6. Endocrinology 2010

6. Endocrinology 2010 - Basic Endocrinology Basic Estrogen...

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Unformatted text preview: Basic Endocrinology Basic Estrogen Receptor Introduction Introduction System of ductless glands Produce chemical messengers called HORMONES hormones help integrate body signals with neural and immune systems Hormones travel to target tissue/cell via blood stream intercellular space Hormones Hormones Come in two major forms peptides / proteins growth hormone, insulin, oxytocin growth oxytocin Lipid-based hormones steroids and prostaglandins Steroidogenesis C holesterol P450ssc 3!HSD Pregnenolone Isomerases Progesterone P450c21 Deoxycorticosterone P450c11 Corticosterone P450c17 3!HSD 17-OH Pregnenolone Isomerases P450c17 P450c21 17-OH Progesterone 11 Deoxycortisol P450c11 Cortisol P450c17 3!HSD P450c17 Testosterone P450 arom 17! Estradiol 17 Keto Dehydroepiandrosterone Androstenedione Reductase Isomerases Target Tissues Receptors Receptors • at the target cell, a hormone interacts with a RECEPTOR • peptide hormones usually interact with membrane receptor • steroid hormones interact with nuclear receptor • many steroid receptors are transcription factors 1. 2. 3. 4. Membrane receptor activates G protein G protein + GTP activates adenylyl cyclase ATP converted to cAMP (2o messenger) Results = cellular response amplified @ each step Amplification Signaltransduction pathways allow for small amounts of a hormone to have a large effect 1. Steroid binds to cytoplasmic or nuclear 1. Steroid or receptor(transcription factor) 2. Receptor hormone complex binds to DNA in nucleus 3. Stimulates transcription of mRNA Nuclear Receptor Evolution Nuclear • Steroid receptors • Transcription factors • Large family of related molecules • Gene duplication • Ancestral form unknown The Nuclear Receptor Superfamily Superfamily d g b , a A/ B C D E F DNA KNOW N RECEPTORS Classical receptors (from bi ochemistr y) GR cortisol MR aldosterone PRα,β progesterone AR α,β testosterone ER α,β,γ estr ogen V DR 1,25 (O H)2 vit D3 TR α,β Thyroid horm one E cR 20-O H ecdysone EX-orphans RAR α,β,γ RXRα,β,γ PPAR α,β,γ LXRα,β FXRα,β BXRα,β all-trans RA 9-cis RA, ? fatty acids oxy-sterols bile acids benzoates LIGAND ORPHAN RECEPTO RS Vertebrate Drosophila TR-2α,β DHR7 8 NGFI-Bα,β,γ DHR3 8 RORα,β,γ DHR3 Rev-erb E75, E78 ? SF-1α,β FTZ-F1α,β COUPα,β,γ sv p HNF-4α,β HNF-4 TLX t ll No known hom ologs ERR α,β,γ knirps DAX-1 knirps-related SHP egon G CNF DHR9 6 C. elegans - 2-3% of genes are nuclear receptors ~250 Drosophila - only about 20 nuclear r eceptors Nearly EX- orphans CA R androstans, xenobiotics SXR ster oids, xenobiotics PXR.1,2 pregnanes, xenobiotics Blumberg, UC Irvine Evolution of Steroid Receptors •Two serial duplications •1st = ER and 3-ketosteroid R •2nd = duplication of 3-KR •Corticoid receptor (CR) •3-ketogonadal steroid R •Androgen •Progesterone •Or both •These 3 duplicated again to form 6 common forms found today in vertebrates Thornton (2001) PNAS 98:5671-5676 Hypothalamus - Pituitary Hypothalamus • considered the master organs of the endocrine system Hypothalamus Hypothalamus Hypothalamus bottom of 3rd ventricle of brain secretes neurohormones that influence synthesis and release of neurohormones that pituitary hormones examples: gonadotropin releasing hormone (GnRH) gonadotropin releasing thyrotropin releasing hormone (TRH) thyrotropin releasing dopamine - Prolactin releasing inhibiting factor dopamine releasing released into hypothalmo-hypophysial portal system released portal blood vessel system between hypothalamus and pituitary Hypothalamo-hypophysial Portal System Portal • A portal system • Vein - vein • Low pressure system • Delivers hypothalamic factors to pituitary Pituitary - Hypophysis Hypophysis • center of the soul in classical times • derived from two tissues embryologically derived embryologically • adenohypophysis (anterior pituitary) - derived from (anterior outpocketing of mouth - Rathke’s pouch outpocketing Rathke pouch • neurohypophysis (posterior pituitary) - derived (posterior from outpocketing of third ventricle and from of hypothalamus • these two extensions meet, interact and form pituitary with two distinct regions as noted Neurohypophysis Neurohypophysis Adenohypophysis Adenohypophysis ...
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