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Purpose <p>Pulsatile gonadotropin-releasing hormone (GnRH) secretion differentially regulates follicle-stimulating hormone β-subunit (<i>Fshb</i>) expression according to pulse frequency; however, the mechanisms by which pituitary gonadotropes decode GnRH pulsatility remain incompletely understood. GnRH activates both Gα<sub>s</sub>- and Gα<sub>q/11</sub>-mediated signaling pathways, and the transcriptional regulators cAMP response element-binding protein (Creb) and inducible cAMP early repressor (Icer) have been implicated in <i>Fshb</i> regulation. This study examined whether distinct G protein-dependent pathways regulate Creb and Icer in a GnRH pulse frequency-dependent manner.</p> Methods <p>Murine gonadotrope-derived LβT2 cells were transduced with lentiviral shRNA targeting <i>Gnas</i> (Gα<sub>s</sub>), <i>Gnaq/Gna11</i> (Gα<sub>q/11</sub>), or scrambled controls. Cells were perifused and stimulated with pulsatile GnRH (10 nM) at low (every 120&#xa0;min) or high (every 30&#xa0;min) pulse frequencies for 20&#xa0;h. Creb and Erk1/2 phosphorylation were assessed by immunoblotting and <i>Icer</i> and <i>Egr1</i> mRNA levels were measured by real-time PCR.</p> Results <p>GnRH induced pulse frequency-dependent signaling, with enhanced Creb phosphorylation at low pulse frequency and preferential <i>Icer</i> induction at high frequency. <i>Gnas</i> knockdown selectively attenuated Creb phosphorylation at low pulse frequency without affecting <i>Icer</i> expression. In contrast, <i>Gnaq/Gna11</i> knockdown reduced <i>Icer</i> induction at high pulse frequency and markedly attenuated Erk1/2 phosphorylation and <i>Egr1</i> expression at both frequencies.</p> Conclusion <p>GnRH pulse frequency is decoded in gonadotropes through differential engagement of G protein-dependent signaling pathways. Gα<sub>s</sub>-mediated signaling pathways preferentially activate Creb at low pulse frequencies, whereas Gα<sub>q/11</sub>-mediated pathways promote Erk-dependent <i>Icer</i> and <i>Egr1</i> induction at higher pulse frequencies, providing a mechanism for differential regulation of FSH and LH synthesis.</p>

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GnRH pulse frequency is decoded by distinct Gαs- and Gαq/11-mediated signaling pathways in gonadotropes in vitro

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • George A. Stamatiades,
  • Iain R. Thompson,
  • Han Kyeol Kim,
  • Rona S. Carroll,
  • Ursula B. Kaiser

摘要

Purpose

Pulsatile gonadotropin-releasing hormone (GnRH) secretion differentially regulates follicle-stimulating hormone β-subunit (Fshb) expression according to pulse frequency; however, the mechanisms by which pituitary gonadotropes decode GnRH pulsatility remain incompletely understood. GnRH activates both Gαs- and Gαq/11-mediated signaling pathways, and the transcriptional regulators cAMP response element-binding protein (Creb) and inducible cAMP early repressor (Icer) have been implicated in Fshb regulation. This study examined whether distinct G protein-dependent pathways regulate Creb and Icer in a GnRH pulse frequency-dependent manner.

Methods

Murine gonadotrope-derived LβT2 cells were transduced with lentiviral shRNA targeting Gnas (Gαs), Gnaq/Gna11 (Gαq/11), or scrambled controls. Cells were perifused and stimulated with pulsatile GnRH (10 nM) at low (every 120 min) or high (every 30 min) pulse frequencies for 20 h. Creb and Erk1/2 phosphorylation were assessed by immunoblotting and Icer and Egr1 mRNA levels were measured by real-time PCR.

Results

GnRH induced pulse frequency-dependent signaling, with enhanced Creb phosphorylation at low pulse frequency and preferential Icer induction at high frequency. Gnas knockdown selectively attenuated Creb phosphorylation at low pulse frequency without affecting Icer expression. In contrast, Gnaq/Gna11 knockdown reduced Icer induction at high pulse frequency and markedly attenuated Erk1/2 phosphorylation and Egr1 expression at both frequencies.

Conclusion

GnRH pulse frequency is decoded in gonadotropes through differential engagement of G protein-dependent signaling pathways. Gαs-mediated signaling pathways preferentially activate Creb at low pulse frequencies, whereas Gαq/11-mediated pathways promote Erk-dependent Icer and Egr1 induction at higher pulse frequencies, providing a mechanism for differential regulation of FSH and LH synthesis.