Gonadotropin-releasing Hormone Stimulated Luteinizing Hormone Secretion is Regulated by the Non-canonical G Protein, Gαs, in Mice

Gonadotropin-releasing Hormone Stimulated Luteinizing Hormone Secretion is Regulated by the Non-canonical G Protein, Gα_s, in Mice

Hailey Schultz¹, Xiang Zhou², Carlos Agustín Isidro Alonso², Caroline David², Ulrich Boehm³, Daniel J. Bernard^1,2

 1. Department of Anatomy & Cell Biology, McGill University, Montréal, QC

2. Department of Pharmacology & Therapeutics, McGill University, Montréal, QC

3. Department of Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg 66421, Germany

Abstract Text:

Gonadotropin-releasing hormone (GnRH), a decapeptide synthesized and released in pulses from hypothalamic neurons, is an essential regulator of reproduction. Loss of GnRH action causes primary or secondary infertility. GnRH binds to its cognate G protein-coupled receptor, GnRHR, on the surface of pituitary gonadotropes, stimulating the pulsatile secretion of luteinizing hormone (LH). LH, in turn, regulates gonadal steroidogenesis (both sexes) and ovulation (females). GnRHR classically couples to the Gα_q/Gα₁₁ (Gα_q/11) pathway. However, GnRHR can also activate Gα_s in vitro. Mice lacking Gα_q/11 in gonadotropes exhibited hypogonadotropic hypogonadism and do not go through puberty. In contrast, LH production and secretion were apparently normal in gonad-intact, gonadotrope-specific Gα_s knockout mice (Gα_s cKO). However, both the amplitude of the LH surge (females) and post-gonadectomy increases in LH (both sexes) were attenuated or blocked in these mice. Here, we report that LH pulse amplitude, but not frequency, was blunted in both gonad-intact and gonadectomized Gα_s cKOs.  Importantly, Gα_s couples to GPCRs in addition to GnRHR, confounding interpretation of the phenotype of these animals. We therefore introduced a point mutation (L80A) into intracellular loop 1 (ICL1) of GnRHR in mice (Gnrhr^L80A/L80A) that reportedly blocks Gα_s but not Gα_q/11 coupling to the receptor. Gnrhr^L80A/L80A mice phenocopied gonadotrope-specific Gα_s cKOs, indicating that GnRHR coupling to Gα_s is required for quantitatively normal GnRH-stimulated LH secretion. We are currently investing the mechanism by which Gα_s regulates GnRH stimulated LH release, which is canonically linked to the Gα_q/11-PLC-IP₃-Ca²⁺, rather than Gα_s-cAMP, pathway.

Funding Sources: Supported by FRQ-NT, NSERC, and CIHR PJT-169184