The Thyroid Gland- Butterfly-shaped with two lobes, right greater than left- Size is proportional to metabolic activity, also varies with iodine intakeo Smaller in wintero Larger in pregnant women, during lactation and puberty- Rate of blood flow determine rate of thyroid hormones into circulation- Two thyroid hormones (T3 & T4) regulate metabolism- TSH binds thyrotropin receptors on thyroid follicle cells, activates Gs & Gq (we will focus on Gs) stimulates:o Iodine uptakeo Production and release of thyroid hormoneo Thyroid growth- Immediate response:o Increased flux of I-, Na+, K+o Protein kinase activationo Cellular metabolism- Delayed response:o Colloid processingo Thyroid hormone secretion- TSH-cAMP complex induces expression of genes for:o Sodium-iodide symporter (NIS): brings Na and I in togethero Thyroglobulin (Tg): glycosylated protein is precursor for hormoneo Thyroperoxidase (TPO)- Epithelial (aka follicular) cells are arranged in spheres called thyroid follicleso Ring of cells surround colloid: dense protein gelo Synthesize thyroglobulin, which is stored in the colloido Thyroid hormone released from Tg by exocytosis- Parafollicular (aka C) cells secrete calcitonin, which regulates blood calcium levelsIodine- Thyroid hormone synthesis is the only physiologic role of iodine- Iodine is scarce in environment, so thyroid gland adapted to collect and storeit- Iodine deficiency impairs hormonogenesis- Transport:o Active cotransport with 2 Na+ across basolateral membrane by NISo I- is concentrated within follicular cellso Passive transport of I- along concentration gradient into colloid, through pendrin channelsI- Na+ Na+Blood_______NIS___________________________basolateral membrane I- Na+ Na+I- I- follicleI- I- I- I- ______pendrin____________________________apical membraneI-colloid- Thyroperoxidase (TPO) uses H2O2 as oxidant to activate iodine then iodinatestyrosine residues of thyroglobulin (Tg) to form mono- and diiodothyronine - TPO combines MIT and DIT to form T3 and T4 and stored in colloid- Endocytosis of colloid + fusion to lysosome to form phagolysosomes w/ endopeptidases that cleave Tg- Exopeptidases allow release of T3 & T4 from intermediates, diffuse into blood and bind carrier proteins- Hydrolysis also releases MIT and DIT but these are metabolized- I- gets recycled and reusedT3 and T4 are hydrophobic and thus, utilize carrier proteins for circulation.- Mainly thyroxine-binding globulin (TBG), a glycoprotein made by liver- TBG affinity for T4 > T3- Transethyretin (TTR) binds T4 but not T3- Albumin has low binding affinity but high serum concentration- T3 and T4 can also bind HDL & LDL- Only free hormone is biologically active; typically kept constant - better measure of metabolic state than total hormoneAt the target tissue, T4 is converted to T3 by 5’-deiodination (outer ring). Major siteof conversion is the liver. There are three deiodinases (Types I, II, & III). - DI in liver, kidney, thyroid, pituitary. Generates circulating T3 for most peripheral target tissues- DII in brain & pituitary. Also thyroid, heart, spinal cord, skeletal muscle, placenta.- DIII in CNS, skin, placenta. May inactivate T3 and T4 by removing I- from inner ring.o Forms T2 from T3o Forms rT3 from T4, which acts as an isomeric antagonist to T3T3 circulating levels are typically lower than those of T4, it has a lower binding affinity to carrier proteins. T3 has greater receptor affinity and is more active at tissues. T4 is physiologically inactive because it does not enter nucleus in high enough concentration. Thyroid Hormone Receptor- Thyroid hormones can diffuse through cell membrane- Three forms of thyroid hormone receptor:o TR-α1: widely expressed, especially cardiac and skeletal muscleo TR-β1: predominantly in brain, liver and kidneyo RR-β2: primarily hypothalamus and pituitary- TR-α2 is widely expressed but does not bind hormone; may act as antagonistbecause it weakly binds thyroid hormone response elements- T3 binds receptor, which pairs with nuclear protein partners such as retinoidX receptor (RXR)- Complex binds thyroid hormone response elements to modify gene expression and influence mRNA stabilityEffects of T3- Increases basal metabolic rate in virtually all tissues- Increases O2 consumption- Increases body heat in peripheral tissue, except brain, gonads and spleen which are heat-sensitive- Cholesterol metabolism:o Stimulate conversion of cholesterol to bileo Increases specific binding of LDL by liver cellso Thus, LDL is rapidly removed from plasmao Hypothyroid  high chol.- Stimulates carbohydrate and protein metabolism- Needed for growth and developmento Regulates endochondral bone formation in epiphyseal plateso May participate in osteoblast differentiation and proliferation by stimulating GH and IGF-I- Cognitive function, mood, behavioro CNS depends on T3 for maturation and functiono Hypothyroidism can lead to mental retardation because it regulates neural development- Reproductive system:o Influences onset of puberty in femaleso Hypothyroidism linked to infertilityo Pregnant women with hypothyroid at increased risk for miscarriage, intrauterine fetal demise, placental abruption, etc- Mitochondrial activityo In the presences of T3, a protein typically found in mitochondrial matrix binds TREs in mitochondrial DNAo T3 also increases expression of mitochondrial transcription factor (TFA)o Both stimulate