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Integrative and Regulatory Physiology

Integrative and Regulatory Physiology. Basic Principles of Reproductive Endocrinology. *. *. *. *. *. *. *. Variable distance. Receptors. One hormone binding site per receptor. The binding of a hormone to its receptor is non-covalent and reversible. [H] + [R]  [HR]

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Integrative and Regulatory Physiology

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  1. Integrative and Regulatory Physiology Basic Principles of Reproductive Endocrinology

  2. * * * * * * *

  3. Variable distance

  4. Receptors One hormone binding site per receptor

  5. The binding of a hormone to its receptor is non-covalent and reversible [H] + [R]  [HR] K = [HR]  [H][R] [HR] = K[H][R] Where: [H] = free hormone concentration [R] = free or unoccupied receptor concentration [HR] = hormone receptor complex or bound hormone concentration K = affinity (association) constant

  6. E/Uterus Same H, Different R or Different H, Same R E/Pituitary Bound

  7. Scatchard Plot

  8. Mutation Polymorphism

  9. Mutation Polymorphism Why “hypergonadotropic?”

  10. Fig. 2.  Direct binding of 33P-labeled H2 relaxin to LGR7 and LGR8 and competition by relaxin-related peptides.A, Scatchard plot analyses of 33P-labeled H2 binding to LGR7 and LGR8. B, competition of 33P-labeled H2 relaxin binding to LGR7 by relaxin-related peptides. C, competition of 33P-labeled H2 relaxin binding to LGR8 by relaxin-related peptides. D, the soluble ectodomain of LGR7 (7BP) blocks H3 relaxin stimulation of cAMP production by LGR7-expressing cells. Sudo S, Kumagai J, Nishi S, Layfield S, Ferraro T, Bathgate R, Hsueh A 2003 H3 relaxin is a specific ligand for LGR7 and activates the receptor by interacting with both the ectodomain and the exoloop 2.2003 J Biol Chem 278(10):7855-62.

  11. The Glycoprotein Hormones

  12. Human Chorionic Gonadotropin (hCG) “A Clasped Embrace” The cystine knot  Blue =  Red =   

  13. LH-hCG Receptor

  14. LH-hCG Receptor

  15. LH-hCG Receptor Extracellular Domain

  16. Different activation mechanisms of glycoprotein hormone receptors, which are members of the G protein-coupled receptor superfamily, have been proposed. For example, the large ectodomain of glycoprotein hormone receptors may function as an inverse agonist keeping the transmembrane domain in an inactive conformation. To provide support for this hypothesis, we have generated different lutropin/choriogonadotropin receptor (LHR) constructs lacking the ectodomain. Although some ectodomain-deficient LHR constructs were targeted to the cell surface, cAMP levels remained unchanged under basal conditions and agonist application but could be increased by a mutation within the transmembrane domain 6 (D578H). Taking advantage of a constitutive activating mutation (S277N) located in the extracellular domain, we showed that the intact leucine-rich repeat-containing ectodomain is essential for constitutive activation of the LHR by mutation of the hinge region. Our findings support an activation scenario in which agonist binding or mutational alterations expose a structure within the ectodomain, which then activates the transmembrane core.

  17. Fig. 1. Differential protease sensitivity of cells expressing the wild-type hLHR as compared to activating mutants of the hLHR. Cells stably expressing hLHR(wt) or one of three different activating hLHR mutants were exposed for the indicated times to protease and then assayed for 125I-hCG binding activity. Data shown are the mean±SEM of four experiments. The 10 and 30 min data points for the hLHR(wt) are statistically different (P<0.005) than those for each of the activating mutants.

  18. Hormone is “First Messenger” Signal Amplification “Second Messenger”

  19. AKAPs: A-Kinase Anchoring Proteins

  20. Nuclear Receptor Ligands and Their Receptors

  21. Steroids & Steroidogenesis

  22. Classic Model of Nuclear Receptor Action

  23. Steroid Hormone Action

  24. Structural Basis of Nuclear Receptor Ligand Binding

  25. Structural Basis of Nuclear Receptor Ligand Binding and Coregulator Recrutiment

  26. Structure of the Nuclear Receptor DBD P box residues make base-specific contacts with DNA. D box residues involved in dimerization and half site spacing.

  27. The NR Hormone Response Elelment Six base pairs form the core recognition motif (in most cases). Two General classes: AGAACA: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors AGGTCA or AGTTCA: estrogen, thyroid hormone, retinoic acid, and vitamin D receptors Core recognition motifs in natural genes usually exhibit some variation from these idealized sequences

  28. Steroid Hormone Action

  29. hCG 10 hours later

  30. ~1 h later

  31. Six base pairs form the core receptor recognition motif.

  32. McKenna NJ, O'Malley BW. Minireview: nuclear receptor coactivators--an update. Endocrinology. 2002 Jul;143(7):2461-5. Review.

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