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Terms in this set (55)
Full name of T4
T3 full name
Inner and outer ring of thyroid hormones
T3 has deiodinized outer ring but iodonized inner ring. Reverse T3 is deiodinized inner ring but iodonized outer ring. T4 has both iodinized. Inactive T2 has neither ionized.
Why do we need thyroid hormones? Developing organism:
Growth and development (neurological). Lack leads to cretinism.
Why do we need thyroid hormones? Mature organism:
Effects through DNA gene transcription. Effect on mitochondria and other organelles not clear. Some positively and some negatively regulated.
Thyroid hormones metabolic effect
Increased size and activity of mitochondria. Increased ions and substrates through cell membranes. Increased Basal Metabolic Rate (BMR), CV system: increased CO, blood flow, heart rate, strength of heart beat. Both hypo/hyperthyroid can cause HTN. GI, CNS (awareness, memmory, anxiety, personality changes), musculoskeletal. Almost every other system and tissue.
Where is thyroid hormone produced?
T4 and 20% of T3 produced in thyroid (no other organ in body), 80% of T3 is produced in peripheral tissue by deidodination of T4 by enzymes.
What happens to T4 and T3 after synthesis? Where are they stored?
Incorporated by thyroglobulin in follicular lumen and stored in lumen until secreted by pinocytosis, fusion with phagolysosome, degradation of thyroglobulin and release into circulation.
Biologic form of free inorganic I-
Covalently bound to protein
Minimal daily requirement of iodine
What is the input into iodine pool?
Dietary iodine, iodide released from thyroid as thyroid hormone/exces, iodide released from diodination of iodothyronines
What is the output of the iodine pool?
Urine secretion, GI tract and enterohepatic circulation absorbes and excretes it not in protein-bound form.
Sodium iodide symporter
Active intake into follicular cells from lumen colloid against chemical and electrical gradient. 8 membrane spanning domains. Energy required and driven by TSH production. More active at low intrathyroidal iodine levels in cell.
Most important player in TH biosynthesis. Glycoprotein produced in thyroid follicular cells. Secreted into follicular lumen via exocytic cesicles. Accumulates as colloid in follicular lumen. Indication of presence of thyroid cells in body (tumors).
What cells produce thyroglobulin?
Thyroid follicular cells ONLY.
Iodine binding to thyroglobulin
Oxidized, covalently bound (organified) to tyrosyl residues in thyroglobulin forming MIT and DIT. Catalized by thyroid peroxidase, requires H2O2. On apical membrane of thyroid follicule cells.
MIT and DIT name
Functions of thyroid peroxidase
1. Iodinating thyroglobulin, 2. coupling of monoiodotyrosine and DIT, making 3 or 4 tyrosine molecules.
Which tyrosines get iodinated?
Not all of them. Discrete and specific tyrosine residues on thyroid binding globulin for formation of MIT and DIT in thyroglobulin. PTU and MMI inhibit TPI at iodinization step.
Couping of MIT and DIT
Thyroid peroxidase catalyzes formation fo T3 and T4 on thyroglobulin.
What does each normal thyroglobulin molecule contain?
6 MITs, 4 DITs, 2 T4s, 0.2 T3 molecules (1/5 thyroglobulins).
Thyroid hormone synthesis off of TGB
T4 and T3 stored in colloid, reabsorbed into the follicular cell by pinocytosis, droplets fuse with lysosomes to liberate hormones and byproducts from thyroglobulin, acidic enzyme breaks down TGB. Driven by TSH (except coupling), defect can result in goiter/hypothyroidism.
Peripheral deiodination of T4 to T3
Type I deiodination, type II deiodination, type III (rT3 formation). All deiodinases contain selenocysteine residue. Without it: 200x less effective.
Type I deiodinase
Nonspecific. Found in liver, kidney, thyroid. Deiodinates inner and outer rings to form inactive T2, reverse T3 or active T3 in cytosol. Provides T3 to plasma and inactivates T3 and T4. High Km for T4, more T4 leads to more deiodination, actively increaed by T4. PTU sensitive.
Type II deiodinase
Found in brain, pituitary, placenta and heart. Specific: diodinates only outer ring to produce active T3. Provides intracellular T3 to specific tissues and to plasma. Not PTU sensitive. Activity decreased by T4, tightly regulated. Sits close to nucleus.
Type III deiodinase
General garbage disposal. Found in brain, placenta, uterus. Deiodinates inner ring only to produce reverse T3 and inactive T2.
Thyroid hormone transport
More T4 is bound to proteins but over 99% of both is serum bound.
What are the plasma proteins that bind thyroid hormones
Thyroid binding globulin (TBG), Transthyrefin (TTR)-also binds retinoic acid, Thyroid Prealbumin (TBPA), albumin (less specific but more frequent), lipoproteins.
Thyroid Binding Globulin (TBG)
Binds T4 10-20x more avidly than T3, 1/1 TBG/T4 binding. 1/4 TBG/T3 binding.
Which thyroid binding protein has the greatest and least affinity to thyroid hormone?
Estrogen effect on TBG
Increases binding capacity. Important for pregnancy because shift to bound thyroid hormone.
Androgen effect on TBG
Disease effect on thyroid binding proteins
How is thyroid hormone measured in the blood?
Free T4 and free T3.
2 forms of regulation of thyroid function
1. Hypothalamic-Pituitary-Thyroid axis. 2. Autoregulatory mechanism
Classic feedback, controls circulating hormone levels on a minute-to-minute basis.
Autoregulatory thyroid mechanism
Inverse relationship between intrathyroidal iodine levels and hormone formation. Serves to stabilize hormone formation in fluctuations of substrate: low/high areas, protection of ingestion of a lot of iodine, more global basis.
Negative feedback of hypothalamus and pituitary
Hypothalamic T3 downregulates TRH production, pituitary T3 downregulates TSH production.
TRH synthesis and secretion
Modified tripeptide derived from prepro-TRH. Neurotransmitter expressed in several tissues: hypothalamus most important, released into portal system. Negatively inhibited by glucocorticoids and T3 (suppresses preproTRH mRNA).
Actions of TRH
Deiodinates T4 to T3. Binds to G-coupled proteins in pituitary. T3 decreases response to pituitary gland. Stimulates release of prolactin and GH.
Regulator of thyroid growth and function. Heterodimeric glycoprotein (common alpha and specific beta).
T3 and dopamine suppress mRNA transcription, TRH increases transcription. Needs to be glycosylated (for function, protects from intracellular degradation and proper folding) and sialyated (to allow proper hepatic clearance and prolongs halflife). Posttranslational processing regulated by TRH. Big changes with small TH changes, need big iodine changes.
hCG and TSH
Cross reactivity, similar beta subunit. When gCH oversialated pathologically or in multiple gestation will react to TSH receptor on thyroid and will increase TH production causing hyperthyroidism of early pregnancy. Shown with low TSH. Not pathological, needed for growth of fetal brain.
Thyroid function measurement
TSH is more indicative than measurement of TRH or T4.
Iodine and thyroid function regulation
Autoregulation of different amounts of iodine maintain constant store of hormone, overcomes obstacles in thyroid hormone synthesis.
Increased dose of outside iodine causes 1: increased organification, then 2: stops organification regardless of TSH. Occurs because NIS transporter inhibited-->decreased intrathyroidal iodine level. Eventually overcome and TSH and TH production returns to normal (escape phenomenon), but in some can't escape and causes hypothyroidism when ingest iodine (cardiac medication-amioderone).
T4 levels fall, TSH increases and T3 levels initially maintained. MIT/DIT and T3/T4 increased. Uptake and organification increased. TSH causes goiter formation from increased (still maintaining a functioning thyroid). In pregnancy: cretinism-mental retardation.
Molecular action of thyroid hormones
Direct transcriptional effect on thryroid responsive genes through intracellular thyroid hormone receptors. Posttranscriptional effect by stabilization of preformed mRNA.
Thyroid hormone receptors
Decrete regions with a DNA binding domain, ligand binding domain and homo/heterodimerization domain. Alternative splicing is possible depending on different cells of body. Ex: TRa, TRa1/CerbAa2 (doesn't bind TH). TRb, TRb1/2 (pituitary and brain, little in liver, kidney, heart). Different isoforms at different stages of development.
Thyroid hormone response elements
Binding patterns to allow for TH binding: usually two hexamer half sites consisting of A\GGGTC\AA with variable spacers. Palindrome with no spacer or with inverted or regular spacer. Cis elements in enhancer region of thyroid responsive gene. Positive: increase transcription and negative (repress-TSH).
Pulsatile secretion with 1-2h fluctuations. Cicadian rhythm: presleep surge, independent of cortisol but also measured in the morning.
Thyroid Nuclear Receptors
Thyroid nuclear receptor can bind to TREs depending on gene: monomers, homodimers (TRTR complexes-usually a repressor) or heterodimers (most common, with thyroid receptor accessory proteins (TRAPS) like RX- increase transcription, COUP-TF-decreases transcription. Release of repression allows transcription.
Presence or absence of various TRAPS
Heterodimerization with RXR increasing transcription or heterodimerization with COUPTF (other accessory protein) decreasing transcription
Estrogen Response elements and thyroid receptors
apoTR can bind to Estrogen Response Elements (not just TRE) and inhibit ER dependent gene expression.
THIS SET IS OFTEN IN FOLDERS WITH...
Physio - GI
Physio - GI regulation
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