Constitutive Activity in Gonadotropin Receptors

Ulloa‐Aguirre, Alfredo; Reiter, Eric; Bousfield, George R.; Dias, James A.; Huhtaniemi, Ilpo

doi:10.1016/b978-0-12-417197-8.00002-x

Cited by 28 publications

(12 citation statements)

References 172 publications

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“…Although this relatively high similarity between the 7 TMD of the gonadotropin receptors might suggest similar mechanisms of receptor activation, mutations in this domain leading to constitutive activation of the FSHR are extremely rare (Figs. 1B and 2) (see below), but this is not the case for the LHCGR (Ulloa-Aguirre et al, 2014a). This difference may be due to the relative stability of the FSHR 7 TMD in the inactive state compared with the LHCGR and the TSHR.…”

Section: Fshr Structurementioning

confidence: 98%

The Follitropin Receptor: Matching Structure and Function

Ulloa‐Aguirre¹,

Zariñán²

2016

Mol Pharmacol

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Follitropin, or follicle-stimulating hormone (FSH) receptor (FSHR), is a G protein-coupled receptor belonging to the glycoprotein hormone receptor family that plays an essential role in reproduction. Although its primary location is the gonad, the FSHR has also been reported in extragonadal tissues including bone, placenta, endometrium, liver, and blood vessels from a number of malignant tumors. The recently resolved crystal structure of FSH bound to the entire FSHR ectodomain has been instrumental in more clearly defining the role of this domain in ligand binding and receptor activation. Biochemical, biophysical, and structural data also indicate that the FSHR exists as a higher order structure and that it may heterodimerize with its closely related receptor, the luteinizing hormone receptor; this association may have physiologic implications during ovarian follicle maturation given that both receptors may simultaneously coexist in the same cell. FSHR heterodimerization is unique to the ovary because in the testes, gonadotropin receptors are expressed in separate compartments. FSHR self-association appears to be required for receptor coupling to multiple effectors and adaptors, for the activation of multiple signaling pathways and the transduction of asymmetric signaling, and for negative and positive receptor cooperativity. It also provides a mechanism through which the glycosylation variants of FSH may exert distinct and differential effects at the target cell level. Given its importance in regulating activation of distinct signaling pathways, functional selectivity at the FSHR is briefly discussed, as well as the potential implications of this particular functional feature on the design of new pharmacological therapies in reproduction.

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Section: Fshr Structurementioning

confidence: 98%

The Follitropin Receptor: Matching Structure and Function

Ulloa‐Aguirre¹,

Zariñán²

2016

Mol Pharmacol

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“…Moreover, our data suggest differences between the two receptors in terms of the basal calcium response, and further investigation will be needed to better understand this aspect of FSHR/LHR signaling. One possible explanation could be that the higher basal level observed in LHR-transfected cells is a reflexion of the fact that this receptor leads to significant constitutive activity while FSHR does not ( 52 , 53 ).…”

Section: Discussionmentioning

confidence: 99%

Assessing Gonadotropin Receptor Function by Resonance Energy Transfer-Based Assays

et al. 2015

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Gonadotropin receptors belong to the super family of G protein-coupled receptors and mediate the physiological effects of follicle-stimulating hormone (FSHR) and luteinizing hormone (LHR). Their central role in the control of reproductive function has made them the focus of intensive studies. Upon binding to their cognate hormone, they trigger complex signaling and trafficking mechanisms that are tightly regulated in concentration, time, and space. Classical cellular assays often fail to capture all these dynamics. Here, we describe the use of various bioluminescence and fluorescence resonance energy transfer (BRET and FRET) assays to investigate the activation and regulation of FSHR and LHR in real-time, in living cells (i.e., transiently expressed in human embryonic kidney 293 cells). Indeed, the dynamics of hormone-mediated heterotrimeric G protein activation, cyclic adenosine-monophosphate (cAMP) production, calcium release, β-arrestin 2 recruitment, and receptor internalization/recycling was assessed. Kinetics and dose–response analyses confirmed the expected pharmacological and signaling properties of hFSHR and hLHR but revealed interesting characteristics when considering the two major pathways (cAMP and β-arrestin 2) of the two receptors assessed by BRET. Indeed, the EC50 values were in picomolar range for cAMP production while nanomolar range was observed for β-arrestin 2 recruitment as well as receptor internalization. Interestingly, the predicted receptor occupancy indicates that the maximal G protein activation and cAMP response occur at <10% of receptor occupancy whereas >90% of activated receptors is required to achieve full β-arrestin 2 recruitment and subsequent receptor internalization. The rapid receptor internalization was also followed by a recycling phase. Collectively, our data reveal that β-arrestin-mediated desensitization, internalization, and the subsequent fast recycling of receptors at the plasma membrane may provide a mechanistic ground to the “spare receptor” paradigm. More generally, the novel tools described here will undoubtedly provide the scientific community investigating gonadotropin receptors with powerful means to decipher their pharmacology and signaling with the prospect of pathophysiological and drug discovery applications.

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“…[92][93][94] Anjali et al 91 wanted to explore the relationship between FSH and IRS-2. The IR-2 protein in GCs of PCOS reduced significantly.…”

Section: The Pi3k-akt Signaling Pathway and Follicular Developmentmentioning

confidence: 99%

Role of the PI3K-Akt Signaling Pathway in the Pathogenesis of Polycystic Ovary Syndrome

et al. 2017

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This review aimed to focus on the recent progress of the understanding of the role of phosphatidylinositol 3-kinase (PI3K) in polycystic ovary syndrome (PCOS). In recent years, it has been increasingly recognized that PI3K plays an important role in PCOS whose pathogenesis is unclear. However, research continues into revealing the details of how PI3Ks are involved in developing PCOS. Previous studies have shown that activation of the PI3K-protein kinase B (Akt) signaling pathway has important effects on insulin resistance and endometrial cancer. Knowledge of the action of PI3K in PCOS might provide valuable information to further validate the pathogenesis of PCOS and suggest new methods of treatment.

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Constitutive Activity in Gonadotropin Receptors

Cited by 28 publications

References 172 publications

The Follitropin Receptor: Matching Structure and Function

The Follitropin Receptor: Matching Structure and Function

Assessing Gonadotropin Receptor Function by Resonance Energy Transfer-Based Assays

Role of the PI3K-Akt Signaling Pathway in the Pathogenesis of Polycystic Ovary Syndrome

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