Gastrointestinal Regulatory Peptides

1 Localization and Colocalization of Gastrointestinal Peptides.- A. Introduction.- B. Coexistence of Messengers.- C. Endocrine and Paracrine Cells.- I. Stomach.- II. Small Intestine.- III. Large Intestine.- IV. Coexistence of Peptides in Gut Endocrine Cells.- D. Enteric Neurons.- I. Distribution of Peptide-Containing Nerve Fibers in the Digestive Tract.- II. Projections of Enteric Neurons in the Rat.- 1. Myenteric Neurons.- 2. Submucous Neurons.- III. Coexistence of Peptides in Enteric Neurons.- References.- 2 Regulation of Gastrointestinal Peptide Hormone Gene Expression.- A. Introduction.- B. Gene Structure.- C. RNA Polymerase II.- D. Transcriptional Regulation Overview.- I. DNA Elements.- II. Transcription Factors.- 1. General Transcription Factors.- 2. Regulated Transcription Factors.- 3. Modulation of Transcription Factor Activity.- III. Transcriptional Repression.- IV. Genes Lacking TATA Elements.- E. Analysis of Gene Expression.- I. RNA Quantitation.- II. Promoter Studies.- F. Regulation of Specific Hormone Gene Expression.- I. Preface.- II. Gastrin/Cholecystokinin Family.- 1. Gastrin: Background.- 2. Luminal Regulation of Gastrin Gene Expression.- 3. Islet Cell Gastrin Expression.- 4. Gastrin Promoter Analysis.- a) Studies in Pituitary Cell Lines.- b) Studies in Islet Cells.- 5. Cholecystokinin: Background.- 6. Cholecystokinin Gene Regulation: RNA Quantitation.- 7. Cholecystokinin: Promoter Analysis.- III. Somatostatin.- 1. Somatostatin Gene Regulation.- 2. Model of cAMP Regulation.- 3. Tissue Specific Expression.- IV. Glucagon.- V. Secretin.- VI. Motilin.- G. Conclusion.- References.- 3 Post-Translational Processing of Regulatory Peptides.- A. Introduction.- B. General Design of Processing Systems.- I. Active Peptide Stored in Secretory Vesicles.- II. Active Peptide Released Constitutively.- III. Precursor Activated in or Near Cell of Origin.- 1. Precursor Stored Intracellularly.- 2. Precursor Anchored to Cell Surface.- IV. Precursor Activated in the Interstitial Space or Blood.- V. Precursor Activated at Target or by Other Cells.- 1. Precursor Stored Outside Target.- 2. Precursor Stored Inside Target.- VI. Mixed Systems.- C. Intracellular Trafficking and Processing Pathways.- D. Processing Sites and General Mechanisms.- I. Two-Step Processing.- II. Dibasic, Monobasic and Nonbasic Sites.- III. Conformation and Consensus Features.- IV. Sequentially Ordered Reactions.- V. Tissue-Specific Processing.- E. Enzymes Involved in the Processing of Prohormones.- I. Dibasic Residue-Specific Endoproteases.- II. Monobasic Residue-Specific Endoproteases.- III. Tetrabasic Residue-Specific Endoproteases.- IV. Exopeptidases.- V. Enzymes Involved in N- and C-Terminal Modification.- 1. Acetyltransferase.- 2. Glutaminyl Cyclase.- 3. Peptidylglycine a-Amidating Monooxygenase.- VI. Enzymes Involved in Sulfation and Phosphorylation.- 1. Tyrosine Sulfation Enzyme.- 2. Serine Phosphorylating Enzymes.- F. Processing of Specific Prohormones.- I. Yeast Pheromones.- II. Proopiomelanocortin.- III. Gastrointestinal Hormones.- 1. Glucagon and Related Peptides.- 2. Cholecystokinin.- 3. Gastrin.- 4. Somatostatin.- 5. Neurotensin and Neuromedin-N.- 6. Pancreatic Polypeptide.- G. Conclusion.- References.- 4 Regulation of Peptide Secretion from Gastroenteric Endocrine Cells.- A. Introduction.- B. Gastroenteric Endocrine Cells.- I. Localization.- II. Methods for Studying Peptide Release.- C. Neurotransmitter and Peptide Regulation of Release.- I. Acetylcholine.- II. Norepinephrine.- III. Somatostatin.- IV. Gastrin-Releasing Peptide and Bombesin.- V. Gastrin and Cholecystokinin.- D. Nutrient Regulation of Peptide Release.- I. Proteins and Amino Acids.- II. Fatty Acids.- E. Regulation of Release by Luminal pH.- F. Summary.- References.- 5 Peptide Receptors and Signal Transduction in the Digestive Tract.- A. Introduction.- B. General Considerations and Methodology.- I. Receptor Concept and General Properties.- II. Methods for Study of Receptors.- 1. Tissue Preparations.- 2. Radiolabeled Ligand.- 3. Separation of Bound and Unbound Ligand.- III. Molecular Characterization and Purification.- IV. Receptor Cloning Strategies.- C. Signal Transduction by Receptors.- I. Adenylyl Cyclase: Cyclic AMP Pathway.- II. Phosphatidyl Inositol Signaling.- D. Peptide Receptors in the Digestive Tract.- I. Vasoactive Intestinal Peptide.- II. Galanin.- III. Neurotensin.- E. Conclusion and Perspectives.- References.- 6 Proteolytic Inactivation of Neurohormonal Peptides in the Gastrointestinal Tract.- A. Introduction.- B. Proteolytic Enzymes Implicated in the Inactivation of Neurohormonal Peptides in the Gastrointestinal Tract.- I. Endopeptidases.- 1. Endopeptidase 24.11.- 2. Endopeptidase 24.15.- 3. Endopeptidase 24.16.- II. Exopeptidases.- 1. Peptidyl Dipeptidase A.- 2. Aminopeptidases.- 3. Dipeptidyl Aminopeptidase IV.- 4. Carboxypeptidases.- C. Pathways of Proteolytic Inactivation of Some Gastrointestinal Hormones.- I. Neurotensin.- II. Gastrin.- III. Cholecystokinin.- IV. Somatostatin.- D. Pathways of Proteolytic Inactivation of Some Gastrointestinal Neuropeptides.- I. Tachykinins.- II. Enkephalins.- III. Vasoactive Intestinal Polypeptide.- E. Conclusion.- References.- 7 Peptidergic Regulation of Gastric Acid Secretion.- A. Introduction.- B. Acid Secretory Control Mechanisms In Vivo.- I. Extrinsic Innervation and Central Control.- II. Intrinsic Innervation.- III. Cephalic and Gastric Phases of Secretion.- 1. Gastrin Release Mechanisms.- 2. Effects of Other Peptides.- IV. Intestinal Factors.- V. Inhibitory Phases of Acid Secretion.- 1. Cephalic Influences.- 2. Antral and Fundic Mechanisms.- 3. Intestinal Inhibitory Mechanisms.- a) Secretin.- b) Cholecystokinin.- c) Gastric Inhibitory Polypeptide.- d) Somatostatin.- e) Neurotensin.- f) Glucagon-Like Peptides.- g) Peptide YY.- 4. Neuropeptide Inhibitors.- a) Substance P.- b) Galanin.- C. Peptide Effects on Isolated Cells.- I. Parietal Cells.- 1. Peptide Activation Mechanisms.- a) Gastrin.- b) Effects of Other Peptides.- 2. Peptide Inhibitory Mechanisms.- a) Somatostatin.- b) Epidermal Growth Factor.- c) Other Inhibitory Peptides.- II. Antral G Cells.- III. Fundic and Antral D Cells.- IV. Histamine-Containing Cells.- References.- 8 Peptides and Enteric Neural Activity.- A. Introduction.- B. Electrophysiology of Enteric Nerves.- C. Actions of Peptides on Enteric Nerves.- I. Tachykinin Peptides.- 1. Tachykinin Peptides in Enteric Nerves.- 2. Tachykinins Depolarize Enteric Neurons.- 3. Tachykinins Decrease Resting Potassium Conductance (GK).- 4. Tachykinin-Induced Depolarizations Associated with a Conductance Increase.- 5. Tachykinin Receptors on Enteric Neurons.- 6. Tachykinin Receptors Coupled to Polyphosphoinositide Hydrolysis.- 7. Synaptic Activation of Tachykinin Receptors.- II. Vasoactive Intestinal Peptide.- 1. Vasoactive Intestinal Peptide Receptors Coupled to GK Decrease.- 2. Vasoactive Intestinal Peptide Receptors May Be Coupled to Adenylate Cyclase in Enteric Nerves.- 3. Synaptic Potentials Mediated by Vasoactive Intestinal Peptide.- III. Calcitonin Gene-Related Peptide.- 1. Calcitonin Gene-Related Peptide Receptors Coupled to GK Decrease.- 2. Transduction Mechanism.- IV. Cholecystokinin.- 1. Cholecystokinin Receptors Coupled to a GK Decrease.- 2. Transduction Mechanism.- 3. Receptors on Enteric Neurons.- 4. Cholecystokinin Facilitates Neurotransmission in Pancreatic and Gallbladder Ganglia.- V. Gastrin-Releasing Peptide/Bombesin.- VI. Motilin.- VII. Opioid Peptides.- 1. Opioid Peptides Hyperpolarize Enteric Neurons and Increase GK.- 2. Opioid Peptides Activate an Inwardly Rectifying GK.- 3. Transduction Mechanism for Opioid-Activated GK.- 4. Opioid Receptors on Enteric Neurons.- 5. Opioid Receptors Coupled to Inhibition of Calcium Channels.- 6. Functional Implications of Opioid Peptide Action on Enteric Nerves.- VIII. Somatostatin.- 1. Somatostatin Hyperpolarizes Enteric Neurons by Increasing an Inwardly Rectifying GK.- 2. AG-Protein Couples the Somatostatin Receptor to the Potassium Channel.- 3. Nonadrenergic Inhibitory Postsynaptic Potential Mimicked by Somatostatin.- 4. Somatostatin Inhibits Calcium Currents.- 5. Functional Consequences of Somatostatin Action on Enteric Neurons.- IX. Galanin.- X. Neuropeptide Y.- D. Conclusions.- References.- 9 Peptidergic Regulation of Smooth Muscle Contractility.- A. Introduction.- B. Regulation of Smooth Muscle by Peptide Hormones.- I. Cholecystokinin.- II. Motilin.- III. Peptide YY and Neuropeptide Y.- IV. Neurotensin.- C. Regulation of Smooth Muscle by Neural Peptides.- I. Vasoactive Intestinal Peptide, Peptide Histidine Isoleucine, and Peptide Histidine Methionine.- II. Tachykinins (Neurokinins).- III. Opioid Peptides.- IV. Somatostatin.- V. Gastrin-Releasing Peptide and Neuromedin B.- VI. Galanin.- VII. Calcitonin Gene-Related Peptide.- References.- 10 Peptidergic Regulation of Intestinal Electrolyte Transport.- A. Introduction.- B. Transport Models for Absorption and Secretion.- I. Sodium, Chloride and Bicarbonate Absorption.- II. Chloride and Bicarbonate Secretion.- III. Potassium Transport.- IV. Paracellular Pathway and Solute Transport.- C. Regulation of Intestinal Transport by Peptide Neurohormones.- I. Peptides That Stimulate Intestinal Secretion or Inhibit Absorption.- 1. Vasoactive Intestinal Peptide and Related Peptides.- 2. Gastrin-Releasing Peptide and Related Peptides.- 3. Substance P and Neurokinins.- 4. Neurotensin.- 5. Natriuretic Peptides.- II. Peptides That Stimulate Intestinal Absorption or Inhibit Secretion.- 1. Angiotensin.- 2. Vasopressin.- 3. Neuropeptide Y.- 4. Somatostatin.- 5. Opioid Peptides.- III. Other Peptides That Regulate Intestinal Electrolyte Transport.- D. Concluding Remarks.- References.- 11 Peptidergic Regulation of Gastrointestinal Blood Flow.- A. Introduction.- B. Gastrointestinal Peptides.- I. Cholecystokinin.- I. Secretin.- III. Gastrin.- IV. Gastric Inhibitory Polypeptide.- V. Neurotensin.- VI. Glucagon.- VII. Vasoactive Intestinal Polypeptide.- VIII. Substance P.- IX. Somatostatin.- X. Calcitonin Gene-Related Peptide.- XI. Peptide YY.- XII. Neuromedin U.- C. Capsaicin-Sensitive Afferent Nerves.- References.- 12 Peptidergic Regulation of Cell Proliferation Through Multiple Signaling Pathways.- A. Introduction.- B. Growth-Promoting Activities of Neuropeptides in Cultured Cells.- I. Mitogenic Action of Bombesin in Swiss 3T3 Cells: A Paradigm for Peptidergic Regulation of Cell Proliferation.- II. Purification and Molecular Cloning.- C. Early Signaling Events.- I. Inositol Phospholipid Turnover and Ca2+ Mobilization.- II. Protein Kinase C and Initiation of DNA Synthesis.- 1. Activation of Protein Kinase C in Intact Fibroblasts.- 2. Cross-Talk Between Protein Kinase C, Cyclic AMP, and Epidermal Growth Factor Receptor Affinity.- III. Monovalent Ion Fluxes.- IV. Neuropeptide Stimulation of Tyrosine Kinase Activity.- V. Arachidonic Acid Release and Prostaglandin Synthesis: Differential Effects of Bombesin and Vasopressin.- VI. Bombesin Induction of the Proto-Oncogenes c-fos and c-myc.- VII Regulation of Cellular Responsiveness to Bombesin-Stimulated Mitogenesis.- D. Evidence for Growth-Promoting Effects of Neuropeptides In Vivo.- I. Trophic Effects of Gastrointestinal Peptides in the Gut.- II. Development, Tissue Repair and Tumorigenesis.- E. Conclusions.- References.- 13 Peptidergic Regulation of Mucosal Immune Function.- A. Introduction.- B. Overview of Immune Function in Gut-Associated Lymphoid Tissue.- C. Peptide Effects on Immune Function.- I. Vasoactive Intestinal Peptide.- II. Somatostatin.- III. Substance P.- IV. Opioid Peptides.- V. Neuropeptide Y.- VI. Calcitonin Gene-Related Peptide.- VII. Cholecystokinin.- D. Conclusion.- References.- 14 Pathophysiological Aspects of Gut Peptide Hormones.- A. Introduction.- B. Esophagus.- I. Anatomy.- II. Achalasia.- III. Reflux Esophagitis.- C. Stomach.- I. Anatomy.- 1. Nerves of the Epithelium.- 2. Interactions.- II. Gastric Ulcer Disease.- III. Gastric Cancer.- IV. Pernicious Anemia.- V. Drugs and Hypergastrinemia.- D. Duodenum.- I. Duodenal Ulcers.- E. Pancreas.- I. Anatomy.- II. Gastrinoma and the Zollinger-Ellison Syndrome.- 1. Treatment.- III. VIPomas and the Verner-Morrison or WDHA Syndrome.- IV. Glucagonomas.- V. Somatostatinomas.- VI. Multiple Hormone Elevations.- VII. Chronic Pancreatitis.- VIII. Pancreatic Cancer.- F. Gallstones.- G. Small Bowel.- I. Anatomy.- II. Effects of Gastric Surgery.- III. Gastrointestinal Hormones During Diarrhea.- IV. Inflammatory Bowel Disease.- H. Colon.- I. Anatomy.- II. Colon and Malabsorption.- III. Polyp and Cancers.- IV. Abnormalities of Gut Peptidergic Innervation in the Colon.- V. Irritable Bowel Syndrome (IBS).- J. Gastrointestinal Hormones and Cardiovascular Function.- K. Conclusions.- References.- 15 Gastrointestinal Peptides as Therapeutic Agents and Targets: Past, Present and Future.- A. Introduction.- B. Diagnostic Use of Gastrointestinal Peptides.- C. Peptides as Agonists in Therapeutics.- I. Somatostatin.- II. Glucagon.- III. Motilin.- D. Antagonists of Peptides in Therapy.- I. Gastrin Antagonists.- II. Cholecystokinin Receptor Blockers.- III. Vasoactive Intestinal Peptide Antagonists.- IV. Substance P Antagonists.- V. Opioid Peptides.- E. The Future.- References.