Transcript Regulation
Let’s Cure Robert Wadlow The Growth Axis Hypothalamus Somatostatin GHRH hypothalamus hypothalamus (-) (+) GH Pituitary Group 2 pituitary IGF-I Liver Group 3 liver T3/T4 cortisol Growth Plate Bone Group 4 bone E2/T Group 1 nutrition Endocrine Secretion: Products, Pathways and Regulation 1. Overview and Quick Review General Cell Biology Regulation 2. One Example in More Depth Glucose Regulation of Insulin Secretion Neil Gesundheit, M.D., and Stephen J. Smith, Ph.D. [email protected], [email protected] Endocrine Signaling Depends on the Regulation of Hormone Secretion Hormone Regulation Analyte or substrate regulation Hormones and Corresponding Secretory Pathways and Regulation Mechanisms Fall into Three Broad Patterns (almost…) 1. Peptides 2. Amines 3. Steroids (The somewhat exceptional case of thyroid hormones will be treated at length in later lectures) Synthesis and Secretion of the Peptide Hormones Examples: Growth Hormone Prolactin TSH, LH, FSH, hCG Somatostatin Hypothal. Releas. Horm. Insulin Glucagon Parathyroid Hormone Many, many others Transcription DNA mRNA Translation Glycosylation Prehormone Processing Packaging Prohormone Storage Exocytosis Hormone Circulation Alpha and Beta Cells of Pancreatic Islets How Do Vesicles Fuse? SNARE complex of proteins merge the synaptic vesicle to the plasma membrane. Free intracellular Ca++ activates the process. [Ca++] [Ca++] Synthesis and Secretion of Peptide Hormones: the Anterior Pituitary Cell Examples: Growth Hormone Prolactin TSH, LH, FSH, hCG Somatostatin Hypothal. Releas. Horm. Insulin Glucagon Parathyroid Hormone Many, many others Regulated Secretion Transcription DNA mRNA Translation Glycosylation Prehormone Processing Packaging Prohormone Storage Exocytosis Hormone Circulation GHRH Administration Produces Rapid Secretion of GH from the Anterior Pituitary 30 GH Concentration (mcg/L) GHRH (2 mcg/kg IV bolus) 20 10 (Adapted from Maccario et al, J Clin Endo Metab 2001; 86:167-171) Synthesis and Secretion of Amine Hormones Primary Regulation (acetylcholine from preganglionic fibers via nicotinic receptors, leads to increases in free Ca++) (PNMT) Sympathetic neurons Sympathetic ganglia Adrenal medulla Ultrastructure of Catecholamine Secretory Cells Cat Adrenal Chromaffin Cells Sympathetic Nerve Ending on Rat Chromaffin Cell Steroid Secretion and Regulatory Pathways: the Adrenal Cortical Cell • ACTH increases cholesterol uptake into mitochondrion • ACTH increases side-chain cleavage in mitochondrion, to produce pregnenolone Steroid Secretion and Regulatory Pathways: Side-Chain Cleavage in the Mitochondrion of the Adrenal Cortical Cell Pregnenolone Cholesterol Side-chain cleavage enzyme • ACTH increases cholesterol uptake into mitochondrion • ACTH increases side-chain cleavage in mitochondrion, to produce pregnenolone Cortisol concentrations after SQ injection of synthetic ACTH ACTH Cosyntropin (synthetic ACTH) administration at time 0 0.5 1.0 1.5 2.0 2.5 3.0 Time (hours) 3.5 4.0 4.5 5.0 Let me challenge you… How would you predict that the beta cell would regulate the secretion of insulin? How does the beta cell sense high and low glucose concentrations? The Regulation of Insulin Secretion from Pancreatic Beta Cells by Glucose 1. In spite of long and intensive searching, no beta-cell “glucose receptor” has been identified 2. Glucose metabolism itself is the glucose “sensor” (Frances Ashcroft) 3. Electrophysiological and ionic mechanisms couple intracellular ATP to insulin secretion K Channel Closure is Linked to Insulin Secretion via Closing of ATP-Sensitive K Channels and Consequent Opening of Voltage-Dependent Ca Channels Sulfonylurea Oral Anti-Diabetic Drugs Act By Promoting the Closing of ATP-Sensitive Potassium Channels Take Home Points Secretion of peptides and amines occurs via secretory vesicles (they are “pre-packaged”), is regulated, and Ca++ from intracellular sources is the key signaling molecule for secretion Secretion of steroid and thyroid hormones occurs by increasing substrate; these hormones are not packaged/stored in secretory vesicles Secretion of insulin is unique: sensing is by changing concentrations of a by-product of glycolyis, ATP; Ca++ triggers secretion and is from extracellular sources Goal of this module is to have you engage in joyful learning!