasmas sit at the bottom of this
range; they are minimal organisms. They occupy very limited ecological
niches, are restricted in their metabolic capabilities, and have the smallest
genomes of any organisms. Genes encoding signal proteins are largely nonexistent, taking up no more than about 1% of their genomes. Prokaryotes
with somewhat larger genomes include the archaeal extremophiles mentioned at the beginning of the chapter, and many obligate bacterial parasites that are the causal agents of diseases in humans. These organisms
live in fairly constant and unvarying environments, and as a result their
requirements on signaling and control are modest. Their signaling proteins
account for no more than a few percent of their genomes.
Prokaryotes that can alter their metabolic and reproductive strategies to
match their changing environmental conditions have larger genomes than

10

1. Introduction

those that live under constant conditions. Because of their ability to adapt
their physiology to their environment, these bacteria may be referred to as
environmentalists. Escherichia coli and Psuedomonas aeruginosa are typical
environmentalists. Their genomes are ﬁve to ten times larger than the
Mycoplasmas and encode ensembles of signaling and regulatory proteins
that are 50 to 100 times larger than those of the Mycoplasmas. As a result,
they are able to thrive in a variety of environments—soil, water, air—and
they deal with many different stresses. Thus, not only are the genomes
becoming larger as the bacteria become more versatile and adaptive, but
the fractions of the genomes devoted to regulatory functions are increasing as well.
Colony-forming bacteria have even larger genomes. These bacteria can
not only cope with environmental changes and stresses, but also they can
assemble into colonies and exhibit a limited form of differentiation. Their
genomes are the largest of all the prokaryotes, and the fraction of their
genomes devoted to signaling and control approaches or exceeds 10%. An
example of a prokaryote that exhibits environmental diversity and colonial
behavior is Streptomyces coelicolor. This versatile soil bacterium is used
for the production of antibiotics such as tetracycline and erythromycin. Its
signaling component accounts for 12% of its genome.
As might be expected, the genomes for multicellular plants and animals
are larger than those for even the most sophisticated prokaryotes, but not
by as much as one might expect. The ﬁrst estimates from the complete
sequencings of the human genome are in the range of 26,000 genes, of which
roughly one quarter is devoted to signaling. There are still some genes that
remain to be identiﬁed, and when further analyses are completed there may
be as many as 32,000 to 40,000 genes. This number appears to be astonishingly low. It is scarcely a factor of three larger than the genomes for some
of the bacteria. Furthermore, the genome for the bacterium S. coelicolor is
nearly as large as that for the highly differentiated, multicellular fruit ﬂy
Drosophila melanogaster.

1.9 Organization and Signaling of Eukaryotic Cell
Eukaryotic cell organization and expanded signaling capabilities make
multicellularity possible.The signiﬁcance of these observations is that something more than a simple increase in genome size produced the greatly
increased complexity associated with multicellular plants and animals. The
answer to the question of what is happening has several parts. It involves
the way eukaryotic cells are organized and the way the expanded repertoire of signaling proteins is organized and used. There are four broad
categories of environmental and regulatory signals. These are as follows:
• Physical and chemical sensations indicative of external conditions.
• Contact signals indicative of ECM-to-cell and cell-to-cell adhesion.

1.9 Organization and Signaling of Eukaryotic Cell

11

• Signals sent from one cell to another that allow the sender to regulate
gene expression and other cellular responses in the recipient.
• Signals and sensations indicative of internal stresses and balances.
The ﬁrst category includes a diverse set of physical and chemical signals.
Most organisms can neither alter their environments nor move over large
strategies to match the environmental conditions in which they ﬁnd themselves. In this grouping of signals are environmental cues important to unicellular organisms, such as light, temperature, osmolarity, pH, and nutrients.
Also included in this category are signals such as odorants and tastants
detected by sensory organs in multicellular animals, or metazoans.
The next category encompasses contact signals between surfaces and is
speciﬁc to multicellular organisms. Proteins embedded in the plasma membrane and in the ECM convey contact signals. These signals allow cells to
establish and maintain physical contact with supporting structures within
the body, and mediate two-way communication between cells in physical
contact. This category is greatly expanded in vertebrates, and includes elements of the immune system such as antibodies that have evolved from
The third category of signals consists of the cell-to-cell messages. This
category includes pheromones, chemical signals that promote mating and
colonial behavior in unicellular organisms, and it includes the signals in
multicellular plants and animals that allow cells in tissues and organs to
work together. In humans, there are several systems of tissues, organs, and
glands that continually send and receive chemical messages. Cells of the
immune systems send and receive cytokines; cells residing in glands of the
endocrine system secrete hormones; and neurons in the nervous system
communicate using neurotransmitters and neuromodulators. Embryonic
development is controlled from cell division to cell division by programs of
gene expression. The category of cell-to-cell signals encompasses the signals
that help establish cell fate and polarity during development, and the
growth factor and hormonal signals that shape and guide the programs of
cell growth and differentiation.
The last category consists of signals generated within the cell that help
maintain proper internal balances, or homeostasis. This category includes
signals indicative of internal stresses such as improper pH conditions, excessive temperatures, and water imbalances. Macromolecules such as DNA
and proteins are marginally stable under physiological conditions. Cellular
by oxidative byproducts of normal cellular processes. In addition, DNA
strand breaks can occur during the DNA replication stage that precedes
mitosis and meiosis. All cells, prokaryotic and eukaryotic, possess DNA
repair systems that continually sense and repair single and double strand
breaks. In multicellular organisms, whenever DNA damage is detected and

12

1. Introduction

found to be irreparable, the cell is targeted for destruction. The process of
eliminating a cell that is damaged, or infected, or deemed to be no longer
needed is called apoptosis. The apoptosis, or cell suicide, machinery cuts up
(cleaves) and disassembles large cellular components—DNA and membranes—and packages the cellular contents in such a way that they do no
harm to neighboring cells. The last category of signals includes those that
integrate growth and survival signals with repair and apoptosis signals,
determining whether a cell grows and proliferates, repairs itself, or dies.

1.10 Fixed Infrastructure and the Control Layer
The proteins responsible for signaling and control form a control layer. This
layer sits on top of a lower layer, the ﬁxed infrastructure, which is responsible for core cellular functions such as metabolism and replication. Proteins belonging to two layers carry out their cellular roles synergistically.
Proteins belonging to the control layer make contact with elements of the
ﬁxed infrastructure at well-deﬁned loci, or control points, where they exert
their regulatory functions, but don’t otherwise interfere with the machinelike operations of those proteins. In turn, eukaryotic architecture, with its
organelles and cytoskeleton, is especially well suited for signaling and is
extensively exploited for that purpose.
Unlike the proteins of the ﬁxed infrastructure, the proteins belonging
to the control layer are not sequestered within a single compartment or
organelle. Instead, they form a meshwork of signaling pathways that extend
throughout the cytoplasm and into organelles, most notably the nucleus,
but other as well. Each signaling pathway has a start point and an end
point. The start points are typically proteins that function as sensors and
as receivers of signals from other cells. These proteins are often associated
with the plasma membrane, where outside meets inside, and are referred to
as receptors. The receptors not only detect the signals but also convert them
into forms that can be understood and processed further within the cell.
This conversion process is called signal transduction.The signaling pathways
terminate at sites where the elements of the control layer come into contact
with the components of the ﬁxed infrastructure.These are the control points
where the environmental and regulatory signals are converted into cellular
responses.
The cell nucleus contains large numbers of control points, and when these
sites are the end points the signaling process is termed gene regulation.
Alternatively, and more generally, the control processes carried out by
signaling proteins is referred to as cell regulation. One of the key factors
making possible the emergence of complex multicellular organisms is the
formation of gene regulatory networks composed of transcription regulating proteins, or transcription factors, and the DNA sequences they bind.

1.11 Eukaryotic Gene and Protein Regulation

13

Table 1.2. Comparison of proteins in the ﬁxed infrastructure and control layer.
Property
Location
Mobility
Structure
Function

Fixed infrastructure
Machines/factories in organelles
Little
Longer
Fixed
Unifunctional

Control layer
Complexes in subcompartments
Considerable
Shorter
Variable
Multifunctional

Changes in how these networks are built rather than in the genes they
control underlie the increased complexity of multicellular life.
Signal proteins are not only the messengers but also the messages. Since
the messages must be conveyed from one place to another, mobility is a
key property of the proteins. Mobility is less important for functions such
as metabolism carried out as part of large molecular machines in the
organelles. Another way signal proteins differ from the other proteins is in
the presence of post-translational modiﬁcations. Signal proteins are subjected to a host of post-translational modiﬁcations. Some are made in the
ER and Golgi as part of the ﬁnishing process, but others, to be discussed in
the next chapter, are part of the signaling process itself. These alterations
endow the proteins with switchlike response properties, turning them on
and off.This property is absolutely essential for a signaling element, keeping
it available for conveying a message, but in an off-conﬁguration until an
activating signal arrives.
There are several other ways that proteins belonging to the control layer
and ﬁxed infrastructure differ from one another (Table 1.2). The function
of a protein, that is, what it does, is determined by its associations, and by
where and when it establishes them. Proteins that function as part of the
transcription machinery in the nucleus or as part of the electron transport
chain in the mitochondria, usually have a single purpose, and they carry
out this task over and over. The signaling proteins form complexes too.
However, the protein complexes are smaller than the large machines used
for metabolism and replication, and the associations and interactions are
more variable. They can be different in different cell types and will even
vary somewhat over time in the same cell type. Because of this ﬂexibility,
signaling proteins are multifunctional, or pleiotropic, in their actions.

1.11 Eukaryotic Gene and Protein Regulation
Eukaryotic genes and proteins can be regulated in several ways. One of the
most important consequences of switch from prokaryotic to eukaryotic cell
organization is the creation of a large number of ways of controlling the

14

1. Introduction

mix of proteins being expressed at any given time in a cell. In place of DNA
regulation of prokaryotic gene and protein expression there is now a multiplicity of eukaryotic control mechanisms. Gene and protein expression can
be controlled through
•
•
•
•
•

DNA regulation
histone modiﬁcation
splicing regulation
translation regulation
nuclear import/export

Histone modiﬁcation has already been discussed. Nuclear import and
export refers to a strikingly simple and widely used form of regulation.
Many transcription factors are parked in convenient locations in the
cytoplasm awaiting activating signals. When activated they diffuse to
the nucleus, where they carry out their transcriptional activities. Exporting
the proteins back out of the nucleus into the cytoplasm is an equally simple
way of terminating their activities.
Translational regulation allows for the placement of messenger RNAs
(mRNAs) in sites where the proteins they encode might be needed at a
later time. Asymmetric distributions of mRNAs and proteins in cells early
in development lead to offspring that are dissimilar. Localized populations
of mRNAs are utilized as part of adult physiology. They are used, for
example, in nerve cells to avoid long time delays arising when signals must
be sent over long distances to the nucleus and the resulting proteins shipped
back out to the distant extrema.
The observation that for every one unique gene there is one unique
protein is correct as far as it goes, but in eukaryotes one must append the
equally true statement that the unique proteins come in several “ﬂavors”.
expressed in different cell types. Eukaryotic genes are larger than their
prokaryotic counterparts and contain greater numbers of units called
domains (these are discussed in the next chapter). In vertebrates there are,
on the average, about three alternative spliced forms, or ﬂavors, for each
protein. Signals sent to the control points in the splicing machinery help
determine which spliced variant, or isoform, gets made at that particular
time in that cell type.
A piece of the mystery of the relatively small size of the eukaryotic
genome is resolved by the observation that alternative splicing creates
many variants from a single gene, alleviating the need to store the instructions for making each variant in the DNA. Alternative splicing and posttranslational modiﬁcations are extensively utilized in the control layer. If
all of these ﬂavors are counted as distinct items, the resulting signaling
protein numbers would comprise most of the genome, and the eukaryotic
totals would be far more impressive. One of the consequences of this multiplicity is that study of the control layer is more difﬁcult than it would be

1.12 Signaling Malfunction Central to Human Disease

15

otherwise. Because of the large numbers of structural variations, and also
because of the multifunctionality, mobility, low copy numbers, and short
lifetimes of the signaling proteins (Table 1.2), understanding of the control
layer is not as advanced as that of the proteins in the ﬁxed infrastructure
involved in, for example, metabolism.
Lying at the heart of biology is the following observation, succinctly
stated by Francois Jacob in a 1977 article in Science: “What distinguishes a
butterﬂy from a lion, a hen from a ﬂy, and a worm from a whale is much
less about differences in chemical constituents than in the organization
and distribution of their components.” In other words, all creatures, great
and small, carry out metabolism, replication, multiplication, and division in
much the same way. They differ from one another mainly in the way their
parts are arranged. Multicellular eukaryotes such as ﬂies and worms are
clearly far more complex than bacteria. Yet it only takes a factor of two or
three more genes to get from one to the other. The answer to how this can
be possible is not in the numbers of genes or in a new type of biochemistry,
but rather in the way that the genes and their products, the proteins, are
used, and in the way eukaryotic cells are organized.

1.12 Signaling Malfunction Central to Human Disease
Malfunctions in molecular and cellular signaling lie at the heart of human
diseases. Proteins belonging to the control layer are involved in a host of
human disorders. They are key elements in cancers and in neurodegenerative disorders in the elderly and mood disorders in the young. Signaling
processes make complex organisms like humans possible, but when there
are malfunctions, the signaling processes give rise to diseases in those very
same organisms.
Improper expression levels and malfunctions of signaling proteins are
responsible for a host of human cancers. The underlying causes of cancers
are mutations and other alterations in DNA. These aberrations produce
malfunctions and inappropriate expression levels of genes encoding
proteins that either promote growth or restrain it, or direct the apoptosis
machinery, or are responsible for DNA damage repair and signaling, and
chromatin remodeling. Erroneous signaling conveys inappropriate growth
signals, fails to turn on the body’s cell suicide program when it is needed, and
fails to repair DNA damage when it occurs.
The brain is the most complex organ in the body. A substantial portion
of the human genome is taken up with encoding brain-speciﬁc signaling
proteins. Some of these, such as the ion channels, endow the neurons
with the ability to generate action potentials, which are used to signal other
neurons and control muscle cells. Improper and excessive rhythms resulting from imbalances between the excitation and inhibition of neurons are
responsible for epileptic seizures and a host of attention, learning, and

16

1. Introduction

mood disorders. Proteolytic processing is a prominent part of the signaling
routes activated during embryonic development. But some of the same processing elements that are crucial for embryonic development early in life
contribute to neurological disorders such as Alzheimer’s disease late in life.
Receptors, the proteins that reside in the plasma membranes of cells and
receive signals from other cells are key targets of therapeutic drugs. These
drugs act as ligands for the receptors, and are intended to elicit one of two
kinds of actions: (1) By binding the receptor, the drug may activate the signaling pathway into the cell, stimulating processes that are otherwise not
properly working; (2) or alternatively, the drug may serve as a null ligand—
one that can bind the receptor but not stimulate signaling when doing so.
This second type of action is that of a blocker, since it ties up the receptor,
preventing other ligands from binding it and activating the signaling
pathway.
The preeminent family of receptors in humans is the G protein-coupled
receptor family. They are responsive to hormones, neuromodulators, and
neurotransmitters. Some 40 to 60% of all drugs target G protein-coupled
receptors. Some of the best known of these are the serotonin and adrenergic receptor-targeted drugs that treat depression, and the dopamine
receptor-directed drugs that treat schizophenia. Other examples are the
vasopressin receptor-mediated drugs that act as antidiuretics and the
angiotensin receptor-targeted drugs that treat hypertension. Three more
examples are: the histamine receptor-targeted drugs that alleviate allergic
symptoms, the opioid receptor-targeted drugs that alter mood, and the
neurokinin receptor-targeted drugs that alleviate pain.

1.13 Organization of Text
The textbook is organized into several parts. Chapters 2 through 5 serve as
an introduction, providing background information helpful for an understanding of signaling. Chapter 2 gives an overview of the control layer and
its relationship to cellular, nuclear, DNA, and protein organization. Chapter
3 examines the principal experimental methods used to probe the structure
of signaling proteins and their interactions with one another. One of the
most interesting and intensively studied processes in all of science is the
folding of newly synthesized proteins into their physiologically functional
three-dimensional shape. Chapter 4 has as its focus energy considerations.
It covers how energy considerations drive protein folding and binding, and
how proteins fold in the cell with the assistance of molecular chaperones.
Chapter 5 deals with the macromolecular forces that underlie not only how
proteins assume their functional forms but also how they interact with each
other.
The next three chapters serve as an introduction to signaling. A good
starting point for any discussion of signaling is the plasma membrane; it is

1.13 Organization of Text

17

the place where environmental conditions are sensed and most cell-to-cell
signals are received. The yeast stress and pheromone signaling systems, the
focus of Chapter 6, and the bacterial chemotaxis system, the main subject
of Chapter 7, are archetypical signaling systems. Yeasts must constantly
adapt to changing conditions in their environment, and, similarly, bacteria
must locate nutrients and sense and respond to changes in their external
environments. These systems exhibit many of the properties and principles
that characterize signaling in more complex organisms. For many years the
plasma membrane was regarded as a fairly homogeneous and passively ﬂuid
substrate into which signaling proteins were embedded. That view has
undergone considerable change over the past few years with the realization
that the plasma membrane is organized into distinct signaling domains, and
that several kinds of lipids serve as signaling intermediaries. This new
picture of the plasma membrane, along with the role of small molecules—
lipid and nonlipid—in signaling is explored