Endocrinology Steroid Hormones Steroid hormones are lipophilic, and they can readily diffuse into the cell. 0 Androstenedione They are usually transported in plasma via carrier proteins. Easily get into the cell due to them being lipids. Thyroxine, they thyroid hormone is similar to these. HO Steroid hormones have nuclear receptors instead of membrane receptors. OH Testosterone OH Estradiol Sex steroids Ligands for nuclear receptors (steroid receptors) Glucocorticoids, mineralocorticoids, and sex hormones have nuclear receptors (steroid receptors). Thyroid hormones have a steroid receptor Retinoic acid is an important molecule involved in development Endogenous lipids (act on the PPARs) - mediators released from adipocytes and are involved in local signalling pathways; adipocytes produce mediators that affect the cells around them. Foreign chemicals (act on PXRs) - exposed to a lipid soluble chemical, it can go straight into the cell and the metabolism has to deal with it. The PXR (receptors) are a defence mechanism against exogenous lipid chemicals that get into the cells and stimulate metabolism enzymes to get rid of them. Chromosome puffing Blowfly has large salivary glands that have large chromosomes, which are permanently condensed and can be seen down a light microscope. + steroid + steroid + inhibitor of mRNA synthesis They were useful model systems. The chromosome started to swell when the steroid was added. This showed mRNA synthesis. He then looked at the chromosomes it with an antibiotic added as well as steroid hormone. It was seen that inhibited mRNA synthesis, which showed no mRNA synthesis, proving the steroid binds directly to the DNA to cause mRNA synthesis. Showed that steroid directly bind to DNA using their nuclear receptor.
Endocrinology Nuclear receptor structure Start with variable region that binds to the DNA N- A/B C-terminus binds to the hormone, which activates the N-terminus It is a modular protein -C Varia ble Region C D T Hinge E/F DNA Binding, Zinc Fingers Ligand Binding Receptor structure Both these receptors are modular proteins in which the N-terminus binds the DNA and the C-terminuls binds to the hormone. Hormone binding DNA binding There are different receptors for mineralcorticoids and glucorticoids, with each receptor stimulating different effects. Mineralcorticoid Binds Aldosterone Glucorticoid Binds cortisol Inhibits COX-2 production Chimeric receptors Produces transport proteins Combining a mineralcorticoid and glucorticoid receptor forms a hybrid receptor; the chimeric receptor now binds to aldosterone (mineralcorticoid) and stimulates effects a glucocorticoid hormone would stimulate. Binds aldosterone Inhibits COX2 production Binding the two receptors together to form a chimera Glucocorticoids Plasma membrane Cytoplasm Hsp90 1 src Non-genomic signaling GPCR Barrestin Rapid actions G GR Src Genomic signaling Nucleus >Simple GRE GR X GILZ ANXA-1 Barr1. TTP >nGRE GR AVAVX >Tethering GR P50 p65 NFKB >Composite TSLP Barr2 - + Osteocalcin IL-1B TE mRNA GR X TT TRENDS in Pharmacological Sciences The steroid hormone (glucocorticoids) enters the cell via transporter or via diffusion. The steroid receptor is associated with accessory proteins, including src and hsp. Src will phosphorylate the tyrosine residues on its target proteins. Hsp (heat shock proteins) are