Diversity of actions of GnRHs mediated by ligand-induced selective signaling.
Geoffrey Wingfield Harris' demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the G(q) signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention.
Millar
Robert P
RP
MRC Human Reproductive Sciences Unit, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. r.millar@hrsu.mrc.ac.uk
Pawson
Adam J
AJ
Morgan
Kevin
K
Rissman
Emilie F
EF
Lu
Zhi-Liang
ZL
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020868:Gene Silencing; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology; D011966:Receptors, LHRH / Q000819:agonists* / Q000502:physiology; D043762:Reproductive Behavior / Q000187:drug effects* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D012726:Sexual Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D008024:Ligands; D020033:Protein Isoforms; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone