Intracellular Calcium

Professor Anthony K. Campbell is Professor in Medical Biochemistry, Cardiff University. He obtained an exhibition at Pembroke College, Cambridge, and then a first class degree in Natural Sciences, and a PhD in Biochemistry at Cambridge University. He moved to Cardiff as lecturer in Medical Biochemistry at the then Welsh National School of Medicine in 1970, and the Professor in Medical Biochemistry, followed by Professor in the School of Pharmacy and Pharmaceutical Sciences at Cardiff University. He has studied intracellular calcium as a cell regulator for over 40 years, pioneering the application of Ca2+-activated photoproteins to measure free Ca2+ in live animal, plant, bacterial and archaeal cells. He is a world authority on bioluminescence, developing the use of genetically engineered bioluminescence to measure chemical processes in live cells. One of his inventions, using chemiluminescence, is now used in several hundred million clinical tests per year worldwide, was awarded the Queen's Anniversary Prize in 1998, and was selected by the Eureka project of Universities UK in 2006 as one of the top hundred inventions and discoveries from UK Universities in the past fifty years. For the past 15 years his research focus has been lactose and food intolerance, which has led to a new hypothesis on the cause of irritable bowel syndrome, and the mystery illness which afflicted Charles Darwin for 50 years, but was never cured. He is now investigating the relevance of this hypothesis to the current diabetic epidemic, Parkinson's and Alzheimer's disease. He has published 9 books, and over 250 internationally peer-reviewed papers on intracellular calcium, bioluminescence, lactose and food intolerance. Several of his patents have been exploited throughout the world.

About the Author xvii

Preface xix

About the Companion Website xxiii

VOLUME ONE

1 Setting the Scene: What is So Special About Calcium? 1

1.1 Discovery of Calcium 2

1.2 A Natural History of Calcium 4

1.3 Elements of Life 8

1.4 Natural Occurrence of Calcium 11

1.5 Requirement of Cells for Ca2+ 19

1.6 Four Biological Roles of Calcium 23

1.7 The Puzzle About Ca2+ Inside Cells 29

1.8 1983 and All That 30

1.9 Darwin and Intracellular Ca2+ 33

1.10 The Scene Set 34

1.11 'Ja Kalzium, das ist alles!' 36


2 Intracellular Ca2+ – Principles and Terminology 39

2.1 The Problem 41

2.2 Some Specific Questions 41

2.3 Types of Intracellular Ca2+ Signal 44

2.4 Rubicon Principle 48

2.5 Key Experiments to Answer Key Questions 54

2.6 Nomenclature – How Things are Named 57

2.7 Model Systems 73

2.8 Darwin and Intracellular Ca2+ 73

2.9 Conclusions 79


3 One Hundred Years Plus of Intracellular Ca2+ 81

3.1 Background 81

3.2 Why Study the History of Science? 85

3.3 Tale of Three Pioneers and What Followed 86

3.4 Ca2+ as an Intracellular Regulator 95

3.5 Conceptual Development of Ca2+ as an Intracellular Regulator 124

3.6 Conclusions 127


4 How to Study Intracellular Ca2+ as Cell Regulator 129

4.1 Pathway to Discover the Role of Intracellular Ca2+ in a Cell Event 130

4.2 Manipulation of Extra- and Intracellular Ca2+ 131

4.3 Measurement of Intracellular Free Ca2+ 135

4.4 Detecting and Imaging Photons 166

4.5 Measurement of Total Cell Ca2+ 174

4.6 Calcium Buffers 176

4.7 Measurement of Ca2+ Fluxes 179

4.8 How to Study Ca2+ and Other Ion Channels 180

4.9 How to Discover How the Rise in Cytosolic Free Ca2+ Occurs and Then Returns to Rest 183

4.10 How to Discover the Intracellular Ca2+ Target and How it Works 184

4.11 Other Ions 185

4.12 Conclusions 185


5 How Ca2+ is Regulated Inside Cells 187

5.1 Principles 187

5.2 How Resting Cells Maintain Their Ca2+ Balance 191

5.3 Electrophysiology of Intracellular Ca2+ 194

5.4 Primary Stimuli Which Produce a Cytosolic Free Ca2+ Signal 200

5.5 Plasma Membrane Ca2+ Channels 204

5.6 Regulation of Intracellular Ca2+ By, and Within, Organelles 222

5.7 Second Messengers and Regulation of Ca2+ Signalling in the Cytosol 251

5.8 Pore Formers and Intracellular Ca2+ 255

5.9 Connexins and Gap Junctions 256

5.10 Other Ion Channels and Ca2+ 257

5.11 Conclusions 257


6 How Ca2+ Works Inside Cells 259

6.1 Biological Chemistry of Ca2+ 261

6.2 Ca2+-Binding Proteins 277

6.3 Ca2+ and Other Intracellular Signals 298

6.4 Ca2+ and Monovalent Ions 305

6.5 Transition Metals, Other Divalent Cations and Lanthanides 309

6.6 Conclusions 310


7 How Ca2+ Regulates Animal Cell Physiology 313

7.1 Ca2+ and How Nerves Work 314

7.2 Ca2+ and Cell Movement 317

7.3 Muscle Contraction 317

7.4 Chemotaxis and Ca2+ 330

7.5 Intracellular Ca2+ and Secretion 334

7.6 Ca2+ and Endocytosis 351

7.7 Intracellular Ca2+ and Intermediary Metabolism 354

7.8 Intracellular Ca2+ and Cell Growth 360

7.9 Intracellular Ca2+ and the Immune Response 371

7.10 Intracellular Ca2+ and Vision 373

7.11 Intracellular Ca2+ and Other Senses 378

7.12 Ca2+ and Bioluminescence 378

7.13 Intracellular Ca2+ and Gene Expression 386

7.14 Conclusions 386


VOLUME TWO

8 Intracellular Ca2+ and Microorganisms 389

8.1 The Puzzle 389

8.2 What Are Microorganisms? 391

8.3 What Do Microorganisms Do? 391

8.4 Indirect Evidence of a Role for Intracellular Ca2+ in Bacteria 393

8.5 Potential Role of Intracellular Ca2+ in Bacteria 394

8.6 How Much Ca2+ is There in Bacteria? 397

8.7 How Bacteria Regulate Their Intracellular Ca2 398

8.8 Ca2+-Binding Proteins in Bacteria 406

8.9 Regulation of Bacterial Events by Intracellular Ca2+ 406

8.10 Role of Intracellular Ca2+ in Archaea 426

8.11 Intracellular Ca2+ and Viruses 430

8.12 Intracellular Ca2+ and Eukaryotic Microorganisms 433

8.13 Conclusions 440


9 Role of Intracellular Ca2+ in Plants and Fungi 443

9.1 Role of Ca2+ in Plants 443

9.2 What Stimulates Plants? 444

9.3 Requirement of Plants for Ca2+ 447

9.4 Where Ca2+ is Stored in Plants 449

9.5 Measurement of Cytosolic Free Ca2+ in Plants 449

9.6 Identification of the Components of the Ca2+ Signalling System in Plants 455

9.7 How Intracellular Ca2+ Can Provoke Cellular Events in Plants 460

9.8 Fungal Elicitors 467

9.9 Apoptosis 467

9.10 Intracellular Ca2+ and Plant Pathology 467

9.11 Ca2+ in Mosses, Liverworts and Ferns 468

9.12 Darwin and Plants 469

9.13 Ca2+ in Fungi 469

9.13.1 Biology of Fungi 469

9.14 Ca2+ and Slime Moulds 472

9.15 Conclusions 472


10 Pathology of Intracellular Ca2+ 473

10.1 What is Pathology? 473

10.2 Types of Pathology 474

10.3 Intracellular Ca2+ – Friend or Foe? 475

10.4 Intracellular Ca2+ and Cell Death 476

10.5 Genetic Abnormalities in Ca2+ Signalling Proteins 483

10.6 Oxygen and Cell Pathology 487

10.7 Inappropriate Ca2+ Signalling 490

10.8 ER Stress Response 494

10.9 Conclusions 498


11 Pharmacology of Intracellular Ca2+ 499

11.1 Background to Compounds That Interact With Intracellular Ca2+ and Ca2+ Movement 499

11.2 Pharmacological Targets for Intracellular Ca2+ 504

11.3 Drugs Used Clinically That Interfere With Intracellular Ca2+ 505

11.4 Anaesthetics 506

11.5 Ca2+ Channel Effectors 508

11.6 Hypertension 516

11.7 Arrhythmia, Tachycardia and Bradycardia 517

11.8 Angina 517

11.9 Heart Failure 518

11.10 Agents Which Inhibit or Activate Adrenergic Receptors 518

11.11 Cardiac Glycosides 520

11.12 Benzodiazapines 521

11.13 Anti-Psychotic Drugs 522

11.14 Stimulants and Drugs of Abuse 525

11.15 Analgesics 527

11.16 Anti-Depressants and Manic Depression 532

11.17 Diabetes 532

11.18 Muscle Relaxants 533

11.19 Anti-Allergics and Anti-Immune Compounds 535

11.20 Xanthines 535

11.21 Substances Used Experimentally to Interfere with Intracellular Ca2+ 536

11.22 Natural Toxins and Poisons 548

11.23 Plant Toxins and Intracellular Ca2+ 557

11.24 Drugs and the Ca2+ Receptor 558

11.25 Bacteria 559

11.26 Ions and Intracellular Ca2+ 559

11.27 Antibodies and Intracellular Ca2+ 561

11.28 Summary and Conclusions 562


12 Darwin and 4000 Million Years of Intracellular Ca2+ 563

12.1 Darwin and Calcium 565

12.2 Evolution and Ca2+ 570

12.3 What is Evolution? 572

12.4 Evolution of Ca2+ Signalling 581

12.5 Darwin and Knock-Outs 593

12.6 Conclusions 596


13 They Think It's All Over 599

13.1 What We Know About the Details of Intracellular Ca2+ 600

13.2 What We Don't Know About Intracellular Ca2+ 603

13.3 Intracellular Ca2+ at School and University 606

13.4 Inspiration of Intracellular Ca2+ 607

13.5 Communicating the Story of Intracellular Ca2+ to Others 610

13.6 End of the Beginning 615


Bibliography 617

Organism Index 739

Subject Index 745