Follicle-Stimulating Isohormones: Characterization and Physiological Relevance

Ulloa‐Aguirre, Alfredo; Midgley, A. Rees; Beitins, Inese Z.; Padmanabhan, Vasantha

doi:10.1210/edrv-16-6-765

Cited by 208 publications

(133 citation statements)

References 193 publications

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“…Mutation of the FSH␤ subunit gene leads to a similar, but slightly less severe, phenotype (14,28). Mutation of the FSH␤ subunit gene may not fully interfere with FSH-R-dependent signaling because of the existence of possible compensatory mechanisms (1). Interesting is the complete block of gametogenesis in both males and females mice lacking the glycoprotein hormone ␣-subunit (29,30).…”

Section: Discussionmentioning

confidence: 99%

Impairing follicle-stimulating hormone (FSH) signalingin vivo: Targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance

Dierich¹,

Sairam²,

Monaco³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

739

466

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authors request that the following corrections be noted. It was accidentally stated that the studies by Kajita et al. (1) and Lee et al. (2) dealt with cinnamoyl-CoA reductase modified plants when in fact they concerned 4-coumarate:coenzyme A ligase (4CL) transgenic plants. Lignin concentration was reduced by down-regulation of 4CL activity in both studies (1, 2). In a subsequent article, Kajita et al. (3) reported a negligible decrease in lignin concentration and a decreased syringyl-toguaiacyl ratio for lignin composition of a sense-suppressed 4CL transgenic tobacco line. Kajita et al. (1) rather than Kajita et al. (3) was inadvertently cited when this later report was contrasted with the large decreases in lignin concentration and an increased syringyl-to-guaiacyl lignin ratio for anti-sense suppressed 4CL Arabidopsis transgenics (2). The authors apologize for the confusion these errors have created for readers of their Commentary and to the authors of the cited work for misrepresenting their research. November 10, 1998, of Proc. Natl. Acad. Sci. USA (95, 13612-13617), the authors request that the following correction be noted: In Fig. 2 appearing on page 13614, the genotype identification for testicular histology in panels C and D were shown reversed. The correct identification is Ϫ͞Ϫ for panel C and ϩ͞ϩ for panel D. The fifth sentence of the figure legend should read as follows: "Histological sections at lower (E) and higher (D) magnification of the seminiferous tubuli from a wild-type and mutant (F and C) mouse."Cell Biology. In the article "Efficient construction of a large nonimmune phage antibody library: The production of highaffinity human single-chain antibodies to protein antigens" by

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Section: Discussionmentioning

confidence: 99%

Impairing follicle-stimulating hormone (FSH) signalingin vivo: Targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance

Dierich¹,

Sairam²,

Monaco³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

739

466

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“…As in other multicellular eukaryote glycoproteins, oligosaccharide structures on glycoprotein hormones are highly variable [115,[119][120][121][122][123][124][125] and play an important role in determining several properties of the hormones [107][108][109][110]126]. For example, in human and equine FSH more than 35 glycans may be identified using mass spectometry of isolated glycopeptides [125,127];~90% of the total glycans in hFSH are sialylated or sulfated [122], and the heterogeneity of this glycoprotein is primarily determined by the variability in these negatively charged species [106,128]. Human FSH contains relatively high amounts of sialic acid-enriched oligosaccharides in their corresponding mono-, di-, tri-or tetra-antennary structures, thus confering an overall negative charge to the molecule [115,116,123,124,129], whereas hLH is sialylated to a lesser extent, is primarily sulfated, and thus is less negatively charged than hFSH [130][131][132].…”

Section: Glycan Structures In Gonadotropins and Their Role In Signal mentioning

confidence: 99%

“…In any case, this concept suggests that ligands with antagonist properties may be developed that either bind to the receptor with very limited or null potency to evoke a biological effect [138,144] or stabilize a particular conformation of the receptor that is signal transduction incompetent or that selectively activates a particular signaling pathway (see below). In both cases, since glycosylation variants of this gonadotropin may provoke diverse effects on signal transduction and end responses in vitro [32,106,128,145], it is possible that some rearrangements in the transmembrane structure of the receptor should occur upon FSH binding.…”

Section: Glycan Structures In Gonadotropins and Their Role In Signal mentioning

confidence: 99%

Novel pathways in gonadotropin receptor signaling and biased agonism

Ulloa‐Aguirre

Crépieux

Poupon

et al. 2011

Rev Endocr Metab Disord

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Gonadotropins play a central role in the control of male and female reproduction. Selective agonists and antagonists of gonadotropin receptors would be of great interest for the treatment of infertility or as non steroidal contraceptive. However, to date, only native hormones are being used in assisted reproduction technologies as there is no pharmacological agent available to manipulate gonadotropin receptors. Over the last decade, there has been a growing perception of the complexity associated with gonadotropin receptors' cellular signaling. It is now clear that the Gs/cAMP/PKA pathway is not the sole mechanism that must be taken into account in order to understand these hormones' biological actions. In parallel, consistent with the emerging paradigm of biased agonism, several examples of ligand-mediated selective signaling pathway activation by gonadotropin receptors have been reported. Small molecule ligands, modulating antibodies interacting with the hormones and glycosylation variants of the native glycoproteins have all demonstrated their potential to trigger such selective signaling. Altogether, the available data and emerging concepts give rise to intriguing opportunities towards a more efficient control of reproductive function and associated disorders.

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“…However, the understanding how this modification conveys specific attributes to the function of the hormones is not without controversy. Conflicting data have existed in this field with several investigators reporting no effect of glycosylation on binding [10][11][12], but with others noting heightened receptor affinity by deglycosylated species [13,14]. More recent work suggests that glycosylation plays an important role in determining the three-dimensional conformation of these ligands, and thus, potentially affects the interaction between hormone and receptor [15].…”

Section: Introductionmentioning

confidence: 99%

Are circulating gonadotropin isoforms naturally occurring biased agonists? Basic and therapeutic implications

Arey

López

2011

Rev Endocr Metab Disord

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The gonadotropins, luteinizing hormone, human chorionic gonadotropin and follicle-stimulating hormone, are key regulators of reproduction. As a result of this function, they have been the focus of research for many years. Isolated or recombinant proteins have been successfully used therapeutically for the treatment of infertility; and, in the case of compounds that block gonadotropin activity, for their potential utility in contraception. Until recently, selective small molecules modulating gonadotropin receptor activity have proven difficult to identify. The gonadotropins are glycoproteins that are released into the plasma as differently glycosylated isoforms and bind to specific G protein-coupled receptors. The degree of glycosylation on the gonadotropins has been shown to be important for the biological activities of these hormones and is differentially regulated depending on the steroidal status. Recent data from the study of glycosylated variants of LH, hCG and FSH have revealed that these isoforms have distinct signaling properties that allow for gonadotropin pleiotropic signals to be transduced effectively at the level of the receptor. Thus, glycosylated variants of the gonadotropins behave as biased agonists. Recently, newly developed, small molecule, synthetic allosteric compounds have been identified that are capable of mimicking this biased signaling. This opens the door to development of orally available, drug-like therapies for reproductive disorders that offer similar pleiotropic richness as that offered by the complex, endogenous hormones.

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Follicle-Stimulating Isohormones: Characterization and Physiological Relevance

Cited by 208 publications

References 193 publications

Impairing follicle-stimulating hormone (FSH) signalingin vivo: Targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance

Impairing follicle-stimulating hormone (FSH) signalingin vivo: Targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance

Novel pathways in gonadotropin receptor signaling and biased agonism

Are circulating gonadotropin isoforms naturally occurring biased agonists? Basic and therapeutic implications

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