The purpose of the present volume, the first of two on the pharmacology, biochemistry, and physiology of cyclic nucleotides, is to provide a comprehensive and up-to-date anthology on the nature and role of these important chemical regulators. Each of the chapters is the work of internationally known researchers who present a lucid and detailed review of their subject and not merely a single laboratory's viewpoint. The chapters emphasize critical assessments of the field rather than mere listings of experimental findings. By so doing, the contributors present the role of cyclic nucleotides in relationship to other intracellular regulators. Each chapter begins with a detailed summary to allow the reader to obtain a rapid overview of subsequent material. In addition, there are extensive bibliographies and a detailed subject index. Wherever pertinent, the chapters contain sections on drug mechanisms, physiological relevance, and disease processes. The Volume is divided into two sections, each beginning with an overview written by Professors T. W. RALL and P. GREENGARD, respectively. The first section focuses on the detailed pharmacology and chemistry of cyclic nucleotides, including their formation, degradation, measurement, and interaction with various modulatory agents, such as receptors and calcium. The second section is concerned with the biochemistry of protein phosphorylation, a process which appears to be one of the most important mechanisms for the intracellular expression of cyclic nucleotide action in eukaryotic cells.

Inhalt

Section I: Biochemistry of Cyclic Nucleotides.- 1 Formation and Degradation of Cyclic Nucleotides: An Overview.- A. Introduction.- B. Historical Review.- I. Discovery of Cyclic AMP.- II. Early Characterization of Adenylate Cyclase and Discovery of Cyclic Nucleotide Phosphodiesterase.- III. Discovery of Cyclic GMP and Guanylate Cyclase.- C. Regulation of Cyclic AMP Accumulation in Tissues.- I. Introduction.- II. Regulation of Cyclic AMP Formation.- 1. Basal and Hormone-Induced Accumilation of Cyclic AMP in Intact Cells.- 2. Effects of Guanyl Nucleotides and Cholera Toxin.- III. Regulation of Cyclic AMP Degradation.- IV. Potentiative Interactions and the Potential Role of Calcium.- D. Concluding Remarks.- References.- 2 Chemistry of Cyclic Nucleotides and Cyclic Nucleotide Analogs..- Overview.- A. Introduction to the Chemistry of Cyclic Nucleotides.- B. Synthesis of Cyclic Nucleotides and Cyclic Nucleotide Analogs.- I. Cyclic Nucleotides Related to Adenosine 3',5'-Cyclic Phosphate.- 1. Substituent Modification of the Purine Base.- 2. Structural Modification of the Carbohydrate Moiety.- 3. Structural Modification of the Cyclic Phosphate Moiety.- II. Cyclic Nucleotide Analogs Related to cAMP.- 1. 1-Deazapurine Cyclic Phosphates.- 2. 3-Deazapurine Cyclic Phosphates.- 3. 7-Deazapurine Cyclic Phosphates.- 4. 2-Azapurine Cyclic Phosphates.- 5. 8-Azapurine Cyclic Phosphates.- 6. Formycin Cyclic Phosphates.- 7. 1,N6-Ethenoadenosine Cyclic Phosphates.- III. Cyclic Nucleotides Related to Guanosine Cyclic Phosphate.- IV. Pyrimidine Cyclic Nucleotides.- V. Miscellaneous Cyclic Nucleotides.- C. Chemical and Physical Properties of Cyclic Nucleotides.- I. Hydrolytic Studies.- II. Spectral Measurements.- III. Ultraviolet Spectrophotometric Measurements.- D. Structure and Enzymic Activity Relationships of Certain Nucleoside 3?,5?-Cyclic Phosphates.- I. Structural Requirements for the Stimulation of Various Protein Kinases.- II. Structural Requirements for Stability Against Cyclic Nucleotide Phosphodiesterases.- III. Cyclic Nucleotides and Inhibition of Cellular Proliferation.- IV. Cyclic Nucleotides and Antiviral Effects.- V. Cyclic Nucleotide Analogs and Cardiovascular Effects.- E. List of Abbreviations Used.- References.- 3 Coupling of Receptors to Adenylate Cyclases.- Overview.- A. Introduction.- B. Guanine Nucleotide Regulation of Adenylate Cyclases.- C. Regulation of Coupling of Hormone Receptor to Adenylate Cyclase.- D. Receptor Regulation and Receptor Forms.- I. Effects of Guanine Nucleotides on Binding of Hormone to Receptor.- II. Definition of an Active Form of Receptor.- III. Number of Sites Involved in Coupling.- E. Concluding Remarks and Future Outlooks.- I. Roles of Mg++.- II. Inhibitory Effects of Hormones.- III. Is GTPase Indeed an Integral Part of Adenylate Cyclases?.- IV. Are Levels of N Regulated?.- V. Molecular Basis for Coupling: Size Studies and Subunit Interactions.- References.- 4 Acute and Chronic Modulation of the Responsiveness of Receptor-Associated Adenylate Cyclases.- Overview.- A. Introduction.- I. Historical Perspective.- II. Scope of the Review.- III. The Structure and Function of Adenylate Cyclase.- B. Agonist-Induced Decreases in the Response of Cells to Hormones.- I. Early Observations.- II. Agonist-Induced Desensitization of Intact Cells.- 1. General Characteristics of Agonist-Induced Desensitization.- 2. Effects of Cyclic AMP and Cyclic AMP Analogs.- 3. Whole Cell Analysis of Rates of Cyclic AMP Synthesis and Degradation.- 4. Conclusions Based on Studies with Whole Cells.- III. Agonist-Induced Changes in Adenylate Cyclase and Hormone Binding.- IV. Separation of Native and Desensitized Beta-Adrenergic Receptors..- V. Catecholamine-Induced Desensitization in C6-2B Glioma Cells.- VI. Agonist-Induced Desensitization in Cell-Free Preparations.- VII. Desensitization of Gonadotropin Receptor-Linked Adenylate Cyclase.- C. Receptor-Mediated Inhibition of Adenylate Cyclase Activity.- D. Physiological Significance of the Regulation of Responsiveness to Hormones.- References.- 5 Guanylate Cyclase: Regulation of Cyclic GMP Metabolism..- Overview.- A. Introduction.- B. Guanylate Cyclase.- I. Activities in Various Tissues and Subcellular Distribution.- II. Altered Enzyme Activity and Subcellular Distribution.- III. Kinetic and Physical Properties of the Multiple Forms.- 1. Molecular Size and Subunits.- 2. Effect of GTP and Other Nucleotides.- 3. Effects of Cations.- 4. Antibodies Against Guanylate Cyclase.- IV. Activation.- 1. Detergents.- 2. Spontaneous Activation.- 3. Effects of Azide and Nitro Compounds.- 4. Oxidation and Hydroxyl Radical.- 5. Fatty Acids and Their Metabolites.- 6. Phospholipase and Lipoxygenase.- 7. Effects of Proteins.- V. Altered Kinetic Properties with Activation.- 1. Cation Dependence.- 2. Effects of Nucleotides.- 3. Formation of Cyclic AMP.- VI. Inactivation.- 1. Hemeproteins.- 2. Other Inhibitors.- C. Cyclic GMP Levels in Tissues.- I. Effects of Hormones and Autacoids.- 1. Effects of Pituitary Hormones and Thyroid Function.- 2. Choline Esters.- 3. Histamine.- 4. Alpha-Adrenergic Agonists.- 5. Insulin.- 6. Ionophore A-23187.- 7. Other Agents.- II. Effects of Nitro Compounds and Nitric Oxide.- III. Effect of E. Coli Heat-Stable Enterotoxin.- D. Conclusion and Hypotheses.- References.- 6 Cyclic Nucleotide Phosphodiesterase..- Overview.- A. The Phosphodiesterase Reaction and Assay.- B. Multiple Forms of Phosphodiesterase.- I. Identification and Separation.- II. Properties.- III. In vitro Alterations and Possible Interconversions.- C. Localization.- D. Activators and Inhibitors.- I. Cyclic Nucleotides as Effectors of Enzyme Activity.- II. Other Effectors.- E. Physiological Roles of the Cyclic Nucleotide Phosphodiesterases.- I. Development.- II. Transformation and Malignancy.- III. Insulin and Other Metabolic Hormone Actions.- IV. Neurotransmission.- F. Prognosis.- References.- 7 Calmodulin Regulation of Cyclic AMP Metabolism..- Overview.- A. Introduction.- B. Calmodulin.- I. Properties of Calmodulin.- II. Preparation and Assay of Calmodulin.- III. Calmodulin-Regulated Cellular Processes.- IV. Mechanism of Action.- C. Adenylate Cyclase.- I. Ca2+ Sensitivity of Adenylate Cyclase.- II. Regulation of Adenylate Cyclase by Calmodulin.- D. Cyclic Nucleotide Phosphodiesterase.- I. Multiple Forms of Phosphodiesterase.- II. Ca2+-Dependent Phosphodiesterase.- E. Biological Significance.- Ref…