Unconventional Actions of Glycoprotein Hormone Subunits: A Comprehensive Review

Abstract

The glycoprotein hormones (GPH) are heterodimers composed of a common α subunit and a specific β subunit. They act by activating specific leucine-rich repeat G protein-coupled receptors. However, individual subunits have been shown to elicit responses in cells devoid of the receptor for the dimeric hormones. The α subunit is involved in prolactin production from different tissues. The human chorionic gonadotropin β subunit (βhCG) plays determinant roles in placentation and in cancer development and metastasis. A truncated form of the thyrotropin (TSH) β subunit is also reported to have biological effects. The GPH α- and β subunits are derived from precursor genes (gpa and gpb, respectively), which are expressed in most invertebrate species and are still represented in vertebrates as GPH subunit paralogs (gpa2 and gpb5, respectively). No specific receptor has been found for the vertebrate GPA2 and GPB5 even if their heterodimeric form is able to activate the TSH receptor in mammals. Interestingly, GPA and GPB are phylogenetically and structurally related to cysteine-knot growth factors (CKGF) and particularly to a group of antagonists that act independently on any receptor. This review article summarizes the observed actions of individual GPH subunits and presents the current hypotheses of how these actions might be induced. New approaches are also proposed in light of the evolutionary relatedness with antagonists of the CKGF family of proteins.

The gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis

“…Furthermore, free dimeric CGA has been reported to increase lactotrope differentiation and prolactin release (reviewed in ref. 75 ). It has also been reported that pancreatic islets and insulin processing are directly regulated by melanocortins via MC4R ( 76 ).…”

“…Indeed, the pars tuberalis has been reported to be a source of a prolactin secretagogue called tuberalin (73,74). Furthermore, free dimeric CGA has been reported to increase lactotrope differentiation and prolactin release, reviewed in (75). It has also been reported that pancreatic islets and insulin processing are directly regulated by melanocortins via MC4R (76).…”

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

“…GSEA indicated that gonadotropins and luteinizing hormone signaling pathways might be affected toward the late stage of the disease (10 months). Among leading-edge genes was Cga , which encodes the alpha subunit of glycoprotein hormones (in humans: chorionic gonadotropin, luteinizing hormone, follicle-stimulating hormone, and thyroid stimulating hormone) ( Bellisario et al, 1973 ; Querat, 2021 ). Furthermore, a significant enrichment of inflammatory pathways was only present in 10 months old BACHD vs. WT, where the inflammatory genes such as H2-Aa and Cd74 had comparable expression levels in 2 months old BACHD to WT littermates.…”

Cell non-autonomous signaling through the conservedC. elegansglycopeptide hormone receptor FSHR-1 regulates cholinergic neurotransmission

“…FSHR-1 ligands, the glycoprotein hormone subunit orthologs gpla-1 and gplb-1, act in a common pathway with fshr-1 to regulate neuromuscular function GPLA-1/GPA2 and GPLB-1/GPB5 encode C. elegans orthologs of the glycoprotein hormone subunits GPA2 and GPB5, which are ancestral to all glycoprotein hormones, including FSH in vertebrates (Oishi et al, 2009;Park et al, 2005;Querat, 2021;Van Sinay et al, 2017). GPLA-1/GPA2 and GPLB-1/GPB5 activate FSHR-1 in vitro and act as cognate FSHR-1 ligands in body size regulation .…”