Cyclic nucleotides are intimately involved in the consequences of either stimulation or blockade of receptors; therefore, an understanding of the biochemistry of cyclic nucleotides ought to be important for pharmacologists. Pharmacology is a science that among other things investigates chemical compounds that affect the physiology of cells, tissues and organs. Frequently pharmacologists account for the effect of low concentrations of a drug upon a tissue by invoking the presence of a receptor upon the surface of the cell. Traditional pharmacologists excelled at identifying and classifying the properties of receptors. A. J. CLARK'S monograph in the earlier series of the Handbook of Experimental Pharmacology (CLARK 1937) summarized the mathematics underlying the traditional pharmacological approach towards receptors. By its nature, however, classic pharmacology provided little useful information about the intracellular events occurring as a consequence of occupying a receptor; for example, ALQUIST (1948) identified the beta-adrenocep­ tor, but he did not provide any insight into how stimulation of the receptor produces tissue-specific physiological responses. The discovery of cyclic AMP by RALL and SUTHERLAND (see RALL, Vol. I) led to biochemical investigations of many different receptors (including ALQUIST'S beta-adrenoceptor) that share a cyclic nucleotide as a common factor in the biochemical mechanisms that translate the occupancy of receptors into physiological effects. Ten years ago, in the introduction to their monograph on cyclic nucleotides, ROBISON et al. (1971) commented on the rapid growth of interest in cyclic nucleotides over the preceding years.

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Section III. Physiology and Pharmacology of Cellular Regulatory Processes.- 16 Regulation of Carbohydrate Metabolism by Cyclic Nucleotides.- Overview.- A. Regulation of Hepatic Glycogenolysis.- I. Glucagon Stimulation of Hepatic Glycogenolysis.- 1. Evidence That Glucagon Exerts Physiological Control on Hepatic Glycogenolysis.- 2. Role of Cyclic AMP in Glucagon Action.- 3. Role of Cyclic AMP-Dependent Protein Kinase.- 4. Role of Phosphorylase b Kinase.- 5. Activation of Phosphorylase.- 6. Possible Role of Phosphoprotein Phosphatase.- 7. Evidence Against a Role for Ca2+ in Glucagon Stimulation of Glycogenolysis.- II. Catecholamine Stimulation of Hepatic Glycogen Breakdown.- 1. Role of Catecholamines and the Sympathetic Nervous System in the Control of Hepatic Glycogenolysis.- 2. The Nature of the Adrenergic Receptors Mediating Catecholamine Effects on the Liver.- 3. Mechanisms Involved in Adrenergic Stimulation of Hepatic Glycogenolysis.- III. Actions of Vasopressin, Angiotensin II and Oxytocin on Hepatic Glycogenolysis.- IV. Insulin Inhibition of Hepatic Glycogenolysis.- 1. Action Against Glucagon.- 2. Action Against Catecholamines.- V. Glucose Modulation of Hormone Effects on Hepatic Glycogenolysis.- VI. Permissive Effects of Glucocorticoids on Hormone Activation of Liver Phosphorylase.- B. Regulation of Hepatic Glycogen Synthesis.- I. Glucose Inhibition of Hepatic Glycogen Synthesis.- II. Catecholamine Inhibition of Hepatic Glycogen Synthesis.- III. Insulin, Glucose, and Glucocorticoid Stimulation of Hepatic Glycogen Synthesis.- C. Regulation of Hepatic Gluconeogenesis.- I. Glucagon Stimulation of Hepatic Gluconeogenesis.- 1. Evidence That Glucagon Exerts Physiological Control on Gluconeogenesis.- 2. Glucagon Inhibition of Hepatic Pyruvate Kinase.- 3. Glucagon Stimulation of Hepatic Pyruvate Carboxylation.- 4. Apparent Non-Involvement of Pyruvate Dehydrogenase in Glucagon Stimulation of Hepatic Gluconeogenesis.- 5. Glucagon Inhibition of Hepatic P-Fructokinase.- 6. Glucagon Induction of P-Enolpyruvate Carboxykinase.- 7. Other Mechanisms Possibly Involved in Glucagon Stimulation of Gluconeogenesis.- II. Catecholamine Stimulation of Hepatic Gluconeogenesis.- III. Insulin Inhibition of Hepatic Gluconeogenesis.- IV. Permissive Effects of Glucocorticoids on Hormone Activation of Hepatic Gluconeogenesis.- D. Regulation of Muscle Glycogenosis.- I. Catecholamine Stimulation of Muscle Glycogenosis.- 1. Physiological Aspects.- 2. Roles of Cyclic AMP, Cyclic AMP-Dependent Protein Kinase, and Phosphorylase b Kinase.- 3. Activation of Phosphorylase.- 4. Possible Role of Phosphorylase Phosphatase.- 5. Permissive Effects of Glucocorticoids on Catecholamine Stimulation of Muscle Glycogenosis.- E. Regulation of Muscle Glycogen Synthesis.- I. Regulation of Glycogen Synthase by Phosphorylation.- II. Catecholamine Inhibition of Muscle Glycogen Synthesis.- III. Insulin Stimulation of Muscle Glycogen Synthesis.- F. Regulation of Pyruvate Metabolism in Muscle.- G. Regulation of Carbohydrate Metabolism in Adipose Tissue.- I. Catecholamine Effects on Glycogen and Pyruvate Metabolism in Adipose Tissue.- II. Insulin Effects on Glycogen Metabolism in Adipose Tissue.- III. Insulin Effects on Pyruvate Metabolism in Adipose Tissue.- References.- 17 Regulation of Lipid Metabolism by Cyclic Nucleotides.- Overview.- A. Cyclic Nucleotides in Regulation of Triglyceride Breakdown in Adipocytes.- I. Role of Lipid Mobilization from Adipocytes.- II. Adenylate Cyclase Regulation.- 1. Short-Acting Hormones Which Active Adenylate Cyclase Through Receptor Binding: Catecholamines.- 2. Regulation of the Coupling of Hormone-Receptor Complexes to Adenylate Cyclase: Thyroid Hormones.- 3. Adenylate Cyclase Regulation by Inhibition of Deactivation: Cholera Toxin.- 4. Regulation Through Synthesis of Components of Adenylate Cyclase: Growth Hormone and Glucocorticoids.- 5. Inhibition of Adenylate Cyclase.- III. Cyclic AMP Phosphodiesterase Regulation.- IV. Protein Kinase Regulation by Cyclic AMP.- V. Activation of Triacylglycerol Lipase by Protein Kinase.- VI. Lipoprotein Lipase Regulation.- VII. Role of Cyclic AMP Independent Processes in Triglyceride Breakdown.- 1. Calcium and Catecholamine Activation of Lipolysis.- 2. Calcium, Phospholipase A2 Activation, and the Lipolytic Action of ACTH.- 3. Regulation of Lipolysis via Substrate Availability.- B. Catecholamine Activation of Thermogenesis in Brown Adipose Tissue via Cyclic Nucleotides.- I. Role of the Na+/K+ Plasma Membrane Pump in Thermogenic Action of Catecholamines.- II. Mitochondrial Uncoupling by Fatty Acids in the Regulation of Thermogenesis.- III. Cyclic AMP as the Mediator of Catecholamine-Activated Lipolysis.- C. Calcium, Cyclic Nucleotides, and Glycogen Synthase Regulation.- I. Calcium-Dependent Regulation of Glycogen Metabolism by Alpha1-Catecholamines.- II. Relationship Between Alpha1-Adrenergic Stimulation of Phos-phatidylinositol Turnover and Ca2+.- D. Mode of Insulin Action Through Cyclic Nucleotides, Ca2+ and Special Mediators.- I. Insulin Action on Adipocytes. Regulation of Glycogen Synthase and Pyruvate Dehydrogenase.- II. Insulin, Cyclic GMP, and Calcium.- III. Insulin and Hexose Transport.- IV. Menadione, Insulin, and H2O2.- V. Insulin, Catecholamines, and Protein Phosphorylation.- E. Conclusion.- References.- 18 Regulation of the Cell Cycle and Cellular Proliferation by Cyclic Nucleotides.- Overview.- A. Role of Cyclic Nucleotides in Cell Proliferation.- I. Cultured Fibroblasts.- 1. The G+-G0 Interconversion.- 2. Other Cell Cycle Effects of cAMP in Fibroblasts.- II. Liver Cells.- 1. Liver Regeneration.- 2. Continuous Cultures of Liver Cells.- III. Neuroblastoma Cells.- IV. Adrenal Cortical Cells.- V. Thyroid Cells.- VI. Melanoma Cells.- VII. Schwann Cells.- VIII. S49 Lymphoma Cells.- IX. Thymic Lymphocytes.- X. Hemopoietic Stem Cells (CFU-S).- XI. HeLa Cells.- XII. Miscellaneous Cell Types.- XIII. Generalizations on the Actions of Cyclic Nucleotides in Cell Proliferation.- 1. Cell Cycle Loci of cAMP Action.- 2. Speculations on the Physiological Role of cAMP in Growth Regulation.- B. Cyclic Nucleotides and Cancer.- I. cAMP and Properties of Transformed Fibroblasts.- II. Cyclic Nucleotides and Tumors of Liver.- III. Cyclic Nucleotide Levels in Tumors.-…