Introduction and MOA of steroidal hormones

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Introduction and MOA of steroidal hormones

  1. 1. Introduction and MOA of Steroidal Hormones Dr. Abhishek Roy Junior Resident (2nd Year), Dept. of Biochemistry, Grant Medical College & Sir J.J. Group of Hospitals, Mumbai Email: mail@abhishek.ro Date: 02/07/2014
  2. 2. Determinants of the Concentration of a Hormone at the Target Cell • The rate of synthesis and secretion of the hormones. • The proximity of the target cell to the hormone source (dilution effect). • The dissociation constants of the hormone with specific plasma transport proteins (if any). • The conversion of inactive or sub-optimally active forms of the hormone into the fully active form. • The rate of clearance from plasma by other tissues or by digestion, metabolism, or excretion.
  3. 3. Determinants of the Target Cell Response • The number, relative activity, and state of occupancy of the specific receptors on the plasma membrane or in the cytoplasm or nucleus. • The metabolism (activation or inactivation) of the hormone in the target cell. • The presence of other factors within the cell that are necessary for the hormone response. • Up- or down-regulation of the receptor consequent to the interaction with the ligand. • Post-receptor de-sensitzation of the cell, including down-regulation of the receptor.
  4. 4. Both Recognition & Coupling Domains Occur on Receptors • The domains responsible for hormone recognition and signal generation have been identified in the protein polypeptide and catecholamine hormone receptors. • The dual functions of binding and coupling ultimately define a receptor, and it is the coupling of hormone binding to signal transduction—so-called receptor-effector coupling —that provides the first step in amplification of the hormonal response. • This dual purpose also distinguishes the target cell receptor from the plasma carrier proteins that bind hormone but do not generate a signal.
  5. 5. Receptors Are Proteins • The insulin receptor is a heterotetramer composed of two copies of two different protein subunits ( α2, β2 ) linked by multiple disulfide bonds in which the extracellular subunit binds insulin and the membrane- spanning subunit transduces the signal through the tyrosine protein kinase domain located in the cytoplasmic portion of this polypeptide. • The receptors for insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) are generally similar in structure to the insulin receptor. • A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains.
  6. 6. General features of Hormone Classes Group I • Types Steroids, Iodothyronines, Calcitriols, retinoids • Solubility Lipophilic • Transport proteins Yes • Plasma half-life Long(Hours to days) • Receptor Intracellular • Mediator Receptor-Hormone Complex Group II Polypeptides,Glycoproteins Catecholamines, Proteins Hydrophilic No Short (Minutes) Plasma Membrane cAMP, cGMP, Ca2+ etc.
  7. 7. Hormones that bind to intracellular receptors • Calcitriol • Glucocorticoids • Mineralocorticoids • Progestins • Retinoic Acids • Thyroid Hormones (T3 and T4)
  8. 8. Hormones that bind to cell surface receptors • Second messenger is c-AMP  α2 and β Adrenergic Catecholamines ACTH ADH Calcitonin FSH CRH LH PTH TSH Somatostatin Glucagon
  9. 9. • The Second Messenger is c-GMP ANF NO • The second Messenger is Ca2+ or Phosphatidylinositol (or Both) α1 Adrenergic catecholamines Cholecystokinin Gastrin Oxytocin TRH PDGF Angiotensin-II
  10. 10. • The second messenger is a kinase or phosphatase cascade • Adiponectin • Chorionic somato-mammotropin • Epidermal growth factor • Erythropoietin • Fibroblast growth factor (FGF) • Growth hormone (GH) • Insulin • Insulin-like growth factors I and II • Leptin • Nerve growth factor (NGF) • Platelet-derived growth factor • Prolactin
  11. 11. The DNA Sequences of Several Hormone Response Elements (HREs) • Glucocorticoids GRE GGTACA NNN TGTTCT • Progestins PRE • Mineralocorticoids MRE • Androgens ARE • Estrogens ERE AGGTCA NNN TGA/TCCT • Thyroid hormone TRE • Retinoic acid RARE AGGTCA N3,4,5 AGGTCA • Vitamin D VDRE • cAMP CRE TGACGTCA

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