Endocrinology6 - Mechanisms of signaling by nuclear and...

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Unformatted text preview: Mechanisms of signaling by nuclear and membrane receptors Small lipophilic molecules: steroid hormones, cholesterol metabolites, bile acids, thyroid hormone, vitamin A metabolites vitamin D3 fatty acids & metabolites numerous xenobiotics & Glucose!!! Peptide hormones Peptide growth factors Small hydrophilic molecules - nuclear receptors (steroid) are located in the cytoplasm until they bind hormone and move into the nucleus - classical theory - glucose can act in a hormonal fashion - glucose inhibits the enzymes necessary for glucanogenesis - glucose is in control of its own biosynthesis - glucose binds to its receptor 1 million times less strongly to estrogen and its receptor - the affinity of glucose to its receptor reflects its strength as a hormonal molecule Nuclear receptors exert their physiological effects largely by regulating the transcription of a (receptor-specific) subset of genes in the human genome. Ultimately, this leads to changes in the types and concentrations of proteins present in target cells, thus altering cell function. -Molecular evidence for the existence of nuclear receptors dates from ca. 1960 with the demonstration by Elwood Jensen that radioactive estrogen associated with an apparent receptor in the nucleus. -Evidence that nuclear receptors might regulate gene transcription dates accumulated through the 1970’s. -First nuclear receptor genes identified in the mid ‘80’s. The first nuclear receptors were identified for classical endocrine hormones: Estrogen Progesterone Androgens Glucocorticoids Mineralocorticoids Thyroid hormone & Vitamin D Steroid hormones Receptor-ligand interactions were characterized by: 1. Lipophilicity of the ligand 2. High ligand-receptor specificity 3. High ligand-receptor affinity (low nM) It is now known that there are 48 genes in the human genome that encode nuclear receptors. All of the nuclear receptors identified since the genes for “classical” endocrine receptors were identified bind vitamins, other dietary constituents (e.g. fatty acids) and their metabolites, or “xenobiotics (foreign molecules like toxic compounds and drugs). Glucose can also regulate the function of a nuclear receptor Techniques are now available for identifying on a large scale (thousands at a time) genes whose transcription is regulated by nuclear receptors. This has provided novel and unexpected insights into the physiological processes regulated by nuclear receptors. New insights into vitamin D physiology 1,25-dihydroxyvitamin D3 Biosynthesis 2 sources: diet, action of UV light from the sun CH3 1 2 3 4 10 5 6 7 24 25 24 25 UV-B vitamin D3 Provitamin D3 Skin leads to a break in one of the steroid rings 5 4 3 2 10 1 OH OH Liver (Skin) 25-hydroxylation Vitamin D receptor 24 25 24 OH Peripheral Tissues (incl. Skin) 1-hydroxylation occurs in kidneys (production of 1hydroxylase in the kidney is regulated by PTH) and immune system too 5 25 OH 4 3 5 10 1 1,25-dihydroxyvitamin D3 OH 4 3 10 1 25-hydroxyvitamin D3 levels of 1-25 D in the circulation is determined by concentrations of 25-D OH 2 OH 2 Vitamin D Winter - depending on the latitude, at certain points of the year there is no UVB light passing through the atmosphere Tavera-Mendoza and White, Sci. American, Nov 2007. Three types of diseases have demonstrated north-south gradients. 1. Certain types of cancers (e.g. colon, prostate). 2. Autoimmune diseases: e.g. multiple sclerosis, Crohn’s disease. 3. Infectious diseases. tuberculosis being exposed to the sun has beneficial effects against TB TB bacilli Sanitorium ~1920 Colon cancer rates and summer surface UVB levels. Colon Cancer rates 1970-94, White males supplementation of vitamin D has been shown to have beneficial effects on colon cancer Spectral UVB exposure kJ/m2 July, 1992 Treatment of cells with 1,25-dihydroxyvitamin D3 induces secretion of antibacterial activity. 0h Bact. colonies (%) 120 100 80 60 40 20 0 Bact. colonies (%) 120 100 80 60 40 20 0 0 24 48h D3 0 24 48h D3 E. coli 48h vitamin D is capable of stimulating the production of chemicals that acts as antibacterials - stain for levels of a particular protein that increases a cells ability to kill bacteria - these types of peptides are also effective against TB P. aerug. 48 hour 1,25dihydroxyvitamin D3 treatment of cells in culture increases levels of antimicrobial proteins inside cells ...
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This note was uploaded on 04/26/2011 for the course PHGY 210 taught by Professor Trippenbach during the Winter '08 term at McGill.

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