Cyclic Nucleotides

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.- References.- 8 Radioimmunoassay Techniques for Cyclic Nucleotides.- Overview.- A. Introduction.- B. Preparation and Characterization of Antisera.- C. Preparation and Purification of [125I]-Labeled Cyclic Nucleotides.- D. Preparation of Samples for Assay.- E. Acetylation or Succinylation.- F. Assay Procedure.- G. Data Analysis.- H. Evaluation of Assay Validity.- I. Total Automation of the Cyclic AMP and Cyclic GMP Assay with the Gamma-Flo Assay System.- References.- 9 Immunocytochemistry of Cyclic Nucleotides and Their Kinases..- Overview.- A. Introduction.- B. Principles.- C. Techniques.- D. Cyclic Nucleotide Immunocytochemistry.- I. Preparation of Antisera.- II. Testing of Antisera for Specificity of Staining.- III. Methodological Considerations.- E. Protein Kinase Immunocytochemistry.- I. Purification of Immunogens.- II. Preparation and Selection of Antisera.- III. Characterization of Antisera for Immunocytochemistry.- 1. Cyclic AMP-Dependent Protein Kinases and Their Subunit Antisera.- 2. Cyclic GMP-Dependent Protein Kinase Antisera.- IV. Determination of Specificity of Protein Kinase Antisera by Radio-immunoassay.- V. Testing of Antisera for Specificity of Staining.- VI. Methodological Considerations.- 1. Crossreactivity of Antibodies for Holoenzyme and Their Subunits.- 2. Avidity of an Antiserum for Available Determinants in Tissue.- 3. Losses and Redistribution of Protein Kinases.- 4. Species Specificity of Protein Kinase Immunocytochemistry.- F. Future Perspectives.- References.- Section II: Biochemistry of Protein Phosphorylation.- 10 Protein Phosphorylation: An Overview.- References.- 11 Cyclic AMP-Dependent Protein Phosphorylation.- Overview.- A. Introduction.- B. History of Discovery of cAMP-Dependent Protein Kinase.- C. Nomenclature and General Activation Mechanism of Protein Kinase.- D. Isolation of cAMP-Dependent Protein Kinase.- E. Physical Properties of Protein Kinase.- F. Naturally Occurring Mechanisms Modulating Protein Kinase Activity.- I. Heat-Stable Protein Inhibitors.- 1. Muscle Inhibitor.- 2. Testis Inhibitor.- II. Nucleotide Effects.- 1. cAMP.- 2. ATP.- III. ATP-Dependent Phosphorylations.- 1. Autophosphorylation of RII.- 2. Phosphorylation of RI.- G. Substrates of cAMP-Dependent Protein Kinase.- I. Primary Sequence Determinants.- II. Higher Order of Structure Effects.- H. Physiological Effects of Phosphorylation.- I. Criteria for Evaluating Physiological Roles of Cyclic Nucleotide-Dependent Phosphorylation Reactions.- II. Methods of Demonstrating Criteria, Problems Encountered, and Interpretation of Results.- III. Effects of Phosphorylation on the Activity or Function of the Substrate.- IV. Proteins of Known Function as Substrates.- I. Current Areas of Research.- I. Current Research on cAMP-Dependent Protein Kinase.- 1. Stoichiometry and Properties of cAMP Binding.- 2. Mechanism of Activation and Inactivation.- 3. Compartmentalization.- 4. Genetic Studies, Mutant Cell Lines.- 5. Differential Regulation of R and C.- II. Current Research on Substrates of Protein Kinase.- 1. Multiple Phosphorylations.- 2. Recently Identified Substrates.- References.- 12 Cyclic GMP-Dependent Protein Phosphorylation.- Overview.- A. Introduction.- B. Enzymology.- I. Distribution.- II. Molecular Properties and Mechanism of Action of Cyclic GMP.- III. General Catalytic Properties.- C. Substrate Proteins.- I. Autophosphorylation of G-PK.- II. Histone.- III. Non-Histone Proteins.- 1. Phosphorylase Kinase.- 2. Glycogen Synthase.- 3. Hormone-Sensitive Lipase and Cholesterol Ester Hydrolase.- 4. Pyruvate Kinase.- 5. Troponin Inhibitory Subunit (TN-I).- 6. Other Proteins.- IV. Membrane and Cytoplasmic Proteins.- D. Factors Influencing Protein Phosphorylation.- I. Stimulatory Modulator.- II. Polyanions, Polycations, and Basic Polypeptides.- E. Physio-Pathologic Aspects of the G-PK System.- F. Concluding Remarks.- References.- 13 Calcium-Dependent Protein Phosphorylation.- Overview.- A. Introduction.- B. Role of Calcium in Regulation of Carbohydrate Metabolism.- C. Role of Calcium in Regulation of Protein Phosphorylation in Intact Systems.- I. Calcium-Dependent Protein Phosphorylation in Brain.- II. Calcium-Dependent Protein Phosphorylation in Mast Cells..- III. Regulation of Protein Phosphorylation in Isolated Hepatocytes.- D. Calmodulin- and Calcium-Dependent Protein Kinase in Biological Membranes.- I. Calcium-Dependent Protein Phosphorylation in Isolated Brain Membranes.- II. Identification of Protein Kinase Activator as Calmodulin.- III. Characteristics of Protein Kinase Activity.- IV. Function of Calcium-Dependent Protein Phosphorylation in Brain.- V. Regulation of Protein I Phosphorylation by cAMP and by Calcium.- E. Widespread Occurrence of Calmodulin- and Calcium-Dependent Protein Phosphorylation in Biological Membranes.- F. Myosin Light Chain Kinase in Skeletal Muscle, Smooth Muscle, and Non-Muscle Cells.- I. Myosin Light Chain Kinase in Skeletal Muscle.- II. Myosin Light Chain Kinase in Smooth Muscle.- III. Myosin Light Chain Kinase in Non-Muscle Cells.- IV. Mechanism of Activation of Myosin Light Chain Kinase.- V. Physiological Function of P-Light Chain Phosphorylation.- G. Phosphorylase Kinase.- I. Regulation of Phosphorylase Kinase by Calmodulin.- II. Activation of Phosphorylase Kinase by Troponin C.- III. Regulation of Phosphorylase Kinase in Vitro.- IV. Regulation of Phosphorylase Kinase in Vivo.- H. Phospholipid-and Calcium-Dependent Protein Kinase.- I. Irreversible Activation of Protein Kinase C by Calcium-Dependent Protease.- II. Reversible Activation of Protein Kinase C by Calcium and Membrane Factor.- I. Concluding Comments.- References.- 14 Photoaffinity Labeling of Cyclic AMP-Dependent and Cyclic GMP-Dependent Protein Kinases.- Overview.- A. Introduction.- I. Principles of Affinity Labeling and Photoaffinity Labeling.- II. Brief Review of cAMP- and cGMP-Receptor Proteins.- B. Photoaffinity Analogues of cAMP and cGMP.- I. Available Photoaffinity Analogues of cAMP and cGMP.- II. Synthesis and Characterization of 8-N3-[32P] cAMP.- III. Procedures for Photoaffinity Labeling and Other Methods to Assay cAMP- and cGMP-Dependent Protein Kinases.- C. Studies with Purified cAMP-Dependent Protein Kinase.- I. Photoaffinity Labeling of Regulatory Subunit.- II. Photoaffinity and Affinity Labeling of Catalytic Subunit.- D. Application of Photoaffinity Labeling to Crude Systems.- E. Specific Examples of the Usefulness of the Photoaffinity Label 8-N3-[32P] cAMP.- I. Distribution and Differences of Type I and Type II cAMP-Dependent Protein Kinase.- II. Proteolytic Fragments of cAMP-Dependent Protein Kinases.- III. Subcellular Distribution of cAMP-Dependent Protein Kinases and cAMP-Receptor Proteins.- IV. Regulation of cAMP-Dependent Protein Kinase and cAMP-Receptor Proteins.- F. Photoaffinity Labeling of cGMP-Dependent Protein Kinase.- G. Problem Areas.- H. Conclusions.- References.- 15 Nuclear Protein Phosphorylation and the Regulation of Gene Expression.- Overview.- A. Introduction.- B. Nuclear Cyclic Nucleotide-Dependent Protein Kinase Activities.- I. Cyclic AMP-Dependent Protein Kinase.- 1. Translocation to Nuclei.- 2. Endogenous Nuclear Cyclic AMP-Dependent Protein Kinase.- II. Cyclic GMP-Dependent Protein Kinase.- III. Cytochemical Localizations of Protein Kinase Activities.- C. Histone Phosphorylation.- I. H1 Phosphorylation.- 1. Cyclic Nucleotide-Dependent H1 Phosphorylation.- 2. Cyclic Nucleotide-Independent H1 Phosphorylation.- II. Phosphorylation of Histones Other than H1.- III. Role of H1 Phosphorylation in Altering Nucleosome Structure.- D. Non-Histone Protein Phosphorylation.- I. Phosphorylation of Eukaryotic DNA-Dependent RNA Polymerases.- II. Phosphorylation of HMG Proteins.- E. Phosphorylation of Ribosomal Proteins.- F. Protein Phosphorylation and Viral Transformation.- G. Functional Aspects of Protein Kinase Substrates: A Procedure for Isolating Newly-Phosphorylated Polypeptides.- H. Protein Phosphorylation as a Means of Altering the Genetic Program: The Problem of Specificity.- I. Conclusions.- References.