title: The metabolite GnRH-(1-5) inhibits the migration of immortalized GnRH neurons.
abstract: The decapeptide GnRH is an important regulator of reproductive behavior and function. In the extracellular matrix, GnRH is metabolized by the endopeptidase EC3.4.24.15 (EP24.15) to generate the pentapeptide GnRH-(1-5). In addition to its expression in the adult hypothalamus, EP24.15 is expressed along the migratory path of GnRH-expressing neurons during development. Although we have previously demonstrated a role for EP24.15 in the generation of the biologically active pentapeptide GnRH-(1-5) in regulating GnRH expression and mediating sexual behavior during adulthood in rodents, the modulatory role of GnRH-(1-5) in the migration of GnRH neurons during development remains unknown. To address this information gap, we examined the effect of GnRH-(1-5) on the cellular migration of a premigratory GnRH-secreting neuronal cell line, the GN11 cell, using a wound-healing assay. Dose- and time-response studies demonstrated that GnRH-(1-5) significantly delayed wound closure. We then sought to identify the mechanism by which GnRH-(1-5) inhibits migration. Because the cognate GnRH receptor is a G protein-coupled receptor, we examined whether GnRH-(1-5) regulates migration by also activating a G protein-coupled receptor. Using a high-throughput β-arrestin recruitment assay, we identified an orphan G protein-coupled receptor (GPR173) that was specifically activated by GnRH-(1-5). Interestingly, small interfering RNA to GPR173 reversed the GnRH-(1-5)-mediated inhibition on migration of GN11 neurons. Furthermore, we also demonstrate that the GnRH-(1-5)-activated GPR173-dependent signal transduction pathway involves the activation of the signal transducer and activator of transcription 3 in GnRH migration. These findings indicate a potential regulatory role for GnRH-(1-5) in GnRH neuronal migration during development.
authors: Program in Molecular and Cellular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors: Darwin O
authors: DO
authors: Larco
authors: Madelaine
authors: M
authors: Cho-Clark
authors: Shaila K
authors: SK
authors: Mani
authors: T John
authors: TJ
authors: Wu
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects
chemical_list: C578985:GPR173 protein, mouse; C495201:LHRH (1-5); D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D007987:Gonadotropin-Releasing Hormone; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase