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We have previously demonstrated that the cleavage product of the full-length GnRH, GnRH-(1–5), is biologically active, binds G protein-coupled receptor 173 (GPR173), and inhibits the migration of cells in the immortalized GnRH-secreting GN11 cell. In this study, we attempted to characterize the GnRH-(1–5) intracellular signaling mechanism. To determine whether the signaling pathway mediating GnRH-(1–5) regulation of migration involves a G protein-dependent mechanism, cells were treated with a generic G protein antagonist in the presence and absence of GnRH-(1–5), and a wound-healing assay was conducted to measure migration. G Protein antagonist 2 treatment abolished the GnRH-(1–5) inhibition of migration, indicating that the mechanism of GnRH-(1–5) is G protein coupled. To identify the potential Gα-subunit recruited by GnRH-(1–5) binding GPR173, we measured the second messengers cAMP and inositol triphosphate levels. GnRH-(1–5) treatment did not alter cAMP levels relative to cells treated with vehicle or forskolin, suggesting that GnRH-(1–5) does not couple to the Gαs or Gαi subunits. Similarly, inositol triphosphate levels remained unchanged with GnRH-(1–5) treatment, indicating a mechanism not mediated by the Gαq/11 subunit. Therefore, we also examined whether GnRH-(1–5) activating GPR173 deviated from the canonical G protein-coupled receptor signaling pathway by coupling to β-arrestin 1/2 to regulate migration. Our coimmunoprecipitation studies indicate that GnRH-(1–5) induces the rapid interaction between GPR173 and β-arrestin 2 in GN11 cells. Furthermore, we demonstrate that this association recruits phosphatase and tensin homolog to mediate the downstream action of GnRH-(1–5). These findings suggest that the GnRH-(1–5) mechanism deviates from the canonical G protein-coupled receptor pathway to regulate cell migration in immortalized GnRH neurons.

β-Arrestin 2 Is a Mediator of GnRH-(1–5) Signaling in Immortalized GnRH Neurons