scholarly journals Modulation of Ligand Selectivity Associated with Activation of the Transmembrane Region of the Human Follitropin Receptor

2004 ◽  
Vol 18 (8) ◽  
pp. 2061-2073 ◽  
Author(s):  
Lucia Montanelli ◽  
Joost J. J. Van Durme ◽  
Guillaume Smits ◽  
Marco Bonomi ◽  
Patrice Rodien ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Hormone Receptors ◽  
Transmembrane Helix ◽  
High Sensitivity ◽  
Site Directed Mutagenesis ◽  
Constitutive Activity ◽  
Glycoprotein Hormone ◽  
Functional Specificity ◽  
Ligand Selectivity

Abstract Recently, three naturally occurring mutations in the serpentine region of the FSH receptor (FSHr) (D567N and T449I/A) have been identified in three families with spontaneous ovarian hyperstimulation syndrome (OHSS). All mutant receptors displayed abnormally high sensitivity to human chorionic gonadotropin and, in addition, D567N and T449A displayed concomitant increase in sensitivity to TSH and detectable constitutive activity. In the present study, we have used a combination of site-directed mutagenesis experiments and molecular modeling to explore the mechanisms responsible for the phenotype of the three OHSS FSHr mutants. Our results suggest that all mutations lead to weakening of interhelical locks between transmembrane helix (TM)-VI and TM-III, or TM-VI and TM-VII, which contributes to maintaining the receptor in the inactive state. They also indicate that broadening of the functional specificity of the mutant FSHr constructs is correlated to their increase in constitutive activity. This relation between basal activity and functional specificity is a characteristic of the FSHr, which is not shared by the other glycoprotein hormone receptors. It leads to the interesting suggestion that different pathways have been followed during primate evolution to avoid promiscuous stimulation of the TSHr and FSHr by human chorionic gonadotropin. In the hFSHr, specificity would be exerted both by the ectodomain and the serpentine portion.

scholarly journals Revisiting and Questioning Functional Rescue between Dimerized LH Receptor Mutants

2012 ◽  
Vol 26 (4) ◽  
pp. 655-668 ◽  
Author(s):  
Meilin Zhang ◽  
Rongbin Guan ◽  
Deborah L. Segaloff
Keyword(s):  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Hormone Receptors ◽  
Resonance Energy ◽  
Extracellular Domain ◽  
Glycoprotein Hormone ◽  
Lh Receptor ◽  
Defective Mutant

Abstract The glycoprotein hormone receptors are G protein-coupled receptors containing a large extracellular domain fused to a prototypical serpentine domain. cis-activation occurs when binding of hormone to the extracellular domain stabilizes the serpentine domain in an active conformation. Studies by others suggested that these receptors can also signal by trans-activation, where hormone binding to one receptor protomer activates the serpentine domain of an associated protomer, as documented by the partial rescue of hormone-dependent signaling when a binding defective mutant is coexpressed with a signaling defective mutant. However, our characterizations of several LH receptor (LHR) mutants used in previous studies differ markedly from those originally reported. Also, when examining a pair of LHR mutants previously shown to functionally rescue in vitro as well as in vivo, in addition to finding that the properties of the individual mutants differ significantly from those originally described, we determined that when this pair of mutants was coexpressed in vitro, quantitative analyses did not indicate functional rescue. Additional data are presented that provide a plausible alternate explanation for the apparent in vivo trans-activation that was reported. Finally, using LHR mutants that we have documented to be expressed at the cell surface but to lack human chorionic gonadotropin binding activity or to be severely impaired in their ability to activate Gs, we did not observe functional rescue of human chorionic gonadotropin-stimulated cAMP when the mutants were coexpressed, even though bioluminescence resonance energy transfer analyses confirmed that the coexpressed mutants formed dimers. Taken altogether, our data substantively question the concept of functional rescue between LHR mutants.

scholarly journals Endocrine and molecular milieus of ovarian follicles are diversely affected by human chorionic gonadotropin and gonadotropin-releasing hormone in prepubertal and mature gilts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adam J. Ziecik ◽  
Jan Klos ◽  
Katarzyna Gromadzka-Hliwa ◽  
Mariola A. Dietrich ◽  
Mariola Slowinska ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Hormone Receptors ◽  
Cell Function ◽  
Ovarian Follicle ◽  
Molecular Transport ◽  
Gonadotropin Releasing Hormone ◽  
Matrix Remodeling ◽  
Releasing Hormone ◽  
Serum Gonadotropin

AbstractDifferent strategies are used to meet optimal reproductive performance or manage reproductive health. Although exogenous human chorionic gonadotropin (hCG) and gonadotropin-releasing hormone (GnRH) agonists (A) are commonly used to trigger ovulation in estrous cycle synchronization, little is known about their effect on the ovarian follicle. Here, we explored whether hCG- and GnRH-A-induced native luteinizing hormone (LH) can affect the endocrine and molecular milieus of ovarian preovulatory follicles in pigs at different stages of sexual development. We collected ovaries 30 h after hCG/GnRH-A administration from altrenogest and pregnant mare serum gonadotropin (eCG)-primed prepubertal and sexually mature gilts. Several endocrine and molecular alternations were indicated, including broad hormonal trigger-induced changes in follicular fluid steroid hormones and prostaglandin levels. However, sexual maturity affected only estradiol levels. Trigger- and/or maturity-dependent changes in the abundance of hormone receptors (FSHR and LHCGR) and proteins associated with lipid metabolism and steroidogenesis (e.g., STAR, HSD3B1, and CYP11A1), prostaglandin synthesis (PTGS2 and PTGFS), extracellular matrix remodeling (MMP1 and TIMP1), protein folding (HSPs), molecular transport (TF), and cell function and survival (e.g., VIM) were observed. These data revealed different endocrine properties of exogenous and endogenous gonadotropins, with a potent progestational/androgenic role of hCG and estrogenic/pro-developmental function of LH.

Effect of peptide nicking in the human chorionic gonadotropin β-subunit on stimulation of recombinant human thyroid-stimulating hormone receptors

1994 ◽  
Vol 130 (1) ◽  
pp. 92-96 ◽  
Author(s):  
Masayoshi Yoshimura ◽  
A Eugene Pekary ◽  
Xuan-Ping Pang ◽  
Loretta Berg ◽  
Laurence A Cole ◽  
...  
Keyword(s):  
Los Angeles ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Hormone Receptors ◽  
Thyroid Stimulating Hormone ◽  
Human Thyroid ◽  
Β Subunit ◽  
Trophoblastic Diseases ◽  
Thyrotropic Activity ◽  
Stimulating Hormone

Yoshimura M, Pekary AE, Pang X-P, Berg L, Cole LA, Kardana A, Hershman JM. Effect of peptide nicking in the human chorionic gonadotropin β-subunit on stimulation of recombinant human thyroid-stimulating hormone receptors. Eur J Endocrinol 1994;130:92–6. ISSN 0804–4643 It is now generally accepted that human chorionic gonadotropin (hCG) has thyroid-stimulating activity. Heterologous forms of the hCG molecule occur in the purified preparations extracted from urine of pregnant women and patients with trophoblastic diseases. This work was undertaken to determine the effect of peptide nicking in the hCG-β subunit on its thyrotropic potency. Using Chinese hamster ovary cells expressing functional human thyroid-stimulating hormone (TSH) receptors, we examined the effect of nicked hCG on cyclic AMP (cAMP) production and receptor binding. The effect of human leukocyte elastase (hLE), a nicking enzyme, on standard hCG also was examined in the cAMP assay and on receptor binding. We studied five hCG preparations extracted from the urine of normal pregnancy (CR-127 and P8) and trophoblastic diseases (C2, C5 and M4). Two preparations (C2, 96% nicked and M4, 100% nicked in the β44–49 region) showed about a 1.5-fold potency of standard hCG CR-127, which is also 20% nicked in the same region. Non-nicked hCG (P8) had the weakest potency among all of the samples tested. Treatment of standard hCG with hLE increased the cAMP response about two-fold. Dose-dependent displacement of bovine [125I]TSH by standard hCG and hLE-digested hCG was observed and was almost identical. We have confirmed the increased in vitro thyrotropic activity of hCG nicked in the β-intercysteine loop on recombinant human TSH receptors. These data suggest that peptide heterogeneity of the hCG molecule may modulate the in vivo thyrotropic activity of hCG in pregnant women and patients with trophoblastic diseases. Jerome M Hershman, Endocrinology-W111D, West Los Angeles VA Medical Center, Los Angeles, California 90073, USA

scholarly journals Specificity and promiscuity of gonadotropin receptors

Reproduction ◽  
2005 ◽  
Vol 130 (3) ◽  
pp. 275-281 ◽  
Author(s):  
Sabine Costagliola ◽  
Eneko Urizar ◽  
Fernando Mendive ◽  
Gilbert Vassart
Keyword(s):  
Hormone Receptors ◽  
Fsh Receptor ◽  
Ovarian Hyperstimulation ◽  
High Concentration ◽  
Glycoprotein Hormone ◽  
Functional Specificity ◽  
The Past ◽  
Glycoprotein Hormone Receptors ◽  
Naturally Occurring ◽  
Available Information

The dichotomy between hormone recognition by the ectodomain and activation of the G protein by the rhodopsin-like serpentine portion is a well established property of glycoprotein hormone receptors. The specificity barrier avoiding promiscuous activation of the FSH receptor by the high concentration of human chorionic gonadotropin (hCG) prevailing during human pregnancy was thus believed to lie in the ectodomain. In the past two years, mutations responsible for rare spontaneous cases of ovarian hyperstimulation syndromes have partially modified this simple view. Five naturally occurring mutations have been identified which cause an increase in the sensitivity of the FSH receptor to hCG. Surprisingly, these mutations are all located in the serpentine portion of the receptor. In addition to their effect on sensitivity to hCG, they increase sensitivity of the FSH receptor to TSH, and are responsible for activating the receptor constitutively. Together, the available information indicates that the ectodomain and the serpentine domain of the FSH receptor each contribute to the specificity barrier preventing its spurious activation by hCG. While the former is responsible for establishment of binding specificity, the latter introduces a novel notion of functional specificity.Recent data demonstrate that LH and FSH receptors can constitute functional homo- and heterodimers. This suggests the possibility that in cells co-expressing the two receptors, such as granulosa cells, the heterodimers might be endowed with functional characteristics different from those of each homodimer.

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