Signaling at the Cell Surface in the Circulatory and Ventilatory Systems docx

Biomathematical and Biomechanical Modeling
of the Circulatory and Ventilatory Systems
Volume 3

For further volumes:
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Marc Thiriet

Signaling at the Cell
Surface in the Circulatory
and Ventilatory Systems


Marc Thiriet
Project-team INRIA-UPMC-CNRS REO
Laboratoire Jacques-Louis Lions, CNRS UMR 7598
Université Pierre et Marie Curie
Place Jussieu 4
75252 Paris Cedex 05
France

ISSN 2193-1682
ISBN 978-1-4614-1990-7
e-ISBN 978-1-4614-1991-4
DOI 10.1007/978-1-4614-1991-4
Springer New York Dordrecht Heidelberg London
Library of Congress Control Number: 2011943886

Springer Science+Business Media, LLC 2012
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Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1

Signal Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1 Main Signaling Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.1 Types of Cell Communications . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.2 Phases of Cell Communications . . . . . . . . . . . . . . . . . . . . . . . .
1.1.3 Main Signaling Mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.4 Signaling Cascade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.5 Features of Signaling Cascades . . . . . . . . . . . . . . . . . . . . . . . . .
1.2 Signal Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.1 Transducers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.2 Molecule Translocation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.3 Proteic Interactions – Interactomes . . . . . . . . . . . . . . . . . . . . .
1.2.4 Lipidic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.2.5 Protein Modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.6 Reversible Oxidation of Kinases and Phosphatases . . . . . . . .
1.2.7 Receptor Endocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.8 Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3 Signaling Triggered by Ligand-Bound Receptor . . . . . . . . . . . . . . . . .
1.3.1 Signaling Initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.2 Molecule Transformations and Multicomponent Complexes . .
1.3.3 Coupled Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.4 Feedback Loops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.5 Cell Type Specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.6 Signal Specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.7 Pathway Complexity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.8 Modeling and Simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.4 MicroRNAs in Cell Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.5 Adenosine Triphosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.5.1 ATP Messenger and Neurotransmitter . . . . . . . . . . . . . . . . . . .
1.5.2 Basal and Stimulated ATP Release . . . . . . . . . . . . . . . . . . . . . .

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VI

Contents

1.5.3
1.5.4
1.5.5
1.5.6
1.5.7

1.5.8
1.5.9
1.5.10
1.5.11
2

Cell Volume Control and Molecular Exchanges . . . . . . . . . . .
Cellular Processes for ATP Release . . . . . . . . . . . . . . . . . . . . .
Neuroregulator ATP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ATP Release by Endothelial Cells . . . . . . . . . . . . . . . . . . . . . .
ATP Release by Thrombocytes . . . . . . . . . . . . . . . . . . . . . . . . .
ATP Release by Leukocytes . . . . . . . . . . . . . . . . . . . . . . . . . . .
ATP Release by Erythrocytes . . . . . . . . . . . . . . . . . . . . . . . . . .
Target Receptors of Extracellular ATP . . . . . . . . . . . . . . . . . . .
Extracellular Metabolism of Nucleotides . . . . . . . . . . . . . . . . .

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Ion Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1 Connexins and Pannexins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1 Connexins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.2 Pannexins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.2 Ion Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1 Ion Carriers in Cell Signaling . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2 Types of Ion Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.3 Transmembrane Transporters . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.4 Ion Carrier Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.5 Ion Channels and Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3 Superfamily of Transient Receptor Potential Channels . . . . . . . . . . . .
2.3.1 Classification of TRP Channels . . . . . . . . . . . . . . . . . . . . . . . .
2.3.2 Structure of TRP Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.3 TRP Channel Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.4 Families of Transient Receptor Potential Channels . . . . . . . .
2.3.5 TRP Channels in the Cardiovascular Apparatus . . . . . . . . . . .
2.3.6 Cyclic Nucleotide-Gated Channels . . . . . . . . . . . . . . . . . . . . . .
2.4 Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels . . .
2.4.1 Molecule Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.2 Cellular Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5 Ligand-Gated Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.1 Superfamily of Cys-Loop Ligand-Gated Ion Channels . . . . .
2.5.2 Nicotinic Acetylcholine Receptor Channel . . . . . . . . . . . . . . .
2.5.3 γ-Aminobutyric Acid Receptor Channel . . . . . . . . . . . . . . . . .
2.5.4 Glutamate Receptor Channels . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.5 Glycine Receptor Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.6 Serotonin Receptor Channels . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.7 Ionotropic Nucleotide Receptors . . . . . . . . . . . . . . . . . . . . . . .
2.5.8 Zinc-Activated Channel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6 Chanzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7 Ion Carriers and Regulation of H+ Concentration . . . . . . . . . . . . . . . .

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Contents

3

Main Sets of Ion Channels and Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1 Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2 Ion Pumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2 Calcium Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1 Calcium Release-Activated Ca++ Channels . . . . . . . . . . . . . .
3.2.2 Calcium Channel-Induced Ca++ Release . . . . . . . . . . . . . . . .
3.2.3 Voltage-Gated Calcium Channels . . . . . . . . . . . . . . . . . . . . . . .
3.2.4 Two-Pore Calcium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.5 Inositol Trisphosphate-Sensitive Calcium-Release Channels . .
3.2.6 Ryanodine-Sensitive Calcium-Release Channels . . . . . . . . . .
3.2.7 Sarco(endo)plasmic Reticulum Calcium ATPase . . . . . . . . . .
3.2.8 Plasma Membrane Calcium ATPase . . . . . . . . . . . . . . . . . . . . .
3.2.9 Secretory Pathway Calcium ATPase . . . . . . . . . . . . . . . . . . . .
3.2.10 Sodium–Calcium Exchangers . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.11 Calcium Channel Expression during the Cell Cycle . . . . . . . .
3.3 Sodium Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.1 Epithelial Sodium Channel . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.2 Hydrogen-Gated Sodium Channels – Acid-Sensing Ion
Channel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.3 Sodium–Hydrogen Exchangers . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.4 Voltage-Insensitive, Non-Selective, Sodium Leak Channel . .
3.3.5 Voltage-Gated Sodium Channels . . . . . . . . . . . . . . . . . . . . . . .
3.3.6 Sodium–Potassium Pump . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.7 Sodium Symporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.4 Potassium Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.1 Ligand-Gated Potassium Channels . . . . . . . . . . . . . . . . . . . . . .
3.4.2 Potassium Channel Structure and Groups . . . . . . . . . . . . . . . .
3.4.3 Gating Modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.4 Inwardly Rectifying Potassium Channels . . . . . . . . . . . . . . . .
3.4.5 Voltage-Gated KV Channels . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.6 Calcium-Gated Potassium Channels BK, IK, and SK . . . . . .
3.4.7 Sodium-Activated Potassium Channels . . . . . . . . . . . . . . . . . .
3.4.8 Hyperpolarization-Activated Cyclic Nucleotide-Gated
Potassium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.9 Potassium Channels of the TWIK Subclass . . . . . . . . . . . . . . .
3.5 Chloride Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.1 Voltage-Gated Chloride Channels . . . . . . . . . . . . . . . . . . . . . .
3.5.2 Chloride Channels of the Anoctamin Family . . . . . . . . . . . . .
3.5.3 Bestrophins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.4 Maxi and Tweety Homologs . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.5 Volume-Regulated Chloride Channels . . . . . . . . . . . . . . . . . . .
3.5.6 Calcium-Activated Chloride (Pseudo)Channels . . . . . . . . . . .
3.5.7 Chloride Intracellular (Pseudo)Channels . . . . . . . . . . . . . . . . .
3.5.8 Nucleotide-Sensitive Chloride Channels . . . . . . . . . . . . . . . . .

VII

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VIII

Contents

3.5.9 Cystic Fibrosis Transmembrane Conductance Regulator . . . .
3.6 Proton Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6.1 Voltage-Gated Proton Channels . . . . . . . . . . . . . . . . . . . . . . . .
3.6.2 Proton Pump . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7 Other Types of ATPases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7.1 Copper-Transporting ATPases . . . . . . . . . . . . . . . . . . . . . . . . .
3.7.2 Phospholipid-Translocating Mg++ ATPases . . . . . . . . . . . . . .
4

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Transmembrane Compound Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.1 Superclass of Solute Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Class of Solute Carrier Organic Anion Transporters (SLCO) . . . . . . .
4.3 Amino Acid Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.1 Members of Solute Carrier Superclass . . . . . . . . . . . . . . . . . . .
4.3.2 Cysteine and Cystine Transporters . . . . . . . . . . . . . . . . . . . . . .
4.4 Symporters or Secondary Active Transporters . . . . . . . . . . . . . . . . . . .
4.4.1 Sodium–Taurocholate Cotransporter, A SLC10 Symporter . .
4.4.2 Monocarboxylate Transporters, SLC16 Members . . . . . . . . .
4.5 Ion Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.1 Copper Exporters and Importers . . . . . . . . . . . . . . . . . . . . . . . .
4.5.2 Iron Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.3 Magnesium Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6 Cation–Chloride Cotransporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.1 K+ –Cl− Cotransporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.2 Na+ –Cl− Cotransporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.3 Na+ –K+ –2Cl− Cotransporters . . . . . . . . . . . . . . . . . . . . . . . . .
4.7 Ion-Coupled Solute Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8 Neurotransmitter Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8.1 Choline and Acetylcholine Transporters . . . . . . . . . . . . . . . . .
4.8.2 Sodium- and Chloride-Dependent Neurotransmitter
Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8.3 Vesicular Monoamine Transporters . . . . . . . . . . . . . . . . . . . . .
4.9 Adenine Nucleotide Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.10 Nucleoside Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.11 Nucleobase–Ascorbate Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.12 Fatty Acid-Binding Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.13 Retinoid-Binding Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.14 Flavonoid Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.15 Citrate and Succinate Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.16 Aquaporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.16.1 Aquaporin Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.16.2 Water-Selective Aquaporins . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.16.3 Aquaglyceroporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.16.4 Structural and Functional Features . . . . . . . . . . . . . . . . . . . . . .
4.16.5 Aquaporins in the Respiratory Epithelium . . . . . . . . . . . . . . . .
4.16.6 Aquaporins in the Nephron . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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IX

4.17 Glucose Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.17.1 Sodium–Glucose Cotransporters – Active Transport . . . . . . .
4.17.2 Glucose Transporters – Passive Transport . . . . . . . . . . . . . . . .
4.18 Superclass of ATP-Binding Cassette Transporters . . . . . . . . . . . . . . . .
4.18.1 Classification of ABC transporters . . . . . . . . . . . . . . . . . . . . . .
4.18.2 Structure of ABC Transporters . . . . . . . . . . . . . . . . . . . . . . . . .
4.18.3 ABC Exporters and Importers . . . . . . . . . . . . . . . . . . . . . . . . . .
4.18.4 Full and Half ABC Transporters . . . . . . . . . . . . . . . . . . . . . . . .
4.18.5 Role of ABC Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.18.6 Class-A ABC Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.18.7 Class-B ABC Transporters (MDR–TAP) . . . . . . . . . . . . . . . . .

4.18.8 Class-C ABC Transporters (MRP–CFTR) . . . . . . . . . . . . . . . .
4.18.9 Class-D of ABC Transporters (ALD) . . . . . . . . . . . . . . . . . . . .
4.18.10Class-E of ABC Transporters (OABP) . . . . . . . . . . . . . . . . . . .
4.18.11Class-F ABC Transporters (GCN20) . . . . . . . . . . . . . . . . . . . .
4.18.12Class-G ABC Transporters (WHITE Class) . . . . . . . . . . . . . .
4.18.13Arsenite Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.19 Gas Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5

Receptors of Cell–Matrix Mass Transfer . . . . . . . . . . . . . . . . . . . . . . . . . .

5.1 Endocytosis-Devoted Low-Density Lipoprotein Receptors . . . . . . . .
5.1.1 Low-Density Lipoprotein Receptor . . . . . . . . . . . . . . . . . . . . .
5.1.2 Low-Density Lipoprotein Receptor-Related Proteins . . . . . . .
5.1.3 ApoER2 (LRP8) and VLDLR . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2 Scavenger Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.1 Class-A Scavenger Receptors . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.2 Class-B Scavenger Receptors . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.3 Other Types of Scavenger Receptors . . . . . . . . . . . . . . . . . . . .

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6

Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.1 Catalytic and Non-Catalytic Receptors . . . . . . . . . . . . . . . . . .
6.1.2 Cell-Surface and Intracellular Receptors . . . . . . . . . . . . . . . . .
6.1.3 Catalytic Receptor-Initiated Signaling . . . . . . . . . . . . . . . . . . .
6.1.4 Organization of Receptors at the Plasma Membrane . . . . . . .
6.1.5 Chemosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2 Plasmalemmal Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.1 Main Families of Catalytic Plasmalemmal Receptors . . . . . .

6.2.2 Ionotropic Receptors – Ligand-Gated Ion Channels . . . . . . . .
6.3 Intracellular or Nuclear Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.1 Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.2 Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.3 Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.4 Transcriptional Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.5 Intracellular Hormone Receptors . . . . . . . . . . . . . . . . . . . . . . .

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6.3.6 Other Nuclear Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4 Guanylate Cyclase Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.1 Plasmalemmal Natriuretic Peptide Receptors . . . . . . . . . . . . .
6.4.2 Soluble Guanylate Cyclase – Nitric Oxide Receptor . . . . . . .
6.5 Adenylate Cyclases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5.1 Plasmalemmal, G-Protein-Regulated Adenylate Cyclases . . .
6.5.2 Sensor Soluble Adenylate Cyclases . . . . . . . . . . . . . . . . . . . . .
6.6 Renin and Prorenin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.7 Imidazoline Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.7.1 Ligands of Imidazoline Receptors . . . . . . . . . . . . . . . . . . . . . .
6.7.2 Types of Imidazoline Receptors . . . . . . . . . . . . . . . . . . . . . . . .
6.8 Receptors of the Plasminogen–Plasmin Cascade . . . . . . . . . . . . . . . . .
6.8.1 Urokinase-Type Plasminogen Activator Receptor . . . . . . . . .
6.8.2 Plasminogen Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9 Adipokine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9.1 Adiponectin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9.2 Apelin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9.3 Chemerin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9.4 Leptin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9.5 Omentin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9.6 Resistin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9.7 Visfatin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.10 Chemosensors of Olfaction and Taste . . . . . . . . . . . . . . . . . . . . . . . . . .
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421
422
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423

G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.1 Agonists vs. Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.2 Alternative Splicing of G-Protein-Coupled Receptors . . . . . .
7.1.3 GPCR–G-Protein Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2 GPCR Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3 Adhesion G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . . . . . . .
7.3.1 EGF-TM7 Class Members . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3.2 TRPP1 (Polycystin-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.4 Proton-Sensing G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . .
7.5 GPCR Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7.6 Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6.1 GPCR Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6.2 GPCR Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6.3 GPCR Basal Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6.4 GPCR Oligomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6.5 GPCR Function in the Vasculature . . . . . . . . . . . . . . . . . . . . . .
7.6.6 Airway Smooth Muscle Tone . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6.7 Platelet Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6.8 Leukocyte Migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.6.9 Mastocyte Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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7.7
7.8
7.9
7.10
7.11

Crosstalk and Transactivations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Regulators of G-Protein Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
G-Protein-Coupled Receptor Kinases . . . . . . . . . . . . . . . . . . . . . . . . . .
G-Protein-Coupled Receptor Phosphatases . . . . . . . . . . . . . . . . . . . . .
Arrestins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.11.1 Post-Translational Modifications of Arrestins . . . . . . . . . . . . .
7.11.2 Receptor Desensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.11.3 Scaffolding of Intracellular Signaling Complexes . . . . . . . . .
7.11.4 Examples of β-Arrestins–GPCR Linkages . . . . . . . . . . . . . . .
7.12 Other Partners of G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . .
7.12.1 Regulation of GPCR Activity . . . . . . . . . . . . . . . . . . . . . . . . . .
7.12.2 Regulation of Intracellular GPCR Transfer and
Plasmalemmal Anchoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.12.3 Regulation of Ligand Binding . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13 Types of G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . . . . . . .
7.13.1 Acetylcholine Muscarinic Receptors . . . . . . . . . . . . . . . . . . . .
7.13.2 Adenosine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.3 Nucleotide P2Y Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7.13.4 Adiponectin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.5 Adrenergic Receptors (Adrenoceptors) . . . . . . . . . . . . . . . . . .
7.13.6 Angiotensin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.7 Apelin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.8 Bile Acid Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.9 Bombesin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.10Bradykinin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.11Calcitonin, Amylin, CGRP, and Adrenomedullin Receptors .
7.13.12Calcium-Sensing Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.13Cannabinoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.14Chemokine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.15Complement (Anaphylatoxin) and Formyl Peptide Receptors
7.13.16Cholecystokinin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.17Corticotropin-Releasing Factor Receptors . . . . . . . . . . . . . . . .
7.13.18Dopamine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.19Endothelin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.20Estrogen G-Protein-Coupled Receptor . . . . . . . . . . . . . . . . . . .
7.13.21Free Fatty Acid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.22Frizzled Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.23γ-Aminobutyric Acid Receptor . . . . . . . . . . . . . . . . . . . . . . . .
7.13.24Galanin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.25Ghrelin Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.26Glucagon Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.27Glutamate Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.28Glycoprotein Hormone Receptors . . . . . . . . . . . . . . . . . . . . . .
7.13.29Gonadotropin-Releasing Hormone Receptors . . . . . . . . . . . . .
7.13.30Histamine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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493
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510
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Contents

7.13.31Kiss1, NPff, PRP, and QRFP Receptors . . . . . . . . . . . . . . . . . .
7.13.32Latrophilin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.33Leukotriene Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.34Lysophospholipid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.35Lysophosphatidic Acid Receptors . . . . . . . . . . . . . . . . . . . . . .
7.13.36Mas1-Related G-Protein-Coupled Receptors . . . . . . . . . . . . .
7.13.37Melanin-Concentrating Hormone Receptors . . . . . . . . . . . . . .
7.13.38Melanocortin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.39Melatonin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.40Motilin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7.13.41G-Protein-Coupled Natriuretic Peptide Receptor . . . . . . . . . .
7.13.42Receptors of Neuromedin-U and Neuromedin-S . . . . . . . . . .
7.13.43Receptors of Neuropeptide-B and Neuropeptide-W . . . . . . .
7.13.44Neuropeptide-S Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.45Neuropeptide-Y Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.46Neurotensin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.47Nicotinic Acid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.48Opioid and Opioid-like Receptors . . . . . . . . . . . . . . . . . . . . . .
7.13.49Orexin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.50Parathyroid Hormone Receptors . . . . . . . . . . . . . . . . . . . . . . . .
7.13.51Platelet-Activating Factor Receptor . . . . . . . . . . . . . . . . . . . . .
7.13.52Prokineticin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.53Prostanoid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.54Tissue Factor and Peptidase-Activated Receptors . . . . . . . . . .
7.13.55Receptors of the Relaxin Family Peptides . . . . . . . . . . . . . . . .
7.13.56Serotonin (5-Hydroxytryptamine) Receptors . . . . . . . . . . . . .
7.13.57Somatostatin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.58Sphingosine 1-Phosphate Receptors . . . . . . . . . . . . . . . . . . . . .
7.13.59Tachykinin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.60Trace Amine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.61Thyrotropin-Releasing Hormone Receptors . . . . . . . . . . . . . .
7.13.62Urotensin-2 Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.13.63Vasopressin and Oxytocin Receptors . . . . . . . . . . . . . . . . . . . .
7.13.64Receptors for VIP and PACAP Peptides . . . . . . . . . . . . . . . . .
8

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Receptor Protein Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1 Receptor Tyrosine Pseudokinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2 Receptor Protein Tyrosine Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.1 Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.2 Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.3 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.4 Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.5 Growth Factor Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.6 Fetal Liver Kinase-2 (CD135) . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.7 Apoptosis-Associated Tyrosine Kinases . . . . . . . . . . . . . . . . .

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8.2.8
8.2.9
8.2.10
8.2.11

8.2.12
8.2.13
8.2.14
8.2.15
8.2.16

XIII

Axl–Mer–TyrO3 (Sky) Class . . . . . . . . . . . . . . . . . . . . . . . . . .
Discoidin Domain-Containing Receptors . . . . . . . . . . . . . . . .
Leukocyte Receptor Tyrosine Kinase . . . . . . . . . . . . . . . . . . . .
Muscle-Specific Kinase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Neurotrophic Tyrosine Receptor Kinases . . . . . . . . . . . . . . . .
Protein Tyrosine Kinase-7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ret Receptor Family – GDNF Family Receptors . . . . . . . . . .
Receptor-like Tyrosine Kinase . . . . . . . . . . . . . . . . . . . . . . . . .
Receptor Tyrosine Kinase-like Orphan Receptor Family
(ROR / WNRRTK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.17 Ros1 Receptor Tyrosine Receptors . . . . . . . . . . . . . . . . . . . . . .
8.2.18 Ephrin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.19 Angiopoietin Receptors TIE . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3 Receptor Serine/Threonine Kinases: TGF Superfamily Receptors . .
8.3.1 TGFβ Receptor- and SMAD Activation . . . . . . . . . . . . . . . . .
8.3.2 TGFβ Signaling in Endosomes . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.3 TGFβ Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.4 TGFβ Superfamily . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.5 TGFβ Receptor Types and Their Regulators . . . . . . . . . . . . . .
8.3.6 Type-1 TGFβ Receptor (TβR1 or ALK5) . . . . . . . . . . . . . . . .
8.3.7 Type-2 TGFβ Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.8 Bone Morphogenetic Proteins and Their Receptors . . . . . . . .

8.3.9 Activin Receptor-like Kinases . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.10 SMAD Mediators – The Canonical Pathway . . . . . . . . . . . . . .
8.3.11 Non-Canonical Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9

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686

Receptor Tyrosine Phosphatases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.1 Protein Tyrosine Phosphatase Receptor-A . . . . . . . . . . . . . . . . . . . . . .
9.2 Protein Tyrosine Phosphatase Receptor-B . . . . . . . . . . . . . . . . . . . . . .
9.3 Protein Tyrosine Phosphatase Receptor-C . . . . . . . . . . . . . . . . . . . . . .
9.4 Protein Tyrosine Phosphatase Receptor-D . . . . . . . . . . . . . . . . . . . . . .
9.5 Protein Tyrosine Phosphatase Receptor-E . . . . . . . . . . . . . . . . . . . . . .
9.6 Protein Tyrosine Phosphatase Receptor-F . . . . . . . . . . . . . . . . . . . . . .
9.7 Protein Tyrosine Phosphatase Receptor-G . . . . . . . . . . . . . . . . . . . . . .
9.8 Protein Tyrosine Phosphatase Receptor-H . . . . . . . . . . . . . . . . . . . . . .
9.9 Protein Tyrosine Phosphatase Receptor-J . . . . . . . . . . . . . . . . . . . . . . .
9.10 Protein Tyrosine Phosphatase Receptor-K . . . . . . . . . . . . . . . . . . . . . .
9.11 Protein Tyrosine Phosphatase Receptor-M . . . . . . . . . . . . . . . . . . . . . .
9.12 Protein Tyrosine Phosphatases Receptor-N and -N2 . . . . . . . . . . . . . .
9.13 Protein Tyrosine Phosphatase Receptor-O . . . . . . . . . . . . . . . . . . . . . .
9.14 Protein Tyrosine Phosphatase Receptor-Q . . . . . . . . . . . . . . . . . . . . . .
9.15 Protein Tyrosine Phosphatase Receptor-R . . . . . . . . . . . . . . . . . . . . . .
9.16 Protein Tyrosine Phosphatase Receptor-S . . . . . . . . . . . . . . . . . . . . . .
9.17 Protein Tyrosine Phosphatase Receptor-T . . . . . . . . . . . . . . . . . . . . . .
9.18 Protein Tyrosine Phosphatase Receptor-U . . . . . . . . . . . . . . . . . . . . . .

689
691
693
696
696
697
698
698
698
698

699
699
699
700
700
700
701
701
701


XIV

Contents

9.19 Protein Tyrosine Phosphatase Receptor-V . . . . . . . . . . . . . . . . . . . . . . 701
9.20 Protein Tyrosine Phosphatase Receptor-Z1 . . . . . . . . . . . . . . . . . . . . . 702
9.21 Transmembrane RPTPs and RPTKs in Vasculo- and Angiogenesis . 702
10

Morphogen Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1 Notch Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1.1 Notch and DSL Family Members . . . . . . . . . . . . . . . . . . . . . . .
10.1.2 Notch Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1.3 Notch Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.2 Hedgehog Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.2.1 Hedgehog Synthesis and Release . . . . . . . . . . . . . . . . . . . . . . .
10.2.2 Hedgehog Signal Reception . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.2.3 Hedgehog Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.2.4 Regulators of the Hedgehog Pathway . . . . . . . . . . . . . . . . . . .

10.3 Wnt Morphogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.3.1 Wnt Family and Their Receptors . . . . . . . . . . . . . . . . . . . . . . .
10.3.2 Wnt Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.3.3 Canonical Wnt Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.3.4 Wnt Signaling in Heart and Blood Vessels . . . . . . . . . . . . . . .
10.3.5 Wnt Signaling in the Nervous System . . . . . . . . . . . . . . . . . . .
10.3.6 Wnt-Mediated Tissue Repair . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.3.7 Wnt Signaling and Cell Fate . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.4 Transmembrane Glycoprotein EpCAM . . . . . . . . . . . . . . . . . . . . . . . .
10.5 Semaphorins and Plexins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.6 Roundabout Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

705
705
706
706
712
720
720
721
722
726
729
729
730
734
746
748
749
749

752
753
755

11

Receptors of the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1 Cytokine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.1 Type-1 Cytokine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.2 Type-2 Cytokine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.3 Families of Interleukins and Their Receptors . . . . . . . . . . . . .
11.1.4 Cytokine Receptors of the Immunoglobulin Superclass . . . . .
11.1.5 Tumor-Necrosis Factor Receptor Superfamily . . . . . . . . . . . .
11.1.6 Chemokine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1.7 Other Cytokine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2 Other Receptors of the Immune System . . . . . . . . . . . . . . . . . . . . . . . .
11.2.1 B-Cell Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2.2 Fc Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2.3 T-Cell Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2.4 Toll-like Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2.5 NOD-like Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2.6 C-Type Lectin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2.7 Triggering Receptors Expressed on Myeloid Cells . . . . . . . . .
11.2.8 Tyro3, Axl, and Mer (TAM) Receptors . . . . . . . . . . . . . . . . . .

757
758
758
759
759

775
775
784
784
784
785
786
789
792
798
802
803
805


Contents

XV

11.2.9 Signaling Lymphocytic Activation Molecules and
SLAM-Associated Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 806
11.2.10Intracellular RNA Helicases – RIG-like Receptors . . . . . . . . 807
Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813
A

Notation Rules: Aliases and Symbols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919
A.1 Aliases for Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920
A.2 Symbols for Physical Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924

List of Currently Used Prefixes and Suffixes . . . . . . . . . . . . . . . . . . . . . . . . . . . 925
List of Aliases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929
Complementary Lists of Notations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 961
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967



Introduction

“ ... sunt quaedam corpora quorum concursus,
motus, ordo, positua, figurae
efficiunt ignis, mutatoque ordine mutant
naturam ...
[... some materials exist, of which interaction, motion,
order, position, configuration produce fire, and if order
differs, a different pattern...] ” (Lucretius) [1]

Volume 3 of the book series Biomathematical and Biomechanical Modeling of
the Circulatory and Ventilatory Systems aims at presenting major sets of signaling
receptors mainly located at the plasma membrane, 1 in a modeling framework rather
than biological perspective. Collecting signaling effectors, their main interactions,
and major properties are the first tasks required for any modeling of cell signaling
processes.
The major objective is to comprehend the complexity of natural phenomena to
model these events. In other words, to yield the maximal amount of known information (i.e., to briefly describe the huge number of signaling mediators and their main
known features) enables the depiction of any signaling cascade using a suitable data
set with a minimal content in required quantities. Handling of complex signaling
networks and their complex behavior leads to a compulsory preview to distinguish
primary from secondary elements. In physics, a similar strategy is carried out during
phenomenological analysis and scaling. Knowledge of all possible known interactors is mandatory to avoid forgetting any important contributor and to understand the

complex behavior of signaling cascades. Once all of the mediators of the pathway
of interest are identified, major contributors are selected as parameters of modeling
equation set and minor are rejected.

1. Signaling receptors involved in cell adhesions are described in Vol. 1 (Chap. 7. Plasma
Membrane). Intracellular receptors sense steroid and thyroid hormones, vitamin-A and -D,
metabolites (e.g., fatty and bile acids and sterols), and xenobiotics.
M. Thiriet, Signaling at the Cell Surface in the Circulatory and Ventilatory Systems,
Biomathematical and Biomechanical Modeling of the Circulatory and Ventilatory Systems 3,
DOI 10.1007/978-1-4614-1991-4_0, © Springer Science+Business Media, LLC 2012

1


2

Introduction
“ The thirty spokes merge in the center to form a wheel;
but it is on the empty central space of the axle that the
usefulness of the wheel depends. Clay is shaped into
pots; but it is on their empty hollowness that our utilization relies. The door and windows are created in walls
for a living space; but it is on the empty space that makes
it livable. ” (Attributed to Lao Tzu: Tao te Ching
[The classic of the way of virtue]; 6th century B.C.E.)

The molecule selection stage is not an obvious task as: (1) the number of known
molecular participants of any signaling cascade is often quite large; (2) involved effectors possess many names; (3) some effector aliases designate different types of
molecules; (4) most mediators interact with many partners; (5) crosstalk exists with
other signaling axes; (6) the finely tuned intracellular cascade of reactions has a complex functioning; and, last but not least, (7) some regulators and mediator properties
as well as values of kinetic coefficients remain unknown.

Presentation of biochemical properties of involved molecules goes beyond the
scope of this book. However, structural motifs are sometimes given to understand
the binding of a signaling mediator or conformational changes that contribute to
activate or inactivate an enzyme involved in the next step of the signaling cascade of
chemical reactions. Similarly, amino acid residues specifically targeted during posttranslational modifications are often given. For example, phosphorylation of a given
target amino acid triggers activation (activatory site of a signaling mediator), whereas
that of another residue (inhibitory site of a signaling mediator) primes deactivation.
“On ne pourra bien dessiner le simple qu’après une
étude approfondie du complexe.
[The simple (model) will be adequately designed only
after a deep investigation of the complex (reality).] ”
(G. Bachelard)

The set of books devoted to Circulatory and Ventilatory Systems in the framework of Biomathematical and Biomechanical Modeling aims at providing basic
knowledge and state of the art on the biology and the mechanics of blood and air
flows. The cardiovascular and respiratory systems are tightly coupled, as their primary function is the supply of oxygen (O2 ) to and removal of carbon dioxide (CO2 )
from the body’s cells. Oxygen is not only a nutrient that is used in cellular respiration,
but also a component of structural molecules of living organisms, such as carbohydrates, proteins, and lipids. Carbon dioxide is produced during cell respiration. It is
an acidic oxide that, in an aqueous solution, converts into anhydride of carbonic acid
(H2 CO3 ). It is then carried in blood mostly as bicarbonate ions (HCO− ) owing to
3
carbonic anhydrase in erythrocytes, but also small fractions that are either dissolved
in the plasma or bound to hemoglobin as carbamino compounds. Carbon dioxide is
one of the mediators of autoregulation of local blood supply. It also influences blood
pH via bicarbonate ions. Last, but not least, it participates in the regulation of air and
blood flows by the nervous system.
Explorations of blood and air flows in the cardiovascular and respiratory systems
will require development of models that couple different length and time scales. Like

Introduction

3

physiology, biomechanics cope with the macroscopic scale. Like molecular biology,
biomathematics can deal with the nano- and microscopic scales that must be coupled
to macroscopic events to take into account the fundamental features of living cells
and tissues that sense, react, and adapt to applied loadings. Therefore, the three basic natural sciences - biology, chemistry, and physics - interact with mathematics to
explain the functioning of physiological flows, such as those experienced by the circulatory and ventilatory systems. In the near future, biomechanical models should be
coupled to biomathematical models of cell signaling and tissue adaptation to better
describe the reality, although its complexity still necessitates abstraction. The main
objective of the present 8-volume publication is to present data that will be used as
inputs for multiscale models.
Biological systems (from molecular level to physiological apparatus) 2 are characterized by their complicated structure, variable nature, and complex behavior. Processing of signals that control the activity of transcription factors and the expression
of genes to direct cell decision (differentiation, growth, proliferation, or death), organization of metabolism, cell communication for coordinated action in a tissue,
all rely on non-linear dynamics that control spatial distribution and clustering of
molecular species at a given time. Fast protein modifications that result from protein interactions in the cytoplasm propagate signals and lead to either relatively slow
transcription and translation or direct release of stored substances.
Complexity arises from the large number of involved quantities that are related by
non-linear relationships. Therefore, kinetic and transport equations with associated
rates, kinetics coefficients, and transport coefficients that govern cell signaling and
tissue remodeling are strongly coupled.
Tier architecture of any living system is characterized by its communication
means and regulation procedures. It allow integration of environmental changes to
adapt. Multiple molecules interact to create the adaptable activity of the cells, tissues,
organs, and body. Any integrative model then incorporates a set of models developed
at distinct length scales that also includes response characteristic times to efficiently
describe the structure–function relationships of the explored physiological system.
Cells communicate with: (1) themselves internally or by secreting regulators
(intra- and autocrine signaling, respectively); (2) neighboring cells by direct contact (juxtacrine signaling) or over short distances (paracrine signaling, when signals

target a similar or different cell type in the immediate vicinity through a tiny space
of extracellular medium); and (3) remote cells, i.e., over large distances (endocrine
signaling). Endocrine signals that are transmitted by endocrine cells are called hormones. They circulate in blood to reach their targets. Neurotransmitters represent
an example of paracrine signals. Some signaling molecules can function as both a
hormone and a neurotransmitter, such as adrenaline and noradrenaline, whether they

2. In physiology, apparatus ([Latin] apparatus: preparation, planning; apparo/apparere: to
prepare [or adparo (ad: toward, paro/parare: to make ready)]) refers to group of organs that
collectively carry out a specific task.


4

Introduction

are released from cells of the adrenal medulla (inner region of the adrenal gland) 3 or
neurons. Certain messengers such as estrogens are released by the ovary and operate
as hormones on other organs such as the uterus or act locally as auto- or paracrine
regulators. Cells receive information from themselves and their environment via proteic receptors of the cell surface.
Cells appropriately respond in a controlled or coherent manner to external stimuli
(adaptation robustness). Specific responses characterized by intracellular biochemical reaction cascades can be generated over a wide range of parameter variation.
Signals are transduced by information processing networks that are characterized by
signal transduction complexity and between-pathway connectivity.
Signaling initiation and first steps of molecular interactions and transformations
of most pathways occur at the cell membrane and cortex. The dynamics of a biochemical process can be represented by a set of equations that link the time variations of concentrations of implicated substances to production and consumption
rates, which depends on concentrations of interacting molecules and spatial coordinates within the cell and possibly the extracellular compartment. The cell is a heterogeneous medium, even inside the cytosol and organelles.
Any complicated physiological system can be analyzed by decomposition into
simple parts with identified functions. The combination of these functions allows us
to deduce system functioning due to linear interactions. Deconstruction into parts of
physiological systems is necessary to understand part behavior as well as to determine between-part interactions. The cell is a complex system constituted of many

components. The features of complex systems are adaptation, self-organization, and
emergence. Cells self-organize to operate with optimal performance. The behavior
of a complex system is not necessarily predictible from the properties of its elementary constituents, which can non-linearly interact with feedback loops, contributing
to system bulk behavior. The organization and bulk behavior of a complex system
not only results from the simultaneous activities of its constituents, but also emerges
from the sum of the interactions among its constituents. A complex system adapts
by changing its organization and possibly its structure to environmental stimuli. Yet,
a predictive model requires a theory, or at least a framework, that involves relationships.
Input data for integrative investigation of the complex dynamic cardiovascular
and respiratory system include knowledge accumulated at various length scales, from
molecular biology to physiology on the one hand, and histology to anatomy on the
other hand. Tier architecture of living systems is characterized by its communication
means and regulation procedures that integrate environmental changes to adapt. Multiple molecules interact to create the adaptable activities of cells, tissues, organs, and
body. A huge quantity of these molecules forms a complex reaction set with feedback
loops and a hierarchical organization. Studies from molecular cascades primed by
mechanical stresses to cell, then to tissues and organs need to be combined to study
living systems with complex dynamics; but future investigations are still needed to
3. Adrenal medullary cells that are grouped around blood vessels operate as postganglionic
neurons of the sympathetic nervous system.


Introduction

5

mimic more accurately system functioning and interaction with the environment, using multiscale modeling. An integrative model also incorporates behavior at various
time scales, including response characteristic times, cardiac cycle (s), and diurnal
periodicities (h), to efficiently describe the structure–function relationships of the
explored physiological system.
Models of biochemical reaction cascades are generally described by mass action

equations based on involved molecule concentrations and chemical kinetic coefficients for each elementary reaction:
substrate + enzyme

complex

enzyme + product.

According to the mass-action law, the rate of change in concentration of a chemical
species in chemical elementary, slow reactions at local equilibrium in ideal gases and
dilute solutions is proportional to the product of the concentrations of the different
involved reagents, raised to given powers. Complex reactions are often considered
as a succession of elementary reactions. Generalized power law models have been
proposed for complex processes.
Chemical reaction cascades, in which the product of a reaction enters another
reaction and different species can be recycled, represent complicated processes. In
addition, in biochemical reactions, enzymes, after catalyzing a chemical reactiont,
are generally released in free forms ready to enter another reaction cycle. However,
enzyme can be sequestered or degraded. Therefore, recycling is not complete.
Models of cell response to environmental stimuli that treat metabolic and signaling networks can have a good predictive potential owing to the limited number
of possible states, as cells optimally function in a bounded parameter space (experienced states are defined by a given set of physical and chemical parameters that
evolve in known value ranges with identified relationships among them).
The text has been split into a book set according to the length scale. Volume 1 of
this book series introduces cells (microscopic scale) involved not only in the architecture of the cardiovascular and respiratory systems as well as those convected by
blood to ensure body homeostasis and defense against pathogens, but also cells that
regulate blood circulation and the body’s respiration to adapt air and blood flows to
the body’s need.
The remote control as well as major events of the cell life are detailed in Volume 2. Cells of the cardiovascular and ventilatory apparatus are actually strongly
regulated by themselves, their neighboring cells, as well as remote cells of the endocrine and nervous systems to adapt to local conditions as well as regional and
general stimuli.
Volumes 3 and 4 are aimed at describing components of cascades of chemical

reactions (nanoscopic scale) that enable cellular responses to environmental stimuli,
in particular mechanical stresses. Extracellular messengers (locally released agents
for auto- and paracrine regulation, hormones, growth factors, cytokines, chemokines,
and constituents of the extracellular matrix, as well as mechanical stresses) activate
various types of receptors to initiate signaling cascades (Vol. 3). Intracellular signaling pathways are usually composed of multiple nodes and hubs that correspond
to major mediators (Vol. 4). Signaling pathways trigger release of substances from


6

Introduction

intracellular stores and gene expression to produce effectors for intra- or autocrine
regulation as well as close or remote control. Cell activities can be modeled using
systems of equations to predict outcomes.
Volume 5 deals with tissues (mesoscopic scale) of the cardiovascular (heart,
blood and lymph vessels, as well as blood and lymph) and respiratory apparatus
(airways and lungs), including interactions between adjoining cells. Cell activities
involved in adaptation (mechanotransduction, stress-induced tissue remodeling in
response to acute or chronic loadings, angiogenesis, blood coagulation, as well as
inflammation and healing) can be described using mathematical models.
The wetted surface of any segment or organ of the cardiovascular system is
covered by the endothelium, which constitutes the interface between the flowing
blood and the deformable solid wall. The endothelium is a layer of connected and
anchorage-dependent cells. The endothelium has several functions. It controls molecule exchange between the blood and the vessel wall and perfused tissues. It regulates
flowing cell adhesion on the blood vessel wall and extravasation, especially for immune defense. It controls coagulation and thrombolysis. It regulates the vasomotor
tone and proliferation of vascular smooth muscle cells via the release of several compounds. It is required in angiogenesis. Endothelial cells detect hemodynamic stresses
via mechanosensors.
The blood vessel wall is a living tissue that quickly reacts to loads applied on it
by the flowing blood. In any segment of a blood vessel, the endothelial and smooth

muscle cells sense the large-amplitude space and time variations in small-magnitude
wall shear stress and wall stretch generated by the large-magnitude blood pressure.
These cells respond with a short time scale (from seconds to hours) to adapt the
vessel caliber according to the loading, especially when changes exceed the limits
of the usual stress range. This regulatory mechanism is much quicker than the nervous and hormonal control. The mechanotransduction pathways determine the local
vasomotor tone and subsequently the lumen bore of the reacting blood vessel.
Volume 6 focuses on the functioning of the cardiovascular and respiratory apparatus (macroscopic scale) and diseases associated with blood and air flows. Local
flow disturbances can trigger pathophysiological processes and/or result from diseases of conduit walls or their environment. Volume 6 contains chapters on anatomy
and physiology of the cardiovascular and respiratory systems as well as medical signals and images, and functional tests. In addition, it presents pathologies of the fluid
convection duct network (i.e., heart, blood vessels, and respiratory tract) and their
treatment that are targeted by biomechanical studies. Nowadays, the development of
medical devices and techniques incorporates a stage of numerical tests in addition to
experimental procedures. Moreover, a huge number of research teams develop tools
for computer-aided diagnosis, therapy (e.g., treatment planning and navigation hardand softwares), and prognosis.
Volume 7 copes with mechanics of air and blood flows (macroscopic scale), taking into account rheology of blood and deformable walls of respiratory conduits and
blood vessels and providing insights in numerical simulations of these types of flows.
Volume 8 presents a set of glossaries to rapidly get a basic knowledge on coonstituents, structures, and parameters used in models, as this information arises from


Introduction

7

diverse scientific disciplines. Specific vocabulary used in each of study field can indeed limit easy access to a field by researchers of other disciplines. Moreover, same
words can be used in different knowledge fields, but with distinct meanings.
The present Volume is composed of 10 chapters. Transduction of mechanical
stresses applied both on the wetted surface of physiological conduits and within
the wall by cells involves plasmalemmal ion carriers and receptors, among other
molecules of the cell surface. The signal then propagates within the cell using specific pathways. Chapter 1 describes signaling pathways that allow the cell to transduce received signals to determine its functioning for given missions. It give insights
on effector stage of the initiated signaling pathways that is achieved by an activation

cascade, with assembling of molecular complexes and reversible protein modifications, especially phosphorylation. Chapters 2 to 5 cope with ion and molecule carriers as well as receptors of the cell–matrix mass transfer. Ion fluxes particularly generate action potential in the heart wall that then travels through conduction (nodal)
tissue and myocardium to trigger contraction of the cardiac pump. Heart contraction requires calcium influx and energy, whereas cardiomyocyte relaxation needs
calcium efflux. Some ion channels are also primed by mechanical loads. Both ion
and molecule carriers participate in cell signaling and exchange between cells and
their environment. Chapter 6 introduces cell-surface receptors to various ligands, details intracellular receptors and their translational partners, reports on some sets of
plasmalemmal receptors (guanylate cyclase receptors for natriuretic peptides and nitric oxide, adenylate cyclase sensors, renin and prorenin receptors, and receptors of
the plasminogen–plasmin cascade), and provides examples with the set of adipokine
receptors. Chapters 7 to 11 describe various families of receptors, starting with the
largest group of plasmalemmal receptors, i.e., G-protein-coupled receptors (Chap. 7).
Then follow receptor protein tyrosine and serine/threonine kinases (Chap. 8), receptor protein tyrosine phosphatases (Chap. 9), receptors implicated in morphogenesis
(Chap. 10; receptors of the Notch, Hedgehog, and Wnt pathways, as well as glycoprotein EpCAM, plexins [semaphorin receptors] and Robo), to terminate on blood
cell receptors, i.e., receptors of the immune system (Chap. 11).
Volume 4 is composed of 10 chapters. This volume is mainly aimed at giving the
major features of intracellular signaling mediators, including their various names, to
handle the complexity of molecular biology. Once the analysis step is completed,
the synthesis step that retains the major signaling components enable mathematical modeling. Chapters 1 to 9 enumerate the main families of signaling mediators
and their members. Volume 4 begins by components of lipid signaling (Chap. 1)
and a preambule to protein kinases (Chap. 2) to give a survey on cytoplasmic protein tyrosine (Chap. 3), serine/threonine (Chap. 4), mitogen-activated protein kinase
modules (Chap. 5), and dual-specificity (Chap. 6) kinases as well as protein phosphatases (Chap. 7). Then follow heterotrimeric and monomeric guanosine triphosphatases (Chap. 8). Chapter 9 presents signaling gas as well as major transcription
factors and coregulators. Chapter 10 gives examples of signaling pathways, such as
those involving cyclic adenosine and guanosine monophosphates, adhesion and matrix molecules, and calcium, as well as those involved in oxygen sensing, insulin
stimulation, angiogenesis, and mechanotransduction.


8

Introduction

Once collected, the set of mediators involved in cell signaling is sorted and selected signaling components constitute the set of model variables. Primary mediators are indeed kept in modeling of regulated cellular processes, whereas multiple secondary signaling components are discarded to handle simple, representative
modeling and eventually manage their inverse problems. As mathematics deals with

abstraction, modeling based on the transport equation may be preferred to that governed by the mass-action law used by chemists. The major drawback of the latter
is the large number of kinetic coefficients, the values of which often still remain
unknown even after efficient data mining.
Common abbreviations such as “a.k.a.” and “w.r.t.” that stands for “also known
as” and “with respect to”, respectively, are used throughout the text to lighten sentences. Latin-derived shortened expressions are also widely utilized (but not italicized despite their latin origin): “e.g.” (exempli gratia) and “i.e.” (id est) mean “for
example” and “in other words”, respectively. Rules adopted for substance aliases as
well as alias meaning and other notations are given at the end of this book.
Acknowledgments
These books result from lectures given at Université Pierre et Marie Curie in
the framework of prerequisite training of Master “Mathematical Modeling”, part of
Master of “Mathematics and Applications”, Centre de Recherches Mathématiques, 4
and Taida Institute for Mathematical Sciences, 5 the latter two in the framework of
agreements with the French National Institute for Research in Computer Science
and Control. 6 These lectures mainly aim at introducing students in mathematics to
basic knowledge in biology, medicine, rheology, and fluid mechanics in order to
conceive, design, implement, and optimize appropriate models of biological systems
at various length scales in normal and pathological conditions. These books may also
support the elaboration of proposals following suitable calls of granting agencies, in
particular ICT calls “Virtual Physiological Human” of the European Commission.
The author takes the opportunity to thank the members of ERCIM office (European
Consortium of Public Research Institutes) and all of the participant teams of the
working group “IM2IM” that yields a proper framework for such proposals. These
books have been strongly supported by Springer staff members. The author thanks
especially S.K. Heukerott and D. Packer for their help and comments.
The author, an investigator from the French National Center for Scientific Research 7 wishes to acknowledge members of the INRIA-UPMC-CNRS team “REO”, 8 and Laboratoire Jacques-Louis Lions, 9 as well as CRM (Y. Bourgault, M.
Delfour, A. Fortin, and A. Garon), being a staff member in these research units, and
4. CRM: www.crm.umontreal.ca.
5. TIMS: www.tims.ntu.edu.tw.
6. Institut National de la Recherche en Informatique et Automatique (INRIA;
www.inria.fr).

7. Centre National de la Recherche Scientifique (CNRS; www.cnrs.fr
8. www-roc.inria.fr/reo
9. www.ann.jussieu.fr