医学课件内分泌生理

Chapter 11 ENDOCRINE PHYSIOLOGY 内分泌生理 Wang Guoqing Department of Physiology, Medical School, Soochow University, Suzhou 215123, China E-mail: TelI. Endocrine and hormone II. Endocrine of hypothalamus-pituitary gland and pineal gland * III. Endocrine of thyroid gland * IV. Endocrine of parathyroid gland, thyroid C cell and VitaminD3 V. Endocrine of pancreatic islet * VI. Endocrine of adrenal gland * VII.Endocrine of tissue hormone and functional organ What will we discuss in this chapter? (Outline) I.Endocrine and hormone 1. Basic principles and organization Definition of the Endocrine System Endocrine and nervous systems coordinate complex body functions. Classic distinction between these two is that the endocrine system communicates to distant tissues through blood-carried chemicals while the nervous system communicates to adjacent tissue by local chemical release (neurotransmitter, 神经递质 ). Organs of the endocrine system include adrenal, gonads, hypothalamus, pancreas, parathyroid, pituitary, thyroid, as well as others, such as the heart, kidney, and gastrointestinal tract. Distinction between these two communication systems Nervous system and Endocrine system Nerves in the posterior pituitary release oxytocin（催产素（催产素 ） and antidiuretic hormone（抗利尿激素）（抗利尿激素） , which act on the breast and kidneys, respectively; Nerves release epinephrine from the adrenal medulla, which acts on the heart, skeletal muscle, and the liver; Nerves of the hypothalamus secrete chemicals (releasing hormones) that act on the anterior pituitary to cause hormone release. Therefore, the definition of the endocrine system should also include such neuroendocrine systems. General definition for hormone Classic definition ( By Starling and Bayliss) The hormones are chemical substances produced by specialized tissues and secreted into blood, in which they are carried to target organs and triggers specific biological functions. Limits of classic definition: Specialized tissues for hormone synthesis Blood for hormone distribution A separate target organ Broader definition A hormone is a chemical non-nutrient, intercellular messenger that is effective at micromolar concentrations or less (high efficiency). Living things that can secrete homones Multicelluar: Animal, Plant, Insect and Some fungi. Concentration Peptidal hormone in animal blood 10-1210-10 M, Steroid hormone in animal blood 10-1010-8 M. Endocrine cell and Target Cell, tissue and organ. Powerful Biological Effects Metabolic and Physiological effect. A further understanding on hormones TABLE ENDOCRINE GLANDS, HORMONES SECRETED, AND TISSUE EFFECT ENDOCRINE GLAND HORMONES SECRETED TISSUE EFFECT Hypothalamus Corticotropin-releasing hormone (CRH) Stimulates ACTH secretion Dopamine Inhibits prolactin secretion Gonadotropin-releasing hormone (GnRH) Stimulates LH and FSH secretion Growth-hormone releasing hormone (GHRH) Stimulates GH secretion Somatostatin Inhibits GH secretion Thyrotropin-releasing hormone (TRH) Stimulates TSH and prolactin secretion Anterior Adrenocorticotropic hormone (ACTH) Stimulates synthesis/secretion pituitary of cortisol, androgens and aldosterone Follicle- stimulating hormone (FSH) Stimulates sperm maturation; development of ovarian follicles Growth hormone (GH) Stimulates protein synthesis and growth Luteinizing hormone (LH) Stimulates testosterone, estrogen, progesterone synthesis; stimulates ovulation Melanocyte-stimulating hormone (MSH) Stimulates melanin synthesis Prolactin Stimulates milk production Thyroid-stimulating hormone (TSH) Stimulates thyroid hormone synthesis/secretion Posterior Oxytocin Stimulates milk ejection and Pituitary uterine contraction Antidiuretic hormone (ADH) Stimulates renal water reabsorption Thyroid Triiodothyronine (T3) and Stimulates growth, oxygen thyroxine (T4) consumption, heat production, metabolism, nervous system development Continued next TABLE ENDOCRINE GLANDS, HORMONES SECRETED, AND TISSUE EFFECT (continued) ENDOCRINE GLAND HORMONES SECRETED TISSUE EFFECT Thyroid Calcitonin Decreases blood Ca concentration Parathyroid Parathyroid hormone (PTH) Increases blood Ca concentration Adrenal cortex Cortisol Increases glucose synthesis; mediates “stress” response Aldosterone Increases renal reabsorption of Na +, secretion of K+, and H+ Androgens Similar to testosterone but weaker Adrenal medulla Epinephrine Stimulates fat and carbohydrate metabolism Pancreas Insulin Decreases blood glucose levels; anabolic effects on lipid and protein metabolism Glucagon Increases blood glucose levels Testes Testosterone Stimulates spermatogenesis and secondary sex characteristics Ovaries Estradiol Stimulates growth/development of female reproductive system and breasts, follicular phase of menstrual cycle, prolactin secretion, and maintains pregnancy Progesterone Luteal phase of menstrual cycle and maintains pregnancy Corpus luteum Estradiol and progesterone See above Placenta Human chorionic gonadotropin (hCG) Stimulates estrogen/progesterone synthesis by corpus luteum Human placental lactogen (hPL) Acts like GH and prolactin during pregnancy Estriol Acts like estradiol Progesterone See above This table lists the major endocrine organs, the hormones each organ secretes, and the major tissue effect of the hormone. Endocrine System 2. Chemical Nature of Hormones Classic definition of a hormone is a chemical produced by an organ in a small amount that is released into the blood stream to act on cells in a distant tissue. This definition needs to be expanded to include chemicals that have paracrine and autocrine functions. Hormones are divided into four groups based on chemical structure: (1) amines，胺类，胺类 (come from the amino acid tyrosine), (2) peptides，肽类，肽类 (less than 20 amino acids), (3) small proteins，小蛋白，小蛋白 (more than 20 amino acids), (4) steroids，类固醇，类固醇 (come from cholesterol). TABLE MAJOR HORMONES GROUPED BY CHEMICAL STRUCTURE AMINES PEPTIDES PROTEINS STEROIDS Dopamine Antidiuretic Adrenocorticotropic Aldosterone hormone (ADH) Hormone (ACTH) Epinephrine Gonadotropin- releasing Calcitonin Cortisol hormone (GnRH) Thyroxine Melanocyte-Stimulating Human chorionic Estradiol (T4) hormone (MSH) gonadotropin (hCG) Triiodothy- Oxytocin Human placental Estriol ronine (T3) lactogen (hPL) Thyrotropin-releasing Corticotropin-releasing Progesterone Hormone (TRH) hormone (CRH) Somatostain Glucagon Testosterone Growth hormone (GH) 1,25- vitamin D Growth hormone-releasing hormone (GHRH) Follicle-stimulating hormone (FSH) Insulin Insulin-like growth factor (IGF-1) Luteinizing hormone (LH) Parathyroid hormone (PTH) Prolactin Thyroid-stimulating hormone (TSH) This table groups the major hormones according to their chemical composition Hormone have four groups based on its chemical structure 3. Communication of the hormones Telecrine signals Neurocrine signals Communication of the hormones Endocrine Cell Endocrine hormone Blood Flow Target Cell Target Cell Paracrine Hormone Autocrine Hormone Paracrine Cell Autocrine Cell Target Cell Paracrine Hormone Receptor 4. Mechanism of hormone action Hormones act through specific receptors that define tissue selectivity and response. Receptors for amine, protein, and peptide hormones are located on the cell membrane, while those for steroid and thyroid hormones are within the cell. Membrane receptors are of four types based on their signaling mechanisms: G protein, tyrosine kinase, guanylyl cyclase, cytokine family. Steroid and thyroid hormones act through nuclear receptors that stimulate gene expression. Membrane-receptor mediated hormones elicit rapid (minutes) cellular responses; nuclear-receptor mediated hormones elicit slow (hours), long lasting cellular responses (because of slow protein degradation). Four Types of the Membrane Receptors Based on Their Intracellular Signaling Mechanisms TABLE HORMONES SIGNALING THROUGH MEMBRANE RECEPTORS G - Protein Receptors Linked to: Adenylyl Phospho- Tyrosine Kinase Guanylyl Cyclase Cytokine Receptor Cyclase lipase C Receptors Receptors Family ACTH, ADH, Insulin, ANP GH, Calcitonin, GHRH, Insulin-like prolactin CRH, GnRH, growth Dopamine Oxytocin, factor-1 Epinephrine, TRH (IGF-1) FSH, Glucagons, hCG, LH, MSH, PTH, Somatostatin, TSH This table groups the major hormones according to their signaling mechanisms. A combination of hormone and receptor Hormone Hormone Receptor Receptor Changes in conformation of hormone combining with receptor A: Changes in configuration of receptor induced by hormone B: Changes in configuration of hormone induced by receptor Labeled Unlabeled or receptor Complex of Hormone and Receptor Labeled Unlabeled Complex A combination of hormone and receptor Receptor quantity limit combination of hormone and receptor Receptor quantity limit combination of hormone and receptor Combination of Ab and Ag Components of membrane receptors Membrane receptors consist of three components: (1) an extracellular domain that binds the hormone; (2) a transmembrane domain that anchors it in the membrane; (3) an intracellular domain that couples the receptor to an intracellular signaling system. It was evidenced that For the G-protein coupled receptors, the transmembrane domain loops back and forth through the membrane 7 times, while for others it passes through only once. When the hormone stimulates the receptor, an intracellular signaling system is activated that initiates a cascade of cellular events culminating in the hormone response. The structure of G-protein G-protein Receptor Receptor Enzyme The structure of G-protein coupled receptors Outside cell Inside cell Cell membrane Carbohydrate group of glycoprotein Receptor of transmembrane 7 times Combining position of phosphorylation Interaction between the hormones, receptors and G- proteins Basic status Receptor activation Subunits disassociation Reactor activation GTPase R: receptor; E: enzyme; H: hormone; S: substance; P: product Signal conductive mechanism of G-protein linked membrane receptors G-protein linked receptors have the characteristic of being linked to an intracellular class of proteins called G proteins. G proteins are a cluster of three proteins (subunits) that, when activated by hormone binding to the extracellular domain of the receptor, cause stimulation of one of two enzymes, adenylyl cyclase (腺苷环化酶腺苷环化酶 AC) or phospholipase C. Activation of AC leads to the formation of cyclic adenosine monophosphate (cyclic AMP, cAMP), and activation of phospholipase C leads to the formation of inositol trisphosphate (IP3) or diacylglyercerol (DAG or DG), or activation of protein kinase C (蛋白激酶蛋白激酶 C, PKC). These named second messenger molecules initiate a cascade of events culminating in the hormone response. Signal transduction mechanism of G-protein coupled receptors R: Regulative subunit C: catalysis subunit Physiological and Biochemical function ACTH, Calcitonin, CRH, Dopamine, FSH, Glucagon, hCG, LH, MSH, PTH, Somatostatin, TSH Cascade of events culminating in the hormone response Effects of Adenylyl Cyclase (AC) Receptors Cell membrane Protein Protein Biological function Mechanism of hormone acting on membrane receptor H: hormone; R: receptor; GP: G-protein; AC: adenylyl cyclase; PDE: phosphodiesterase; PKr: protein kinase regulative subunit; PKc: protein kinase catalysis subunit phosphorylation Signal transduction of G-protein coupled receptors ACTH, Calcitonin, CRH, Dopamine, Epinephrine, FSH, Glucagon, hCG, LH, MSH, PTH, Somatostatin, TSH Theory of the second messengers for G-protein coupled receptor Cell membrane Adenylyl cyclase Hormone Hormone Hormone Inactive protein kinase Active protein kinase Protein phosphorylation Glycogen decomposition Fat decomposition Steroid Hormones synthesis Histone-nucleic acid synthesis Nuclein-protein synthesis Membrane protein-membrane permeability Canaliculus secreted movementAC: Adenylyl cyclase; R: regulative part in the receptor; C: part for reaction Principle of hormone acting on membrane receptor AC Physiological and Biochemical Functions Second Messenger Working mechanism of phospholipase C receptor Cell membrane Hormone (ADH, GHRH, GnRH, OXT, TRH) Receptor G-protein Phospholipase C Endoplasmic reticulum Physiological and Biochemical reaction Signal transduction processes of phospholipid acyl inositol PIP2: phospholipid acyl inositol disphosphate; DG: diacylglyercerol; IP3: inositol trisphosphate; PKC: protein kinase C; CaM: calcium-mediated protein Second Messenger Effects of Guanylyl Cyclase (GC) Receptors The guanylyl kinase receptors (on the membrane, combined with ANP) have the enzyme guanylyl cyclase（尿苷酸激酶）（尿苷酸激酶） as a portion of their intracellular domain. Binding of hormone to the extracellular domain leads to activation of guanylyl cyclase and the formation of cyclic guanosine monophosphate (cyclic GMP or cGMP). This second messenger initiates the hormone response. Formation and mechanism of several second messengers Cyclic adenosine monophosphate (cAMP) Cyclic guanosine monophosphate (cGMP) Inositol trisphosphate Regulative subunit catalysis subunit Protein kinase A (PKA) Diacylglyercerol Release Protein kinase G (PKG) Protein kinase C (PKC) PK (IP3) R: receptor; Rs: stimulative receptor; Ri: inhibitory receptor; G: G-protein; Gs: stimulative G- protein; Gi: inhibitory G-protein; AC: adenylyl cyclase; GC: guanylyl cyclase; PC: phospholipase C; CaM: calcium-modulated protein; Tn: troponin C. (DG is actually in the cell membrane) Effects of Tyrosine Kinase (TK) Receptors The tyrosine kinase（酪氨酸激酶）（酪氨酸激酶） receptors are distinguished by having an intracellular domain that phosphorylates proteins on specific tyrosine molecules. These tyrosine- phosphorylated proteins act as second messengers to initiate a cascade of events leading to hormone response. Mechanism of tyrosine kinase (TK) receptors Cell membrane Outside cell Inside cell Inactive tyrosine kinase (TK) Active tyrosine kinase (TK) Hormone Receptors Receptors Second Messenger Insulin, IGF-1 Summarization PLEASE TAKE DOWN Mechanisms of hormone acting on membrane receptors (summing-up) Effects of Cytokine Receptors Family Cytokine receptor family is distinguished by the fact that receptor (on the membrane, combined with GH, Prolactin) activation indirectly leads to intracellular protein tyrosine phosphorylation. Hormone binding to the extracellular receptor domain enables the intracellular domain to bind soluble tyrosine kinases called Janus kinases (or JAK kinases). Binding activates the JAK kinases, which phosphorylate intracellular proteins and produce the hormone response. Effects of Steroid and Thyroid Hormones Steroid and thyroid hormones (primarily T3) signal through intracellular receptors, which act solely to initiate gene expression. Both hormone types diffuse through the cell membrane to act on their intracellular receptors. The receptors are protein molecules that bind to specific DNA sequences known as hormone response elements (激素反应元激素反应元 件件 HRE). The hormone-receptor complex activates the HRE, initiating DNA transcription leading to protein synthesis. Mechanism of Steroid Hormones Effect Hormone Cell membrane Cytoplasmic receptor Nuclear membrane Nuclear receptor Specific mRNA Ribosome New produced protein 1. Structural domain combined with hormone; 2. Structural domain of signal orientation in the nucleus; 3. Structural domain combined with DNA; 4. Structural domain of transcriptional activation Theory of the Genes Expressions Mechanism of Steroid Hormones Effect Cell membrane Nucleus Hormone Receptor Changes in receptor configuration Transcription Translation Specific protein Metabolic reaction Mechanism of Steroid Hormones Effect Mechanisms of T3 and T4 Effects Cell membrane Mitochondria Nucleus Nucleus receptor Transcription Translation Specific protein Enzyme 5. General characteristics of hormone action Specific action: one hormone, one target, like one key, one lock; Messenger effect: serve as first messenger; High efficiency Interaction ： coordination, confrontation and permissive action, etc. 6. Synthesis of hormones Peptide and protein hormones are synthesized from amino acids as prohormones or preprohormones, which are subsequently modified and stored in intracellular vesicles until secreted by exocytosis. Amine and steroid hormones are synthesized from precursor molecules (tyrosine, cholesterol) present in the blood. Thyroid and steroid hormones are not stored in secretory vesicles, but the amine hormone epinephrine is. Synthesis and release of peptide and protein hormones (Rough ER) Processes from preprohormone to hormone Processes from prohormone to hormone 7. Control of Hormone Release Most hormones are released in a pulsatile m