Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling

Follicle-stimulating hormone (FSH) and its target G protein-coupled receptor (FSHR) are essential for reproduction. Recent studies have established that the hypo-glycosylated pituitary FSH glycoform (FSH21/18), is more bioactive in vitro and in vivo than the fully-glycosylated variant (FSH24). FSH21...

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Autores principales:	Uchechukwu T. Agwuegbo, Emily Colley, Anthony P. Albert, Viktor Y. Butnev, George R. Bousfield, Kim C. Jonas
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	follicle-stimulating hormone receptor follicle-stimulating hormone gonadotropic hormones G protein-coupled receptors (GPCR) oligomers oligomerization Diseases of the endocrine glands. Clinical endocrinology RC648-665
Acceso en línea:	https://doaj.org/article/0be72419f62b4829957f4e9975955289
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spelling	oai:doaj.org-article:0be72419f62b4829957f4e99759552892021-12-03T10:34:53ZDifferential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling1664-239210.3389/fendo.2021.765727https://doaj.org/article/0be72419f62b4829957f4e99759552892021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fendo.2021.765727/fullhttps://doaj.org/toc/1664-2392Follicle-stimulating hormone (FSH) and its target G protein-coupled receptor (FSHR) are essential for reproduction. Recent studies have established that the hypo-glycosylated pituitary FSH glycoform (FSH21/18), is more bioactive in vitro and in vivo than the fully-glycosylated variant (FSH24). FSH21/18 predominates in women of reproductive prime and FSH24 in peri-post-menopausal women, suggesting distinct functional roles of these FSH glycoforms. The aim of this study was to determine if differential FSH glycosylation modulated FSHR oligomerization and resulting impact on cAMP signaling. Using a modified super-resolution imaging technique (PD-PALM) to assess FSHR complexes in HEK293 cells expressing FSHR, we observed time and concentration-dependent modulation of FSHR oligomerization by FSH glycoforms. High eFSH and FSH21/18 concentrations rapidly dissociated FSHR oligomers into monomers, whereas FSH24 displayed slower kinetics. The FSHR β-arrestin biased agonist, truncated eLHβ (Δ121-149) combined with asparagine56-deglycosylated eLHα (dg-eLHt), increased FSHR homomerization. In contrast, low FSH21/18 and FSH24 concentrations promoted FSHR association into oligomers. Dissociation of FSHR oligomers correlated with time points where higher cAMP production was observed. Taken together, these data suggest that FSH glycosylation may modulate the kinetics and amplitude of cAMP production, in part, by forming distinct FSHR complexes, highlighting potential avenues for novel therapeutic targeting of the FSHR to improve IVF outcomes.Uchechukwu T. AgwuegboEmily ColleyAnthony P. AlbertViktor Y. ButnevGeorge R. BousfieldKim C. JonasFrontiers Media S.A.articlefollicle-stimulating hormone receptorfollicle-stimulating hormonegonadotropic hormonesG protein-coupled receptors (GPCR)oligomersoligomerizationDiseases of the endocrine glands. Clinical endocrinologyRC648-665ENFrontiers in Endocrinology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	follicle-stimulating hormone receptor follicle-stimulating hormone gonadotropic hormones G protein-coupled receptors (GPCR) oligomers oligomerization Diseases of the endocrine glands. Clinical endocrinology RC648-665
spellingShingle	follicle-stimulating hormone receptor follicle-stimulating hormone gonadotropic hormones G protein-coupled receptors (GPCR) oligomers oligomerization Diseases of the endocrine glands. Clinical endocrinology RC648-665 Uchechukwu T. Agwuegbo Emily Colley Anthony P. Albert Viktor Y. Butnev George R. Bousfield Kim C. Jonas Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling
description	Follicle-stimulating hormone (FSH) and its target G protein-coupled receptor (FSHR) are essential for reproduction. Recent studies have established that the hypo-glycosylated pituitary FSH glycoform (FSH21/18), is more bioactive in vitro and in vivo than the fully-glycosylated variant (FSH24). FSH21/18 predominates in women of reproductive prime and FSH24 in peri-post-menopausal women, suggesting distinct functional roles of these FSH glycoforms. The aim of this study was to determine if differential FSH glycosylation modulated FSHR oligomerization and resulting impact on cAMP signaling. Using a modified super-resolution imaging technique (PD-PALM) to assess FSHR complexes in HEK293 cells expressing FSHR, we observed time and concentration-dependent modulation of FSHR oligomerization by FSH glycoforms. High eFSH and FSH21/18 concentrations rapidly dissociated FSHR oligomers into monomers, whereas FSH24 displayed slower kinetics. The FSHR β-arrestin biased agonist, truncated eLHβ (Δ121-149) combined with asparagine56-deglycosylated eLHα (dg-eLHt), increased FSHR homomerization. In contrast, low FSH21/18 and FSH24 concentrations promoted FSHR association into oligomers. Dissociation of FSHR oligomers correlated with time points where higher cAMP production was observed. Taken together, these data suggest that FSH glycosylation may modulate the kinetics and amplitude of cAMP production, in part, by forming distinct FSHR complexes, highlighting potential avenues for novel therapeutic targeting of the FSHR to improve IVF outcomes.
format	article
author	Uchechukwu T. Agwuegbo Emily Colley Anthony P. Albert Viktor Y. Butnev George R. Bousfield Kim C. Jonas
author_facet	Uchechukwu T. Agwuegbo Emily Colley Anthony P. Albert Viktor Y. Butnev George R. Bousfield Kim C. Jonas
author_sort	Uchechukwu T. Agwuegbo
title	Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling
title_short	Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling
title_full	Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling
title_fullStr	Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling
title_full_unstemmed	Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling
title_sort	differential fsh glycosylation modulates fshr oligomerization and subsequent camp signaling
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/0be72419f62b4829957f4e9975955289
work_keys_str_mv	AT uchechukwutagwuegbo differentialfshglycosylationmodulatesfshroligomerizationandsubsequentcampsignaling AT emilycolley differentialfshglycosylationmodulatesfshroligomerizationandsubsequentcampsignaling AT anthonypalbert differentialfshglycosylationmodulatesfshroligomerizationandsubsequentcampsignaling AT viktorybutnev differentialfshglycosylationmodulatesfshroligomerizationandsubsequentcampsignaling AT georgerbousfield differentialfshglycosylationmodulatesfshroligomerizationandsubsequentcampsignaling AT kimcjonas differentialfshglycosylationmodulatesfshroligomerizationandsubsequentcampsignaling
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Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling

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