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CU-Boulder IPHY 4440 - Lipid Soluble

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IPHY 4440 1st Edition Lecture 7Outline of Last Lecture I. Steroid synthesisII. Metabolism of steroids Outline of Current Lecture II. Thyroid transport mechanismsIII. Metabolism of thyroid hormonesIV. Eicosanoid SynthesisV. Mechanisms of actionVI. Ligand receptor complex depends on two thingsVII. Ligand mimics (both artificially made)VIII. Family of receptors IX. Receptors on the cell surfaceX. Lipid soluble moleculesXI. Membrane receptor structuresCurrent LectureI. Thyroid transportA. Transport in bloodi. TGBs: thyroid binding globulin - Binds to plasma proteins with increasing affinity  a2-globulins >prealbumin (TTR- transthyretin) > albumin loosely - Must be bound to binding proteins in the blood because hydrophobic and very abundantB. Transport into the celli. T3 enters the cell faster than T4 through facilitated diffusion: no energy required to enter the cellii. Must bind to MCT8 (transport proteins) to properly bind thyroid hormones C. In the blood the T4 binds better to binding proteins = 99.99% bound- T3 binds less than T4 in the blood = 99% bound - However more total T3 than T4- In order to properly diagnose thyroid hormone levels in the blood, need to know both the TOTAL and FREE hormone levels - Really difficult to diagnose thyroid problems because of the huge reservoir of thyroid hormones in the bodyThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.- If something is wrong there is no sudden change, very gradualII. Metabolism of Thyroid hormonesA. 80% deiodinationB. 15% conjugationC. 5% enzymatic inactivation -Occurs primarily in the liver and target tissues III. Thyroid hormone mechanismsA. T3 binds more tightly to receptors than T4B. T4 binds more tightly to binding proteinsC. T4 often converted to T3 inside target tissuesIV. Eicosanoid SynthesisMade pretty much everywhere in bodyMade of two fatty acid chains A. Arachidonic Acid  (enzyme: cyclooxygenase)  prostaglandins (increase body temperature and increase pain from inflammation) important for reproduction/pregnancy V. Mechanisms of actionReceptors have direct or indirect effectsA. Direct: more useful, some receptors are channels, enzymes or transcription factorsB. Indirect: less useful, stimulate second messengers to induce biological effects VI. Ligand receptor complex depends on two things:A. Affinity: how tightly the ligand binds to its receptorB. Concentration: how much of each determines direction of the reaction* receptor affinity is not good enough to tell how much is bound, must take into account both factorsVII. Ligand mimics (both artificially made)A. Agonists: completely mimic natural ligand and activates target cell Ex: trenbolone (androgen) norgestimate (progesterone) used for oral contraceptive B. Antagonists: partially mimic natural ligand and do NOT activate the target cell. Blocks the receptorEx: RU486 (anti-progesterone- abortion)Tamoxifen (anti-estrogen – useful for breast cancer)- Both of these mimics are potent and useful pharmacological agents- Both metabolize very slowly (stay in the system longer than natural ligands)VIII.Family of receptorsSimilar ligands have similar receptorsSimilar receptor families stem from a single ancestral typeReceptors have multiple receptor forms (isoforms) that are produced by a separate gene or by a mRNA splice variants from one geneIf a hormone is secreted at a constant level throughout your whole life, can you conclude that this hormone is important throughout life?- No, because the hormone’s receptor concentration and/or affinity may be important during a particular phase of life. Must look at both factors and know the complete history of a receptor to know what the ligand does. IX. Receptors on the cell surfacea. Water-soluble regulators b. Cant cross cell membrane readily c. Receptors embedded in the membraned. So bind to water soluble molecules like: biogenic amines, peptides, and proteins X. Lipid soluble moleculesSteroids and thyroid hormonesOptions of binding to both inside the cell and outside the cell - Considered to have intra-cellular receptors and have membrane receptors in certain tissues as well (exert something different depending on where it’s bound) XI. Membrane receptor structures2 domains1) Ligand-binding domain= extracellular (always bind outside the cell)2) Transmembrane domain= crosses membrane and contacts cytosol 3) Intracellular domains: inside the cytoplasm A. G-protein coupled receptor= most abundant membrane receptor in our bodies- Not an enzyme, ion channel, or transcription factor! Relies on generation of second messengers to activate


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