Multiple facets of follicle-stimulating hormone receptor function

Ulloa‐Aguirre, Alfredo; Zariñán, Teresa; Pasapera, Ana M.; Casas‐González, Patricia; Dias, James A.

doi:10.1007/s12020-008-9041-6

Cited by 79 publications

(60 citation statements)

References 146 publications

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“…The ligand recognition and signaling of FSHR, a representative member in group A of the LGR family, have been extensively studied (Fan and Hendrickson 2005;Ulloa-Aguirre et al 2007), and the complex structure of the FSHR-ECD with its ligand, FSH, has also been determined (Fan and Hendrickson 2005;Jiang et al 2012). The LGR4-ECD has an architecture similiar to the FSHR-ECD, including similiar LRRNT, multiple LRR modules (17 in LGR4 and nine in FSHR), and LRRCT.…”

Section: Structural Insights Into Signaling Differences Betweenmentioning

confidence: 99%

Structural basis for R-spondin recognition by LGR4/5/6 receptors

et al. 2013

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The R-spondin (RSPO) family of secreted proteins (RSPO1-RSPO4) has pleiotropic functions in development and stem cell growth by strongly enhancing Wnt pathway activation. Recently, leucine-rich repeat-containing G-proteincoupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors for RSPOs. Here we report the complex structure of the LGR4 extracellular domain (ECD) with the RSPO1 N-terminal fragment (RSPO1-2F) containing two adjacent furin-like cysteine-rich domains (FU-CRDs). The LGR4-ECD adopts the anticipated TLR horseshoe structure and uses its concave surface close to the N termini to bind RSPO1-2F. Both the FU-CRD1 and FU-CRD2 domains of RSPO1 contribute to LGR4 interaction, and binding and cellular assays identified critical RSPO1 residues for its biological activities. Our results define the molecular mechanism by which the LGR4/5/6 receptors recognize RSPOs and also provide structural insights into the signaling difference between the LGR4/5/6 receptors and other members in the LGR family.

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Section: Structural Insights Into Signaling Differences Betweenmentioning

confidence: 99%

Structural basis for R-spondin recognition by LGR4/5/6 receptors

et al. 2013

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“…The alpha subunits of FSH, LH, TSH, and hCG are identical, whereas the beta subunit is unique and endows each hormone with the ability to binds to its own receptor (60). FSH interacts with a receptor protein that has seven transmembrane-spanning domains; its binding is transduced into an intracellular signal via the heterotrimeric G proteins (61). Following coupling of the FSHR to G␣ s adenylyl cyclase is stimulated, followed by production of cAMP and activation of PKA, which phosphorylates structural proteins, enzymes, and transcriptional activators (32,66).…”

Section: )] (41)mentioning

confidence: 99%

Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

Mancinelli¹,

Onori²,

Gaudio³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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mones regulate cholangiocyte hyperplasia in bile duct-ligated (BDL) rats. We studied whether follicle-stimulating hormone (FSH) regulates cholangiocyte proliferation. FSH receptor (FSHR) and FSH expression was evaluated in liver sections, purified cholangiocytes, and cholangiocyte cultures (NRICC). In vivo, normal female and male rats were treated with FSH or immediately after BDL with antide (a gonadotropin-releasing hormone antagonist blocking FSH secretion) or a neutralizing FSH antibody for 1 wk. We evaluated 1) cholangiocyte proliferation in sections and cholangiocytes and 2) changes in secretin-stimulated cAMP (functional index of cholangiocyte growth) levels, and ERK1/2 and Elk-1 phosphorylation. NRICC were stimulated with FSH before evaluation of proliferation, cAMP/IP3 levels, and ERK1/2 and Elk-1 phosphorylation. To determine whether FSH regulates cholangiocyte proliferation by an autocrine mechanism, we evaluated the effects of 1) cholangiocyte supernatant (containing FSH) on NRICC proliferation and 2) FSH silencing in NRICC before measuring proliferation and ERK1/2 and Elk-1 phosphorylation. Cholangiocytes and NRICC express FSHR and FSH and secrete FSH. In vivo administration of FSH to normal rats increased, whereas administration of antide and anti-FSH antibody to BDL rats decreased 1) ductal mass and 2) secretin-stimulated cAMP levels, proliferation, and ERK1/2 and Elk-1 phosphorylation in cholangiocytes compared with controls. In NRICC, FSH increased cholangiocyte proliferation, cAMP levels, and ERK1/2 and Elk-1 phosphorylation. (8), prolactin (58), and progesterone (25). The cAMP/ERK1/2/Elk-1 signaling has been shown to play a key role in the regulation of cholangiocyte proliferation (18,20,24,27,37). For example, whereas increased cAMP levels sustain cholangiocyte growth (20,24,27,37), decreased cAMP synthesis results in inhibition of cholangiocyte hyperplasia (24,27,37).Follicle-stimulating hormone (FSH) is the central hormone of the mammalian reproduction (55). FSH, also called gonadotropin because it stimulates the gonads, is produced from the anterior pituitary gland of the brain (60). FSH is a large glycoprotein composed of alpha and beta subunits, similar to those of luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG) (1). The alpha subunits of FSH, LH, TSH, and hCG are identical, whereas the beta subunit is unique and endows each hormone with the ability to binds to its own receptor (60). FSH interacts with a receptor protein that has seven transmembrane-spanning domains; its binding is transduced into an intracellular signal via the heterotrimeric G proteins (61). Following coupling of the FSHR to G␣ s adenylyl cyclase is stimulated, followed by production of cAMP and activation of PKA, which phosphorylates structural proteins, enzymes, and transcriptional activators (32,66). Whether the FSH receptor is also linked to G␣ i has not yet been completely defined. In fact, the treatment of Sertoli cells with pertussis toxin (PTX, a G␣ i inhib...

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“…It is essential for women and plays a role in the follicle development, oocyte maturation, steroidgenesis regulation, proliferation of granulosa cells and induces synthesis of the androgen-converting enzyme aromatase [2,3,4,5]. …”

Section: Introductionmentioning

confidence: 99%

Ala307Thr and Asn680Ser Polymorphisms ofFSHRGene in Human Reproduction Outcomes

Trevisan¹,

Peluso²,

Cordts³

et al. 2014

Cell Physiol Biochem

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Background/Aims: It is known that some markers of ovarian stimulation can help to personalize the treatment, adjusting the dose of exogenous rFSH, thus preventing excessive wear of the patient. We aimed to evaluate Ala307Thr and Asn680Ser genotypes of the FSHR gene in infertile women and correlate the findings with the results of ovarian response and assisted reproduction outcomes. Methods: Cross-sectional study covering 149 infertile women submitted to assisted reproduction treatment. Genotyping of FSHR variants were performed using TaqMan methodology by real time PCR. FSH and estradiol were measured by ELFA. The data was analyzed statistically. Results: The frequencies of the FSHR Ala307Thr and Asn680Ser genotypes considering the ovarian hyper stimulation response also did not differ statistically. Considering assisted reproduction outcomes, we observed that the polymorphism Ala307Thr have a statistical difference for the number of MII oocytes and embryos (p=0,051 and p=0.037, respectively), which the genotype Ala/Ala showed more embryos. The polymorphisms did not determine the FSH and estradiol serum levels and the ovarian response in the assisted reproduction treatment. Conclusions: The polymorphisms Ala307Thr and Asn680Ser did not determine the FSH and estradiol serum levels and the ovarian response in the assisted reproduction treatment. However, we observed that the Ala307Thr may influence the number of embryos produced.

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Multiple facets of follicle-stimulating hormone receptor function

Cited by 79 publications

References 146 publications

Structural basis for R-spondin recognition by LGR4/5/6 receptors

Structural basis for R-spondin recognition by LGR4/5/6 receptors

Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

Ala307Thr and Asn680Ser Polymorphisms ofFSHRGene in Human Reproduction Outcomes

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