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Gn-RH and Gn-RH receptors

Gn-RH and Gn-RH receptors. Fertility Center Cardito. Dr. Vincenzo Volpicelli. Hypothalamic anatomy. Hypothalamus is a pars of diencephalon Under thalamus Is floor of the third ventriculus. Hypothalamic anatomy. Optic Chiasm Mammillary bodies Median eminence Infundibulum.

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Gn-RH and Gn-RH receptors

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  1. Gn-RH and Gn-RH receptors Fertility Center Cardito Dr. Vincenzo Volpicelli

  2. Hypothalamic anatomy • Hypothalamus is a pars of diencephalon • Under thalamus • Is floor of the third ventriculus

  3. Hypothalamic anatomy • Optic Chiasm • Mammillary bodies • Median eminence • Infundibulum

  4. Neurotransductor effects on Gn-RH release Legenda: b- END = b-endorfine; CRF = Corticotropin Releasing Factor; OT = Somatostatina; DA = Dopamina; GABA = Acido g-Amino-Butirrico; ACh = Acetilcolima; NPY = Neuropeptide Y; NA = Noradrenalina

  5. leptine • Modulates NY •  • Gn-RH secretion

  6. Leptine

  7. medial eminence (ME) ventromedial nucleus (VM) arcuate nucleus (AR) Hypothalamic nuclei

  8. hypothalamic nuclei

  9. Hormones of the hypothalamus • Corticotropin-releasing hormone (CRH) • Dopamine (DA) • Gonadotropin-releasing hormone (Gn-RH) • Growth hormone releasing hormone (GH-RH) • Somatostatin (ST) • Thyrotropin-releasing hormone (TRH) • Antidiuretic Hormone (ADH)

  10. Gn-RH Human Luteinizing hormone-releasing hormone gene (LH-RH) is located on short arm of chromosome 8 (region 8p11.2 → p21) * • Gn-RH neurons are inside the medium-basal hypothalamus (arcuate nucleus and median eminence) • Lately scientists showed Gn-RH syntesis in pituitary gland too. Teresa L. Yang-Feng, Peter H. Seeburg and Uta Francke: Somatic Cell and Molecular GeneticsVolume 12, Number 1 / January, 1986

  11. Gn-RH • Gn-RH is considered a neurohormone • produced in a specific neural cell and released at its neural terminal • A key area for production of Gn-RH1 is the preoptic area of the hypothalamus, that contains most of the Gn-RH1-secreting neurons. • Gn-RH1 is secreted in the hypophysial portal bloodstream at the median eminence • The portal blood carries the Gn-RH1 to the pituitary gland, which contains the gonadotrope cells, where Gn-RH1 activates its own receptor, gonadotropin-releasing hormone receptor (Gn-RH-R), located in the cell membrane

  12. Gn-RH • Gn-RH neurons are closely connected with noradrenergic, dopaminergic, serotoninergic, oppioid ones.

  13. Gn-RH frequency • Low frequency Gn-RH pulses lead to FSH release • high frequency Gn-RH pulses stimulate LH release

  14. Gn-RH-r • Gn-RH-r is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family • It is expressed on the surface of pituitary gonadotrope cells* * as well as lymphocytes, breast, ovary, and prostate

  15. Gn-RH-r Function • Following binding of Gn-RH activate a phosphatidylinositol (PtdIns)-calcium second messenger system. • Activation of GNRH-r ultimately causes the release of FSH and LH

  16. Gn-RH • Gn-RH is considered a neurohormone • produced in a specific neural cell and released at its neural terminal • A key area for production of GN-RH1 is the preoptic area of the hypothalamus, that contains most of the GNRH1-secreting neurons. • GN-RH1 is secreted in the hypophysial portal bloodstream at the median eminence • The portal blood carries the GN-RH1 to the pituitary gland, which contains the gonadotrope cells, where GN-RH1 activates its own receptors, gonadotropin-releasing hormone receptors (GN-RH-R), located in the cell membrane

  17. Gn-RH • Gn-RH neurons are closely connected with noradrenergic, dopaminergic, serotoninergic, oppioid ones.

  18. Males/females Gn-RH secretion • in males, Gn-RH1 is secreted in pulses at a constant frequency • in females the frequency of the pulses varies during the menstrual cycle • there is a large surge of GNRH1 just before ovulation

  19. Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteaseor by intramolecular digestion. Gn-RH is degraded by proteolysis within a few minutes Proteolysis

  20. Control of FSH and LH • At the pituitary, Gn-RH1 stimulates the synthesis and secretion of FSH and LH • These processes are controlled by: • the size and frequency of Gn-RH1 pulses, • feedback from androgens and estrogens

  21. Gn-RH-R Function • Following binding of Gn-RH activate a phosphatidylinositol(PtdIns)-calcium second messenger system. • Activation of Gn-RH-R ultimately causes the release of FSH and LH

  22. receptors • Hormones and active metabolites bind to different types of receptors. Water-soluble molecules (i.e., insulin) cannot pass through the lipid membrane of a cell and thus rely on cell surface receptors to transmit messages to the interior of the cell. In contrast, lipid-soluble molecules (i.e., certain active metabolites) are able to diffuse through the lipid membrane to communicate messages directly to the nucleus

  23. Gn-RH-R • Gn-RH-R is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. • It is expressed on the surface of pituitary gonadotrope cells* * as well as lymphocytes, breast, ovary, and prostate.

  24. Gn-RH biochemistry • a decapeptide (10 amino acids) in mammals. • This chain is represented by: pyroGlu-His-Tyr-Ser-Gly-Leu-Arg-Pro-Gly-NH2 • previously called LH-RH The identity of GN-RH1 was clarified by the 1977 Nobel Laureates Roger Guillemin and Andrew V. Schally

  25. Gn-RH • Gn-RH is considered a neurohormone • produced in a specific neural cell and released at its neural terminal. • A key area for production of Gn-RH1 is the preoptic area of the hypothalamus, that contains most of the Gn-RH1-secreting neurons. • Gn-RH1 is secreted in the hypophysial portal bloodstream at the median eminence. • The portal blood carries the Gn-RH1 to the pituitary gland, which contains the gonadotrope cells, where Gn-RH1 activates its own receptor (Gn-RH-R), located in the cell membrane.

  26. Gn-RH neural junctions • Gn-RH neurons are closely connected with: • noradrenergic, • dopaminergic, • serotoninergic, • oppioid ones.

  27. Gn-Receptors • Upon binding Hormone externally to the membrane, a transduction of the signal takes place that activates the G protein • that is bound to the receptor internally

  28. Gn-Receptors • With Hormone attached, the receptor shifts conformation • mechanically activates the G protein, which detaches from the receptor and activates the cAMP system.

  29. G Protein System Alfred G. Gilman and Martin Rodbell received the 1994 Nobel Prize in Medicine and Physiology for the discovery of the G Protein System

  30. Gn-RH-R Function • Following binding of Gn-RH activate a phosphatidylinositol (PtdIns)-calcium second messenger system. • Activation of Gn-RH-R ultimately causes the release of FSH and LH

  31. Gonadotropin-releasing hormone receptor • Gn-RH-R is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. • It is expressed on the surface of pituitary gonadotrope cells* * as well as lymphocytes, breast, ovary, and prostate.

  32. The seven transmembrane α-helix structure of a G protein-coupled receptor

  33. hormone receptor* • I° messenger: hormone • Hormone + Receptor • G-Protein activation: • Adhesion H-R complex • Scission H-R complex • Subunit a production * A protein on the surface of a cell to which a specific hormone binds

  34. hormone receptors • a subunit activates  • intracellular effectors (enzymes) • adenyl-ciclases cAMP • guanil-cyclase cGMP • phospholipase DAG*, IP3* • ionic ducts (K+ , Ca++) (II° messenger) *Diacilglicerolo, Inositolo trifosfato

  35. PO4 by cAMP-dependent PKA • II° messenger  activates Protein kinasi (PKA)  • activates Phosphorylation (PO4) of: • citoplasmatic protein • nuclear transcription factors (cAMP Responsive Element Binding Protein, CREB).

  36. DNA transcription CREB modulates transcription of genes interacting directely with specific DNA string

  37. hormone receptors

  38. Control of FSH and LH • At the pituitary, Gn-RH1 stimulates the synthesis and secretion of FSH and LH • These processes are controlled by: • the size and frequency of GN-RH1 pulses • feedback from androgens and estrogens • Gn-receptors wholeness

  39. Control of FSH and LH • Low frequency Gn-RH pulses lead to FSH release • high frequency Gn-RH pulses stimulate LH release

  40. Gn-RH secretion males/females • in males, GN-RH1 is secreted in pulses at a constant frequency • in females the frequency of the pulses varies during the menstrual cycle • there is a large surge of GN-RH1 just before ovulation

  41. Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteaseor by intramolecular digestion. Gn-RH is degraded by proteolysis within a few minutes Gn-RH proteolysis

  42. Gn-RH-a • A gonadotropin-releasing hormone agonist (GnRH agonist) is a synthetic peptide modeled after the hypothalamic neurohormone GnRH that interacts with the gonadotropin-releasing hormone receptor to elicit its biologic response, the release of the pituitary hormones FSH and LH

  43. Gn-RH-a Triptorelin is an agonist with only a single substitution at position 6.

  44. Gn-RH-a administration mode • These medications can be administered • intranasally, • by injection, • or by implant. • Injectables have been formulated for daily, monthly, and quarterly use; and implants can last from 1 to 3 months.

  45. Gn-RH-a Downregulation • after their initial stimulating action – termed a “flare” effect -, eventually caused a paradoxical and sustained drop in gonadotropin secretion. • This second effect was termed “downregulation” and can be observed after about 10 days. • While this phase is reversible it can be maintained with further GnRH agonist use for a long time.

  46. Gn-RH-a Downregulation • refers to the decrease in the number of receptor sites. • This can be accomplished by metabolizing bound LH-R sites. • The bound LCGR complex is brought by lateral migration to a “coated pit” where such units are concentrated and then stabilized by a framework of clathrins. • A pinched-off coated pit is internalized and degraded by lysosomes. Proteins may be metabolized or the receptor can be recycled. Use of long-acting agonists will downregulate the receptor population.

  47. Gn-RH-a Desensitization • The LH-Rs become desensitized when exposed to LH for some time. • A key reaction of this downregulation is the phosphorylation of the intracellular receptor domain by protein kinases • This process uncouples Gs protein from the LH-R • Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.

  48. Gn-RH antagonist • GnRH antagonists are also derivates of the natural GnRH decapeptide with multiple amino acid substitutions • A gonadotropin-releasing hormone antagonist (GnRH antagonist) is an analogue that blocks the GnRH receptor resulting in an immediate drop in gonadotropin (FSH, LH) secretion • The Gn-RH antagonist is primarily used in IVF treatments to block premature surge of LH

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