Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling.
Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling.
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DOI：
10.3389/fendo.2021.765727
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发表时间：
2021
影响因子：
5.2
通讯作者：
Jonas KC
中科院分区：
文献类型：
--
作者：
Agwuegbo UT;Colley E;Albert AP;Butnev VY;Bousfield GR;Jonas KC
促卵泡激素（FSH）及其靶G蛋白偶联受体（FSHR）对生殖至关重要。最近的研究已经确定，低糖基化垂体FSH糖型（FSH 21/18）在体外和体内比完全糖基化变体（FSH 24）更具生物活性。FSH 21/18在生育高峰期女性中占主导地位，FSH 24在围绝经期女性中占主导地位，表明这些FSH糖型的不同功能作用。本研究的目的是确定差异FSH糖基化是否调节FSHR寡聚化以及对cAMP信号传导的影响。使用改良的超分辨率成像技术（PD-PALM）来评估表达FSHR的HEK293细胞中的FSHR复合物，我们观察到FSH糖型对FSHR寡聚化的时间和浓度依赖性调节。高浓度的eFSH和FSH 21/18迅速将FSHR寡聚体解离成单体，而FSH 24显示较慢的动力学。FSHR β-arrestin偏向性激动剂，截短的eLH β（Δ 121 - 149）与天冬酰胺56-去糖基化的eLH α（dg-eLHt）联合使用，增加FSHR同源化。相反，低FSH 21/18和FSH 24浓度促进FSHR结合成寡聚体。FSHR寡聚体的解离与观察到较高cAMP产生的时间点相关。总之，这些数据表明，FSH糖基化可以调节cAMP产生的动力学和幅度，部分通过形成不同的FSHR复合物，突出了FSHR的新治疗靶向以改善IVF结局的潜在途径。
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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影响因子：
3.7
作者：
AHARONI, D;DANTES, A;AMSTERDAM, A
通讯作者：
AMSTERDAM, A
影响因子：
5.8
作者：
Casarini L;Lazzaretti C;Paradiso E;Limoncella S;Riccetti L;Sperduti S;Melli B;Marcozzi S;Anzivino C;Sayers NS;Czapinski J;Brigante G;Potì F;La Marca A;De Pascali F;Reiter E;Falbo A;Daolio J;Villani MT;Lispi M;Orlando G;Klinger FG;Fanelli F;Rivero-Müller A;Hanyaloglu AC;Simoni M
通讯作者：
Simoni M
影响因子：
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作者：
Chu, Lianhe;Li, Jianzhen;Cheng, Christopher H. K.
通讯作者：
Cheng, Christopher H. K.
影响因子：
13.6
作者：
Dwivedi-Agnihotri, Hemlata;Chaturvedi, Madhu;Shukla, Arun K.
通讯作者：
Shukla, Arun K.
影响因子：
4.6
作者：
Guixà-González R;Javanainen M;Gómez-Soler M;Cordobilla B;Domingo JC;Sanz F;Pastor M;Ciruela F;Martinez-Seara H;Selent J
通讯作者：
Selent J