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Deborah A. Roess - One of the best experts on this subject based on the ideXlab platform.
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Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors.
Diseases, 2020Co-Authors: Duaa Althumairy, Xiaoping Zhang, Nicholas Baez, George Barisas, Deborah A. Roess, George R. Bousfield, Debbie C. CransAbstract:Signal transduction by Luteinizing Hormone Receptors (LHRs) and follicle-stimulating Hormone Receptors (FSHRs) is essential for the successful reproduction of human beings. Both Receptors and the thyroid-stimulating Hormone receptor are members of a subset of G-protein coupled Receptors (GPCRs) described as the glycoprotein Hormone Receptors. Their ligands, follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH) and a structurally related Hormone produced in pregnancy, human chorionic gonadotropin (hCG), are large protein Hormones that are extensively glycosylated. Although the primary physiologic functions of these Receptors are in ovarian function and maintenance of pregnancy in human females and spermatogenesis in males, there are reports of LHRs or FSHRs involvement in disease processes both in the reproductive system and elsewhere. In this review, we evaluate the aggregation state of the structure of actively signaling LHRs or FSHRs, their functions in reproduction as well as summarizing disease processes related to receptor mutations affecting receptor function or expression in reproductive and non-reproductive tissues. We will also present novel strategies for either increasing or reducing the activity of LHRs signaling. Such approaches to modify signaling by glycoprotein Receptors may prove advantageous in treating diseases relating to LHRs or FSHRs function in addition to furthering the identification of new strategies for modulating GPCR signaling.
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restricted lateral diffusion of Luteinizing Hormone Receptors in membrane microdomains
Journal of Biological Chemistry, 2011Co-Authors: Amber L Wolfringwall, Deborah A. Roess, Peter Winter, Jingjing Liu, Alan Van Orden, George B BarisasAbstract:Abstract Single particle tracking was used to evaluate lateral motions of individual FLAG-tagged human Luteinizing Hormone (LH) Receptors expressed on CHO cells and native LH Receptors on both KGN human granulosa-derived tumor cells and M17 human neuroblastoma cells before and after exposure to human chorionic gonadotropin (hCG). Compared with LH Receptors on untreated cells, LH Receptors on cells treated with 100 nm hCG exhibit restricted lateral diffusion and are confined in small, nanometer-scale, membrane compartments. Similar to LH Receptors labeled with Au-hCG, LH Receptors labeled with gold-deglycosylated hCG, an hCG antagonist, also exhibit restricted lateral diffusion and are confined in nanoscale membrane compartments on KGN cells treated with 100 nm hCG. LH receptor point mutants lacking potential palmitoylation sites remain in large compartments despite treatment with 100 nm hCG as do LH Receptors on cells treated with cytochalasin D. Finally, both polarization homotransfer fluorescence resonance energy transfer imaging and photon counting histogram analysis indicate that treatment with hCG induces aggregation of YFP-coupled LH Receptors stably expressed on CHO cells. Taken together, our results demonstrate that binding of hCG induces aggregation of LH Receptors within nanoscale, cell surface membrane compartments, that hCG binding also affects the lateral motions of antagonist binding LH Receptors, and that receptor surface densities must be considered in evaluating the extent of Hormone-dependent receptor aggregation.
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Luteinizing Hormone Receptors translocate to plasma membrane microdomains after binding of human chorionic gonadotropin
Endocrinology, 2006Co-Authors: Steven M L Smith, Jingjing Liu, George B Barisas, Ying Lei, Mary E Cahill, Guy M Hagen, Deborah A. RoessAbstract:Receptor-mediated signal transduction by G protein-coupled Receptors can involve redistribution of plasma membrane Receptors into membrane structures that are characterized by insolubility in Triton X-100 and low buoyant density in sucrose gradients. Here we describe the translocation of wild-type (wt) rat LH Receptors (LHR-wt) from the bulk membrane into membrane microdomains (rafts) after the binding of human chorionic gonadotropin (hCG). In sucrose gradient ultracentrifugation of plasma membranes from cells stably expressing FLAG-tagged LHR-wt, Receptors were located in high-density membrane fractions before binding of Hormone and in low-density fractions after hCG treatment. Receptor translocation to low-density sucrose fractions did not occur when cells were pretreated with 1% methyl-β-cyclodextrin, which reduces membrane cholesterol and disrupts rafts. Single-particle tracking of individual FLAG-LHR-wt Receptors showed that hCG-treated Receptors become confined in small compartments with a diameter ...
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self association and raft localization of functional Luteinizing Hormone Receptors
Biology of Reproduction, 2003Co-Authors: Deborah A. Roess, Steven M L SmithAbstract:Abstract Membrane motions of LH Receptors following binding of Hormone agonists are consistent with Hormone-driven aggregation. It is increasingly apparent that G protein-coupled Receptors, including the LH receptor, are engaged in dynamic interactions with one another and other membrane components. These interactions are governed, in part, by a number of factors including whether the receptor has bound ligand, whether the receptor is capable of transducing a Hormone-mediated signal, and the nature of the membrane environment within which the receptor is found. Microscopic methods, including laser-optical techniques, are ideally suited to probe dynamic events on cell membranes and provide an opportunity to examine interactions between Receptors and other membrane components on viable cells. We and others have used a variety of techniques, some of which are summarized below, to examine functional and nonfunctional LH Receptors on viable cells and the membrane environment of these Receptors during cell sign...
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membrane organization of Luteinizing Hormone Receptors differs between actively signaling and desensitized Receptors
Journal of Biological Chemistry, 2003Co-Authors: Mary Hunzickerdunn, George Barisas, Jinming Song, Deborah A. RoessAbstract:Abstract Signaling by the Luteinizing Hormone/choriogonadotropin receptor (LHR) is of considerable interest because of its requirement for successful reproduction. Time-resolved phosphorescence anisotropy and fluorescence resonance energy transfer were used to investigate the organization of endogenous LHRs in porcine follicular membranes in two distinct signaling states, active and desensitized. Desensitized LHRs exhibited ∼3-fold slower rotational correlation times compared with active LHRs (59 ± 4 and 21 ± 9 μs, respectively), suggesting that with agonist-dependent desensitization the Receptors are organized into larger protein complexes. Incubation of membranes with inhibitors of LHR desensitization, such as neutralizing anti-arrestin antibodies, a synthetic peptide corresponding to the third intracellular loop of the LHR but not the corresponding scrambled peptide, or catalytically inactive ARNO, resulted in faster rotational diffusion times equivalent to those of actively signaling LHRs. Furthermore, desensitized LHRs exhibited a 2.4-fold increase in fluorescence resonance energy transfer between LHRs suggesting that the larger protein aggregates formed during desensitization contain more self-associated LHRs. These results indicate that agonist-dependent LHR desensitization precedes organization of LHRs at the cells surface into larger protein aggregates.
C V Rao - One of the best experts on this subject based on the ideXlab platform.
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Protective Effects of Human Chorionic Gonadotropin Against Breast Cancer: How Can We Use This Information to Prevent/Treat the Disease?
Reproductive Sciences, 2017Co-Authors: C V RaoAbstract:Breast cancers (BCs) are the most common malignancies among women worldwide. Giving birth to a first child before 24 years of age decreases the BC risk by about half, when women reach menopausal years. The scientific evidence suggests that the actions of human chorionic gonadotropin (hCG) are responsible for this decrease. Human BC cells and tissues contain hCG/Luteinizing Hormone Receptors. The activation of the Receptors results in an increase in cell differentiation and apoptosis. Conversely, it decreases the cell proliferation, invasion, and survival. The hCG actions are primarily cyclic adenosine monophosphate/protein kinase A mediated, require the presence of Receptors, and involve blocking the activation and nuclear translocation of the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB). The women with a higher hCG levels during pregnancy tend to have a lower BC incidence and those with the receptor-positive tumors have a longer metastasis-free survival. The long-term benefits of pregnancy/hCG seem to come from permanent signature genomic imprinting and expression changes, which are characterized by low cell proliferation, increased efficiency of DNA repair mechanisms, cell differentiation, and cells resistance to carcinogenesis. These findings could provide clinical opportunities to use hCG for the prevention of BC in this modern era of increasing number of young women in our societies waiting longer than ever to have their first child. In addition, hCG may be useful to reduce and/or eliminate cellular targets of carcinogenic changes during an active ongoing disease.
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identification of immunoreactive Luteinizing Hormone Receptors in the adrenal cortex of the female rhesus macaque
Reproductive Sciences, 2016Co-Authors: Bill L Lasley, Alan J Conley, John H Morrison, C V RaoAbstract:Female laboratory macaques were studied under a variety of treatment protocols to determine if immunoreactive Luteinizing Hormone/gonadal chorionic gonadotropin (LH/CG) Receptors were present in the adrenal cortex. All adrenal tissues revealed an absence of immunoreactivity in the in the medulla while staining was present in all three outer zones of the cortex. Increased staining was observed in the zonae reticularis with least staining in the zonae glomerulosa. Moderate and variable staining was found in the zonae fasciculata. These results demonstrate that LH/CG Receptors in the adrenal cortex may be more common in higher primates than previously recognized and help explain some aspects of the endocrine changes observed in mid-aged women during the menopausal transition when circulating LH concentrations are rising.
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Luteinizing Hormone receptor expression in leiomyomatosis peritonealis disseminata.
Obstetrics and gynecology, 2000Co-Authors: D Danikas, V T Goudas, C V Rao, D K BriefAbstract:Leiomyomatosis peritonealis disseminata has been attributed to estrogen stimulation and is seen only rarely in postmenopausal women. In such cases, pathogenesis is uncertain. Leiomyomatosis peritonealis disseminata tumors were resected from a postmenopausal woman. She was receiving tamoxifen therapy for breast cancer and had bilateral ovarian Brenner tumors. Estrogen and progesterone Receptors were detected. Immunohistochemical analysis indicated that LH Receptors were present. Luteinizing Hormone Receptors were identified in leiomyomatosis peritonealis disseminata in one woman. Levels of FSH and LH increase after menopause, and immunohistochemical analysis showed the presence of LH Receptors, so gonadotropin rather than estrogen stimulation might have contributed to development of leiomyomatosis peritonealis disseminata in this uncommon case.
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expression of human chorionic gonadotropin hcg Luteinizing Hormone Receptors and regulation of the cyclooxygenase 1 gene by exogenous hcg in human fetal membranes
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: P Toth, Z M Lei, C V RaoAbstract:The present study characterized hCG/LH Receptors from messenger ribonucleic acid (mRNA) to protein and whether exogenous hCG can bind and regulate the expression of the cyclooxygenase-1 (COX-1) gene in human fetal membranes from term pregnancy. Northern blotting showed that fetal membranes contain 6.0, 4.4, 2.4, and 1.4 kilobases of hCG/LH receptor mRNA transcripts. In situ hybridization revealed that amnion, chorion, and decidua contain receptor transcripts. Western immunoblotting and immunocytochemistry showed that amnion, chorion, and decidua also contain an 80-kDa receptor protein. Ligand blotting demonstrated that the 80-kDa receptor protein in fetal membranes can bind [125I]hCG, and this binding was inhibited by excess unlabeled hCG. Treatment of fetal membranes with highly purified hCG resulted in a dose- and time-dependent increase in immunoreactive COX-1 protein. The response of hCG was seen in all layers of fetal membranes. The treatment with hCG also resulted in an increase in steady state COX-...
Ch V Rao - One of the best experts on this subject based on the ideXlab platform.
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human fetal nongonadal tissues contain human chorionic gonadotropin Luteinizing Hormone Receptors
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: M A Abdallah, Z M Lei, Natalie Greenwold, Steven T Nakajima, Eric Jauniaux, Ch V RaoAbstract:Human chorionic gonadotropin (hCG), a heterodimeric glycoprotein Hormone produced in abundance by placental syncytiotrophoblasts, is preferentially secreted into maternal circulation. Fetal circulation also contains low levels of hCG that are probably derived from fetal kidney, liver, anterior pituitary gland, etc. In addition, the fetus has access to hCG present in exocoelomic and amniotic fluids. hCG has been found in a number of fetal tissues known to stimulate fetal adrenal and testicular steroidogenesis and is also thought to play a role in growth and differentiation of fetal tissues. This led us to test the hypothesis that fetal nongonadal tissues, as in the adult, may also contain hCG/LH Receptors. This hypothesis was tested by immunocytochemistry, Western blotting, in situ hybridization, and RT-PCR. The results demonstrate that kidney, liver, pancreas, lung, small and large intestines, and adrenals contained hCG/LH Receptors. Although the role of fetal nongonadal hCG/LH Receptors is not known, they may mediate the pleiotropic actions of hCG in the growing human fetus.
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Luteinizing Hormone receptor expression in leiomyomatosis peritonealis disseminata.
Obstetrics & Gynecology, 2000Co-Authors: D Danikas, Ch V Rao, V T Goudas, D K BriefAbstract:Abstract Background: Leiomyomatosis peritonealis disseminata has been attributed to estrogen stimulation and is seen only rarely in postmenopausal women. In such cases, pathogenesis is uncertain. Case: Leiomyomatosis peritonealis disseminata tumors were resected from a postmenopausal woman. She was receiving tamoxifen therapy for breast cancer and had bilateral ovarian Brenner tumors. Estrogen and progesterone Receptors were detected. Immunohistochemical analysis indicated that LH Receptors were present. Conclusion: Luteinizing Hormone Receptors were identified in leiomyomatosis peritonealis disseminata in one woman. Levels of FSH and LH increase after menopause, and immunohistochemical analysis showed the presence of LH Receptors, so gonadotropin rather than estrogen stimulation might have contributed to development of leiomyomatosis peritonealis disseminata in this uncommon case.
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human myometrial chorionic gonadotropin Luteinizing Hormone Receptors in preterm and term deliveries
The Journal of Clinical Endocrinology and Metabolism, 1994Co-Authors: J Zuo, Z M Lei, Ch V RaoAbstract:Nonpregnant human myometrium contains functional hCG/LH Receptors. The present study investigated whether pregnant human myometrium also contains these Receptors and whether they vary as a function of delivery in preterm or term pregnancies. Northern blotting revealed that pregnant human myometrium contains 4.3- and 2.2-kilobase receptor messenger ribonucleic acid transcripts. Immunoblotting with a specific hCG/LH receptor antibody showed that myometrium contains 70- and 50-kilodalton immunoreactive proteins. Ligand blotting demonstrated that only the 50-kilodalton protein could bind [125I]hCG, and this binding was inhibited by excess unlabeled hCG. In situ hybridization and immunocytochemistry revealed that the receptor messenger ribonucleic acid and receptor protein are present in myometrial and vascular smooth muscle. The myometrial smooth muscle receptor levels were lower during labor compared to those before labor at preterm and term pregnancy. In summary, our study demonstrates that pregnant human myometrium express hCG/LH receptor gene. The receptor levels were lower during labor compared to those before labor in preterm or term pregnancy. These data suggest that hCG, via its Receptors, may contribute to myometrial quiescence until labor begins at the end of pregnancy.
J M Saez - One of the best experts on this subject based on the ideXlab platform.
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growth Hormone and insulin like growth factor i treatment increase testicular Luteinizing Hormone Receptors and steroidogenic responsiveness of growth Hormone deficient dwarf mice
Endocrinology, 1991Co-Authors: P Chatelain, P Sanchez, J M SaezAbstract:To test the hypothesis that insulin-like growth factor (IGF-I) is required for the in vivo development of testicular Leydig cell function, either recombinant human GH [(hGH)(1.5 μg/g BW) or recombinant IGF-I (1 μg BW) was injected three times daily into immature Snell dwarf mice (dw/dw) and into phenotypically normal control (Dw/–) for 7 days. In dw/dw mice hGH enhanced significantly body, liver, kidney, and testicular weight. In addition, hGH increased testicular LH Receptors and the acute steroidogenic response to human CG, but there was no significant effect on basal plasma testosterone or plasma LH levels. The effects of IGF-I in body and kidney weight were less pronounced than those produced by hGH, but its effects on testicular weight and LH Receptors, as well as on the acute steroidogenic response to human CG, were similar to that observed after hGH treatment. In Dw/- mice hGH had no effect on either body or organ weight or on testicular function, despite the fact that it induced a significant incr...
George B Barisas - One of the best experts on this subject based on the ideXlab platform.
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restricted lateral diffusion of Luteinizing Hormone Receptors in membrane microdomains
Journal of Biological Chemistry, 2011Co-Authors: Amber L Wolfringwall, Deborah A. Roess, Peter Winter, Jingjing Liu, Alan Van Orden, George B BarisasAbstract:Abstract Single particle tracking was used to evaluate lateral motions of individual FLAG-tagged human Luteinizing Hormone (LH) Receptors expressed on CHO cells and native LH Receptors on both KGN human granulosa-derived tumor cells and M17 human neuroblastoma cells before and after exposure to human chorionic gonadotropin (hCG). Compared with LH Receptors on untreated cells, LH Receptors on cells treated with 100 nm hCG exhibit restricted lateral diffusion and are confined in small, nanometer-scale, membrane compartments. Similar to LH Receptors labeled with Au-hCG, LH Receptors labeled with gold-deglycosylated hCG, an hCG antagonist, also exhibit restricted lateral diffusion and are confined in nanoscale membrane compartments on KGN cells treated with 100 nm hCG. LH receptor point mutants lacking potential palmitoylation sites remain in large compartments despite treatment with 100 nm hCG as do LH Receptors on cells treated with cytochalasin D. Finally, both polarization homotransfer fluorescence resonance energy transfer imaging and photon counting histogram analysis indicate that treatment with hCG induces aggregation of YFP-coupled LH Receptors stably expressed on CHO cells. Taken together, our results demonstrate that binding of hCG induces aggregation of LH Receptors within nanoscale, cell surface membrane compartments, that hCG binding also affects the lateral motions of antagonist binding LH Receptors, and that receptor surface densities must be considered in evaluating the extent of Hormone-dependent receptor aggregation.
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Luteinizing Hormone Receptors translocate to plasma membrane microdomains after binding of human chorionic gonadotropin
Endocrinology, 2006Co-Authors: Steven M L Smith, Jingjing Liu, George B Barisas, Ying Lei, Mary E Cahill, Guy M Hagen, Deborah A. RoessAbstract:Receptor-mediated signal transduction by G protein-coupled Receptors can involve redistribution of plasma membrane Receptors into membrane structures that are characterized by insolubility in Triton X-100 and low buoyant density in sucrose gradients. Here we describe the translocation of wild-type (wt) rat LH Receptors (LHR-wt) from the bulk membrane into membrane microdomains (rafts) after the binding of human chorionic gonadotropin (hCG). In sucrose gradient ultracentrifugation of plasma membranes from cells stably expressing FLAG-tagged LHR-wt, Receptors were located in high-density membrane fractions before binding of Hormone and in low-density fractions after hCG treatment. Receptor translocation to low-density sucrose fractions did not occur when cells were pretreated with 1% methyl-β-cyclodextrin, which reduces membrane cholesterol and disrupts rafts. Single-particle tracking of individual FLAG-LHR-wt Receptors showed that hCG-treated Receptors become confined in small compartments with a diameter ...
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Luteinizing Hormone Receptors are self associated in slowly diffusing complexes during receptor desensitization
Molecular Endocrinology, 2001Co-Authors: Regina D Horvat, George B Barisas, Deborah A. RoessAbstract:We have previously shown that rat LH Receptors (LHRs) occupied by human CG (hCG) exhibit slow receptor lateral diffusion and are self-associated. Here we have examined whether LHRs become self-associated and enter slowly diffusing structures in response to Hormone binding and whether these Receptors retain this organization while in the desensitized state. Before Hormone exposure, wild-type rat LHRs coupled at the C terminus to enhanced green fluorescent protein (GFP-LHR-wt) exhibited fast lateral diffusion, as assessed by fluorescent photobleaching recovery (FPR) methods, and most Receptors were laterally mobile. After 30 min exposure to hCG and subsequent removal of Hormone by low pH wash, Hormone challenge at any time within the next 4 h produced no increase in cellular cAMP levels. During this time, LHRs were either laterally immobile or exhibited slower lateral diffusion. When LHRs were again responsive to binding of Hormone, the rate of receptor lateral diffusion had become significantly faster and ...
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Luteinizing Hormone Receptors are self associated in the plasma membrane
Endocrinology, 2000Co-Authors: Deborah A. Roess, Regina D Horvat, Heidi M Munnelly, George B BarisasAbstract:We have evaluated rat LH receptor self-association and lateral dynamics for functional and nonfunctional Receptors after binding of Hormone. We demonstrate, for the first time, that grouped Receptors observed in electron or light microscopy represent actual receptor dimers or oligomers rather than simply the concentration of Receptors within membrane microdomains. Fringe fluorescence photobleaching recovery methods showed that, after binding of either LH or human CG (hCG), functional wild-type LH Receptors, expressed on 293 cells (LHR-wt cells), have mobilities that are 25% lower than those of nonfunctional LH Receptors containing an arginine substitution for lysine at position 583 (LHR-K583R cells). Because lateral diffusion coefficients in two dimensions depend only on the logarithm of the molecular size of the diffusing species, this result implies that functional Receptors exist in substantially larger membrane complexes than do nonfunctional Receptors. In single-cell measurements of fluorescence ener...
