Differential FSH glycosylation modulates FSHR oligomerization and subsequent cAMP signaling

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Agwuegbo, Uche C.
Colley, Emily
Albert, Anthony P.
Butnev, Vladimir Y.
Bousfield, George R.
Jonas, Kim C.
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Follicle-stimulating hormone receptor , Follicle-stimulating hormone , Gonadotropic hormones , G protein-coupled receptors (GPCR) , Oligomers , Oligomerization
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Agwuegbo, U. T., Colley, E., Albert, A. P., Butnev, V. Y., Bousfield, G. R., & Jonas, K. C. (2021). Differential FSH glycosylation modulates FSHR oligomerization and subsequent cAMP signaling. Frontiers in Endocrinology, 12 doi:10.3389/fendo.2021.765727

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.

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Frontiers in Endocrinology;Vol. 12
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