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Thyroid Endocrinology Chapter 9 in Randall et al. “Eckert Animal Physiology” Chapters 4 & 13 in Hadley “Endocrinology” Chapters 2 & 14 in Hill et al., “Animal Physiology” Chapters 2, 7 & 8 in Norris “Vertebrate Endocrinology” Major concepts covered in thyroid section: — Negative feedback regulation of hypothalamus-pituitary hormone secretion — Positive feedback actions of hormone — Multi-hormonal interactions in controlling a biological response — Local “non-endocrine” as well as endocrine regulation of hormone release — Parallel mechanisms of actions of thyroid hormones and steroid hormones (intracellular receptors) — General mechanisms of nuclear receptors and receptor action — Local activation of circulating hormones, another concept of “prohormone” — Plasma binding proteins for hormones Some major functions of thyroid hormones in mammals — decrease cholesterol level in plasma — affect development of the nervous system, increase myelination — increase brain activity — increase glucose absorption by gut — increase basal metabolic rate and O2 consumption — increase heart rate — potentiates the action of growth hormone (permissive action of thyroid hormone) — other growth and differentiation effects Some major functions of thyroid hormones in lower vertebrates — promotes growth and protein synthesis — influences food conversion in somatic growth — stimulates molting in snake and growth of feathers in birds (epidermal action) — stimulates parr-smolt transformation in salmonids and metamorphosis in amphibians Several major kinds of thyroid hormones (all are iodinated thyronines or conjugated tyrosines) OH I I I I O I OH OH O O I I I I I CH2 CH2 CH2 CH CH CH COOH NH2 Thyroxine , T4 (tetraiodothyronine) (Major form released) COOH NH2 3,5,3’-triiodothyronine, T3 (More active than T4) COOH NH2 3,3’,5’-triiodothyronine, rT3 (reverse T3, inactive form) Thyroid tissue - thyroid follicle Thyroid Basic unit for thyroid tissue - thyroid follicle Thyroid follicular cells (produces thyroid hormone and its precursor protein) Blood capillary Thyroid colloid (containing precursor protein that can form thyroid hormones) Basic unit for thyroid tissue - thyroid follicle “Active” - thick columnar epithelium, colloid vacuolated “Inactive” - thin cuboidal epithelium, colloid “full” Thyroid gland of mammals contains several endocrine tissues — Thyroid follicles (produces thyroid hormones) — C-cells (produces calcitonin) — Parathyroid (produces parathyroid hormone) — Another example of a gland with multiple endocrine secretions (— Why this kind of association?) Origin of Thyroid Gland — Thyroid hormone is the only iodine-containing hormone — Iodine concentrating cells are found even in invertebrates but most of these are cells exposed to the external environment — Vertebrate thyroid develops as an evagination of the floor of the oral epithelium behind the oral plate (thyroid diverticulum) — Subpharyngeal gland in larvel lamprey concentrates iodine and produces iodine-containing proteins and is open to the oral cavity via the subpharyngeal duct — Thyroid hormones might have originated as compounds released into the gut and then subsequently used as a hormone Thyroid Hormone Synthesis and Release (1) 1) thyroglobulin has to be synthesized OH OH tyrosines on thyroglobulin CH2 CH2 CH CH Thyroid Hormone Synthesis and Release (2) Synthesis of iodinated thyronine via thyroid peroxidase action 1) thyroglobulin has to be synthesized 4) Storage of iodinated thyroglobulin in the colloid OH OH tyrosines on thyroglobulin CH2 CH2 CH CH Thyroid peroxidase 2) Iodination of tyrosine residues (organification of iodine e.g., forming DIT) I I I CH2 CH2 CH CH OH I I O I OH OH I 3) Conjugation of iodinated tyrosine residues to form iodinated thyronine (coupling reaction) Example shows two DIT conjugating to form tetraiodothyronine. Thyroid peroxidase I CH2 CH Iodinated thyroglobulin Thyroid Hormone Synthesis and Release (3) Stored iodinated thyroglobulin in colloid OH I Reabsorption of colloid by phagocytotic Action of thyroid epithelial cells I I Enzymatic processing of reabsorbed thyroglobulin in thyroid epithelial cells + O I CH2 Fragments of thyroglobulin CH COOH NH2 Thyroxine , T4 (tetraiodothyronine) Fragments recycled T4 can be released Thyroid Hormone Synthesis and Release (4) — Several potential forms of iodinated thyronine can be synthesized in the thyroid — This depends on the conjugation of iodinated tyrosines on the thyroglobulin molecule DIT + DIT T4 MIT + DIT T3 or reverse T3 (3,3’,5’-triiodothyronine) MIT + MIT MIT + T DIT + T T2 forms T1 forms T2 forms Neuroendocrine Control of Thyroid Gland Activity External & Internal Influences Long-loop -ve feedback (–) Brain Hypothalamus TRH (+) (–) DA (–) Pituitary thyrotropes (+) TSH Thyroid Action on Target cell T4 and T3 BLOOD or TISSUE FLUID TSH Na+/K+ ATPase TSH receptor Na+ ATP Pentose PO4 Pathway Peroxide vesicular transport of Tg to colloid Amino acids recycling Degradation of Tg in lysosome I- cAMP/PKA Thyroglobulin (Tg) synthesis Free T4 (& T3) Na+/I- cotransport Tg MIT DIT & Tg fragments I I Tg Recycling of Free I Pinocytosis & reuptake of colloid Iodothyronines In Tg in colloid Thyroid Follicular Epithelial Cells Release of T4 & T3 by diffusion COLLOID SPACE TSH ACTION ON THYROID Na+ I I Tg Membrane Thyroid Peroxidase Activity Iodination of tyrosine & formation of iodothyronines Changes in Thyroid Hormone Regulation During Metamorphosis in Frogs T3/T4 TSH Acquisition of hypothalamic sensitivity to +ve feedback by thyroid hormones Premetamorhposis TRH Prometamorphosis Resumption of -ve feedback regulation by thyroid hormones Climax Postmetamorphosis Stages of amphibian development Neuroendocrine Control of Thyroid Gland Activity Just Prior To and At Metamorphosis in Amphibians External & Internal Influences Long-loop +ve feedback (+) Action on Target cell E.g., gill & tail reabsorption Brain Hypothalamus TRH (+) (+) DA (–) Pituitary thyrotropes (+) TSH Thyroid T4 and T3 Further Processing of Thyroxine Once Released from Thyroid OH I I Outer Ring Deiodination Outer Ring 3,5,3'-triiodotyronine, T3 (more active hormone) Deiodinase I & II (Type I - liver, thyroid & kidney; II- brain, pituitary, placenta, BAT) O I I Inner Ring Deiodination Inner Ring CH 2 CH COOH NH 2 Thyroxine T4 Deiodinase III Other metabolites 3,3',5'-triiodotyronine, rT3,reverse T3 (inactive hormone form) Schematic of Nuclear Receptor Domains and Functions Hinge Hsp90-binding Leucine-rich Heptads Zinc-Fingers Hormone-Binding DNA-Binding NH2 A&B Transactivation Nuclear localization signal Dimerization Basal Phosphorylation COOH C D E F Nuclear Receptors Superfamily — includes receptors for steroids, thyroid hormones, vitamins, xenobiotics, and other “orphaned receptors” — these are intracellular phosphoproteins — these are DNA-binding transcription factors — DNA-binding is achieved through zinc-fingers Hypothetic DNA-binding zinc-finger (modified from Bolander: “Molecular Endocrinology”) Zn2+ — although nuclear receptors mediate the action of membrane permeant steroid and thyroid hormones, these hormones are also known to bind to membrane receptors Idealized Hormone-responsive elements (HREs) as two half-sites (Consensus sequences; directionality indicated by arrows) GRE (Glucocorticoid) ERE (Estrogen) TRE (Thyroid Hormone) DR+3(VDRE) (Vitamin D3) A G A A C A n n n T G T T C T T C T T G T n n n A C A A G A A G G T C A n n n T G A C C T T C C A G T n n n A C T G G A A G G T C A T C C A G T T G A C C T A C T G G A A G G T C A n n n T C C A G T n n n A G G T C A T C C A G T Schematic of steroid hormone receptor action on transcription C horm horm + horm horm change in conformation and DNA-independent phosphorylation + C C C horm Receptor dimerization via Leu-rich region horm C HRE C HRE DNA binding & DNA-dependent hyperphosphorylation target gene Stabilization of receptor dimer and DNA binding Recruitment of adaptor proteins and interactions with nuclear transcription factors and transcription activators/regulators elements Regulation of gene transcription Thyroid Hormone in Circulation & Mechanisms of Action BP Plasma binding protein RA Retinoids Thyroid hormone receptor Retinoid receptor BP T4 BP T4 BP T3 Target Cell Nucleus T3 T3 T3 DII DI T4 legend T3 RA Transcription Regulation RNA T4 protein T3 T3 mRNA Biological Effects Note 1: — isoforms of nuclear receptors also present, e.g., TRα and TRβ — tissue selective expression of receptor isoforms observed (e.g., heart expresses more TRα while liver expresses more TRβ) — active selectivity may also result from this Note 2: — TR and RXR are also located in the mitochondria — some effects on mitochondrial DNA can also be exerted via these receptors — not all effects of TH on mitochondria are necessarily mediated by “mitochondria genomic action” Membrane Receptors for thyroid hormones — the presence of a modified nTR on plasma membrane has not been shown but thyroid hormones are also known to activate PLC via membrane actions — around 2002-2003, evidence suggest that TH can bind to integrin αVβ3 which can activate PLC — this “receptor” is characterized by the ability to bind TETRAC which acts here as an antagonist to block the actions of thyroid hormones on membrane ion fluxes Non-endocrine Regulators of Thyroid Activity — iodine availability in food — insufficient iodine - TSH-induced hypertrophy and goiter — great excess of iodine - poisoning of the peroxidase enzyme — inhibitors of iodine uptake — thiocyanate - cabbage, Brussels sprouts, turnips, broccoli etc. contain thioglucosides which form thiocyanates upon digestion — other small negatively charged molecules can also compete for the uptake pump — other thio-compounds also inhibit the peroxidase enzyme