Discovery of new receptors regulating luteinizing hormone and follicle-stimulating hormone secretion by bovine gonadotrophs to explore a new paradigm for mechanisms regulating reproduction

• Published in: Journal of Reproduction and Development Vol. 66; no. 4; pp. 291 - 297
• Main Author: KADOKAWA, Hiroya
• Format: Journal Article
• Language: English
• Published: Japan The Society for Reproduction and Development 2020; Japan Science and Technology Agency
• Subjects: 17β-Estradiol; Activin; Anterior pituitary; Anti-Mullerian hormone receptor type 2; Cattle; Cell surface; Estrogen receptors; Estrone; Follicle-stimulating hormone; G protein-coupled estrogen receptor-1; G protein-coupled receptors; Gonadotropin-releasing hormone; Gonadotropin-releasing hormone receptor; Gonadotropins; Inhibin; Lipid raft; Lipid rafts; Luteinizing hormone; mRNA; Pituitary (anterior); Receptor mechanisms; Secretion; SRD Outstanding Research Award 2019; Zearalenone; Anterior pituitary; G protein-coupled estrogen receptor-1; Lipid raft; Anti-Mullerian hormone receptor type 2; Gonadotropin-releasing hormone receptor
• ISSN: 0916-8818; 1348-4400
• DOI: 10.1262/jrd.2020-012

Previous studies in the 1960s and 1970s have reported that both gonadotropin-releasing hormone (GnRH) and estradiol-activated nuclear estrogen receptors regulate gonadotropin secretion in women. However, I had previously reported that gonadotroph function is regulated by complex crosstalk between several membrane receptors. RNA-seq had previously revealed 259 different receptor genes expressed in the anterior pituitary of heifers. However, the biological roles of most of these receptors remain unknown. I identified four new receptors of interest: G protein-coupled receptor 30 (GPR30), anti-Mullerian hormone (AMH) receptor type 2 (AMHR2), and G protein-coupled receptors 61 and 153 (GPR61 and GPR153). GPR30 rapidly (within a few minutes) mediates picomolar, but not nanomolar, levels of estradiol to suppress GnRH-induced luteinizing hormone (LH) secretion from bovine gonadotrophs, without decreasing mRNA expressions of the LHα, LHβ, or follicle-stimulating hormone (FSH) β subunits. GPR30 is activated by other endogenous estrogens, estrone and estriol. Moreover, GPR30 activation by zearalenone, a nonsteroidal mycoestrogen, suppresses LH secretion. AMHR2, activated by AMH, stimulates LH and FSH secretion, thus regulating gonadotrophs, where other TGF-β family members, including inhibin and activin, potentially affect FSH secretion. I also show that GPR61, activated by its ligand (recently discovered) significantly alters LH and FSH secretion. GPR61, GPR153, and AMHR2 co-localize with the GnRH receptor in unevenly dispersed areas of the bovine gonadotroph cell surface, probably lipid rafts. The findings summarized in this review reveal a new paradigm regarding the mechanisms regulating reproduction via novel receptors expressed on bovine gonadotrophs.