The additional N-glycosylation site of the equine LH/CG receptor is not responsible for the limited cyclic AMP pathway activation by equine chorionic gonadotropin relative to luteinizing hormone

LH and chorionic gonadotropin (CG) are glycoproteins fundamental to sexual development and reproduction. Because they act on the same receptor (LHCGR), the general consensus has been that LH and human CG (hCG) are equivalent. However, separate evolution of LHβ and hCGβ subunits occurred in primates, resulting in two molecules sharing ~85% identity and regulating different physiological events. Pituitary, pulsatile LH production results in an ~90-minute half-life molecule targeting the gonads to regulate gametogenesis and androgen synthesis. Trophoblast hCG, the "pregnancy hormone," exists in several isoforms and glycosylation variants with long half-lives (hours) and angiogenic potential and acts on luteinized ovarian cells as progestational. The different molecular features of LH and hCG lead to hormone-specific LHCGR binding and intracellular signaling cascades. In ovarian cells, LH action is preferentially exerted through kinases, phosphorylated extracellular-regulated kinase 1/2 (pERK1/2) and phosphorylated AKT (also known as protein kinase B), resulting in irreplaceable proliferative/antiapoptotic signals and partial agonism on progesterone production in vitro. In contrast, hCG displays notable cAMP/protein kinase A (PKA)-mediated steroidogenic and proapoptotic potential, which is masked by estrogen action in vivo. In vitro data have been confirmed by a large data set from assisted reproduction, because the steroidogenic potential of hCG positively affects the number of retrieved oocytes, and LH affects the pregnancy rate (per oocyte number). Leydig cell in vitro exposure to hCG results in qualitatively similar cAMP/PKA and pERK1/2 activation compared with LH and testosterone. The supposed equivalence of LH and hCG has been disproved by such data, highlighting their sex-specific functions and thus deeming it an oversight caused by incomplete understanding of clinical data.

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Two Hormones for One Receptor: Evolution, Biochemistry, Actions, and Pathophysiology of LH and hCG

Casarini

et al. 2018

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Hormonal and Allosteric Regulation of the Luteinizing Hormone/Chorionic Gonadotropin Receptor

Shpakov

2024

Front. Biosci. (Landmark Ed)

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Luteinizing hormone (LH) and human chorionic gonadotropin (CG), like follicle-stimulating hormone, are the most important regulators of the reproductive system. They exert their effect on the cell through the LH/CG receptor (LHCGR), which belongs to the family of G protein-coupled receptors. Binding to gonadotropin induces the interaction of LHCGR with various types of heterotrimeric G proteins (Gs, Gq/11, Gi) and β-arrestins, which leads to stimulation (Gs) or inhibition (Gi) of cyclic adenosine monophosphate-dependent cascades, activation of the phospholipase pathway (Gq/11), and also to the formation of signalosomes that mediate the stimulation of mitogen-activated protein kinases (β-arrestins). The efficiency and selectivity of activation of intracellular cascades by different gonadotropins varies, which is due to differences in their interaction with the ligand-binding site of LHCGR. Gonadotropin signaling largely depends on the status of N- and O-glycosylation of LH and CG, on the formation of homo- and heterodimeric receptor complexes, on the cell-specific microenvironment of LHCGR and the presence of autoantibodies to it, and allosteric mechanisms are important in the implementation of these influences, which is due to the multiplicity of allosteric sites in different loci of the LHCGR. The development of low-molecular-weight allosteric regulators of LHCGR with different profiles of pharmacological activity, which can be used in medicine for the correction of reproductive disorders and in assisted reproductive technologies, is promising. These and other issues regarding the hormonal and allosteric regulation of LHCGR are summarized and discussed in this review.

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The additional N-glycosylation site of the equine LH/CG receptor is not responsible for the limited cyclic AMP pathway activation by equine chorionic gonadotropin relative to luteinizing hormone

Cited by 2 publications

References 16 publications

Two Hormones for One Receptor: Evolution, Biochemistry, Actions, and Pathophysiology of LH and hCG

Two Hormones for One Receptor: Evolution, Biochemistry, Actions, and Pathophysiology of LH and hCG

Hormonal and Allosteric Regulation of the Luteinizing Hormone/Chorionic Gonadotropin Receptor

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