Table Of ContentCyclic ADP-Ribose and NAADP
Structures, Metabolism and Functions
Cyclic ADP-Ribose and NAADP
Structures, Metabolism and Functions
Editor Hon Cheung Lee, Minneapolis, USA
Cover Designs: Front - the space-filling model on the left is that of cADPR and is based on X-ray
crystallography. The molecule on the right is NAADP. The secondary structure of a homo-dimer of the
Aplysia ADP-ribose cyclase is shown in the middle. The background is derived from a micrograph of
cADPR crystals. Back - ball-and-stick models of cADPR and NAADP. Graphics designed by HC Lee.
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Cataloging-in-Publication Data
Cyclic ADP-Ribose and NAADP: Structures, Metabolism and Functions
Hon Cheung Lee (ed.)
ISBN 978-1-4613-4996-9 ISBN 978-1-4615-0269-2 (eBook)
DOI 10.1007/978-1-4615-0269-2
Copyright © 2002 Springer Science+Business Media New York
Originally published by Kluwer Academic Publishers in 2002
Softcover reprint of the hardcover 1st edition 2002
All rights reserved. No part of this work may be reproduced, stored in a retrieval
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Printed on acid-free paper.
Contents
V Contents
XVII Preface
Cyclic ADP-Ribose and NAADP
A Story of Two Calcium Messengers
Lee HC, Minneapolis, USA
1 Introduction
1 Ca2+ Releasing Effects ofNAD and NADP
4 Cyclic ADP-Ribose (cADPR)
7 Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)
11 ADP-Ribosyl Cyclase
12 CD38-A Mammalian ADP-Ribosyl Cyclase
13 Ca2+ Mobilization by cADPR and NAADP
14 Endogenous Cyclic ADP-Ribose
15 A Decade of Exploration
17 References
ADP-Ribosyl Cyclases - A Family of cADPR and NAADP
Metabolizing Enzymes
Lee HC, Munshi CB and GraeffR , Minneapolis, USA
23 Introduction
23 A New Family of Enzymes
25 The Multi-functionality of the ADP-Ribosyl Cyclases
26 Structural Homology ofthe ADP-Ribosyl Cyclase Family
27 Distribution of ADP-Ribosyl Cyclases in Cells and Tissues
29 Structure of the Ap/ysia ADP-Ribosyl Cyclase
31 Structure of CD3 8
33 Structure ofCD157/BST-l
33 A Unified Model of Catalysis of ADP-Ribosyl Cyclase
Contents
36 Physiological Functions ofCD38
38 Concluding Remarks
38 References
Regulation of Synthesis of cADPR and NAADP
Galione A, Oxford, UK
45 Introduction
46 Enzymology of cADPR Production
47 Regulation of cADPR Synthesis by cGMP
48 A Role for cGMP at Fertilization
51 cAMP Interactions with cADPR Signaling Pathways
52 Other Ways of Regulating cADPR Synthesis
52 Tyrosine Kinase-Linked Receptors
53 cADPR Synthesis Linked to Cellular Metabolic Changes
54 Regulation by A TP
54 Regulation by NADH
54 Regulation by NAD levels
54 Regulation by ADP-ribose
55 Changes in Enzyme Levels
55 G Protein-Linked Receptors and cADPR Signaling
56 NAADP Synthesis
56 Conclusions
59 References
A Natural History ofthe Human CD38 Gene
Ferrero E and Malavasi F, Turin, Italy
65 Introduction
66 The Genescape
68 Human CD38: Gene Structure and Expression
70 Human CD38: Gene Regulation and Transcripts
70 Promoter Control
71 Elongation and Termination
72 Transcripts
72 Human CD38: Polymorphism
73 CD38 in Phylogenesis
75 Acknowledgements
75 References
VI
Contents
A Yeast Expression System of Higb Efficiency for Producing
Recombinant Enzymes
Munshi CB and Lee HC, Minneapolis, USA
81 A Yeast Expression System
83 Materials
83 Methods
84 Construction of Human CD38, Cyclase, CD157, and NMN-AT
Clones
84 The pPICZaAlCD38 Clone
86 The pPICZaA/Cyciase Clone
87 The pYEXlCD157 Clone
88 The pPICZaAINMN-AT Clone
89 Screening of Yeast Transformants for the ADP-Ribosyl Cyclase
Activity
90 Screening of X-33 Yeast Transformants for NMN-AT Activity
90 High Biomass Fermentation
91 The Starter Culture Phase
91 The Biomass Phase
91 The Induction Phase
93 Expression of Recombinant Proteins in Shaker Cultures
94 Purification of the Cyclase
95 Purification ofCD38
96 Purification ofCD157
97 Purification ofNMN-AT
97 Summary
98 References
Novel Cycling Assays for cADPR and NAADP
GraeffR and Lee HC, Minneapolis, USA
101 Introduction
102 Materials
102 A Cycling Assay for cADPR
106 Removal ofNucleotides Interfering with the cADPR Assay by
Enzyme Treatment
107 Procedures for Measuring Endogenous Levels of cADPR
108 Changes in cADPR, NAD and NADH Levels in HL-60 Cells
110 The Endogenous cADPR Levels in CD38 Knockout Mice
111 Advantages of the Cycling Assay for cADPR
112 A Cycling Assay for NAADP
113 Purification ofNMN-AT
114 The Cycling Assay Procedure
VII
Contents
115 Removal ofNucleotides Interfering with the NAADP Assay by
Enzyme Treatment
116 A Cycling Assay for Nicotinic Acid
117 Summary
118 References
Pharmacology of Cyclic ADP-Ribose and NAADP
Synthesis and Properties of Analogs
Walseth TF and Lee HC, Minneapolis, USA
121 Introduction
122 Synthesis of cADPR Analogs
124 cADPR Antagonists
126 Hydrolysis-Resistant cADPR Analogs
128 cADPR Analogs with N9-Ribosyl Modifications
129 Fluorescent cADPR Analogs
130 Caged cADPR
131 Other cADPR Analogs
132 NAADP Analogs
133 NAADP Analogs with the Pyridine Base Modified
134 NAADP Analogs with the Adenine Modified
135 NAADP Analogs with the Adenine Ribose Modified
135 Other NAADP Analogs
136 Concluding Remarks
136 Acknowledgements
136 References
Separate but Interacting Calcium Stores
Lee HC, Minneapolis, USA
143 Introduction
144 Cells Responsive to cADPR and NAADP
147 Mechanisms ofCa2+ Mobilization Mediated by cADPR and NAADP
148 The cADPR- and NAADP- Sensitive Ca2+ Stores
148 Endoplasmic Reticulum (ER)
150 Secretory Vesicles/Granules
150 Nucleus
151 Plant Vacuoles
151 NAADP-Sensitive Ca2+ Stores
151 Spatial Segregation of Ca2+ Stores
153 Ca2+ Mobilization and Influx
154 Ca2+ Mobilization and Cell Functions
154 Singular Ca2+ Stores and Specialization
VIII
Contents
155 MUltiple Ca2+ Stores and Specificity
156 Multiple Ca2+ Stores and Redundancy
157 Interacting Ca2+ Stores
159 A Emerging Theme
159 References
Sensitizing Calcium-Induced Calcium Release
Role of cADPR as an Endogenous Modulator
Morgan AI and Galione A, Oxford, UK
167 Regulation of Ca2+ Release
169 Ca2+-Induced Ca2+ Release
170 Molecular Elements
170 Cyclic ADP-Ribose-Induced Ca2+ Release
170 Background
171 Experimental Approaches for Assessing cADPR-Induced Ca2+
Release
172 Effect of cADPR Upon Intracellular Ca2+ Signals
173 Intercellular Messages
173 cADPR and Ca2+-Induced Ca2+ Release
174 RyR and Ca2+-induced Ca2+ Release
175 cADPR, CICR and Calmodulin
178 Luminal Ca2+ and CICR
179 Sulfhydryl Agents and CICR
180 RYRs as Targets for cADPR
181 Candidate cADPR Receptors
182 cADPR: CICR Activator or Modulator
183 Interaction of cADPR with other Ca2+ Homeostatic Mechanisms
183 cADPR as an Amplifier of Ca2+ Signals
185 cADPR-Induced Ca2+ Release Upstream of Other Channels
186 Potential Novel Aspects of cADPR Signaling
187 Summary
187 References
Spatial and Temporal Control of Calcium Signaling by NAADP
Churchill GC, Patel S, Thomas IM and Galione A, Oxford, UK
199 Importance of Ca2+ Signaling in Time and Space
200 Ca2+- Mobilizing Messengers
201 Unique Properties ofNAADP
201 Traditional Mechanisms Underlying Ca2+ Oscillations and Waves
201 Hierarchical Structure Supports Spatiotemporal Ca2+ Signals
202 Mechanisms of Ca2+ Oscillations
IX
Contents
203 NAADP-Mediated Ca2+ Waves
203 Propagation by NAADP Diffusion
205 NAADP Responses are Amplified Locally by CICR
205 Model for the Control of Spatial Ca2+ Signaling by NAADP
206 NAADP Mediates a Spatiotemporal Ca2+ Memory
206 NAADP Forms a Spatial Memory
208 Recovery ofNAADP Sensitivity Provides a Temporal Memory
208 Possible Physiological Implications
208 NAADP-Induced Ca2+ Oscillations
209 Oscillations Require Functional CICR Pathways
210 NAADP Operates via a Two-Pool Mechanism
211 Possible Physiological Implications
211 Generalized Roles for NAADP in Ca2+ Signaling
212 References
Regulation of Immune Responses by CD38 and cADPR
Lund FE, Randall TD and Partida-Sanchez S, Saranac Lake, USA
217 Introduction
218 Role ofCD38 in Innate and Adaptive Immune Responses
218 Crosslinking ofCD38 Induces Signal Transduction in Lymphocytes
Independently of Enzyme Activity
221 CD38 is Required for Optimal Adaptive and Innate Immune
Responses
222 CD38 Deficient Neutrophils are Unable to Migrate to Sites of
Infection and are Responsible for the Defective Innate Immune
Response ofCD38 KO Mice
225 CD38 and cADPR Regulate Intracellular Free Calcium Levels in
Response to FPR Ligation and Control Neutrophil Chemotaxis to
Bacterially-Derived Peptides
227 Modified Substrates ofCD38 can Modulate Neutrophil Chemotaxis
227 Remaining Questions
228 Where is CD38 Localized in Neutrophils
228 How Does CD38 Access Substrate
229 How Does cADPR Arrive at Its Intracellular Location
230 Is cADPR a Calcium Mobilizing Second Messenger in Neutrophils
230 How Does cADPR Regulate Intracellular Calcium Release and
Extracellular Calcium Influx in tMLP Stimulated Neutrophils
232 Does CD38 Catalyzed ADPR or NAADP Influence Calcium
Responses in Neutrophils
233 Working Model for CD38-Mediated Regulation ofInnate Immune
Responses
234 Acknowledgements
x
Contents
234 References
Subcellular and Extracellular Trafficking of NAD+ and Cyclic
ADP-Ribose: A New Way for Regulating Intracellular Calcium
Homeostasis
De Flora A, Guida L, Franco L, Bruzzone Sand Zocchi E, Genova,
Italy
241 Introduction
243 The Topological Paradox of the CD38/cADPR System
243 Phenomenological Data
245 NAD+ Transport: Role of Connexin 43 Hemichannels
247 Role ofCD38 as a Catalytically Active Transporter ofcADPR
248 Other cADPR Transporters
249 Intracellular Trafficking ofNAD+ and cADPR: The Autocrine Model
253 Extracellular Trafficking ofNAD+ and cADPR: Paracrine
Mechanisms
254 Interaction Between Mucosal Cells and Smooth Myocytes in
Bovine Trachea
255 CD38+/CD38-3T3 Murine Fibroblasts
257 Interactions Between CD38+ Stromal Cells and Human
Hemopoietic Progenitors
261 Interactions between CD38+ Rat Astrocytes and Hippocampal
Neurons
262 Conclusions
264 Acknowledgements
264 References
The CD38-Cyclic ADP-Ribose Signal System in Pancreatic 8-
Cells
The Discovery and Biological Significance of a Novel Signal
System in Mammalian Cells
Takasawa S and Okamoto H, Sendai, Japan
269 Historical Background
272 The CD38-Cyclic ADP-Ribose Signal System in Insulin Secretion
273 Cyclic ADP-Ribose Acts as a Second Messenger for Insulin
Secretion by Glucose
275 CD38 as a Major Enzyme for cADPR Metabolism in Mammalian
Cells
277 Mechanism oflntracellular Ca2+ Mobilization by cADPR in B-cells
280 The CD38-Cyclic ADP-Ribose Signal System in Pathological
Conditions
XI
