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dc.contributor.authorZarinan, Teresa
dc.contributor.authorButnev, Viktor Y.
dc.contributor.authorGutierrez-Sagal, Ruben
dc.contributor.authorMaravillas-Montero, Jose Luis
dc.contributor.authorMartinez-Luis, Ivan
dc.contributor.authorMejia-Dominguez, Nancy R.
dc.contributor.authorJuarez-Vega, Gillermo
dc.contributor.authorBousfield, George R.
dc.contributor.authorUlloa-Aguirre, Alfredo
dc.date.accessioned2020-05-14T02:05:46Z
dc.date.available2020-05-14T02:05:46Z
dc.date.issued2020-05
dc.identifier.citationTeresa Zariñán, Viktor Y Butnev, Rubén Gutiérrez-Sagal, José Luis Maravillas-Montero, Iván Martínez-Luis, Nancy R Mejía-Domínguez, Guillermo Juárez-Vega, George R Bousfield, Alfredo Ulloa-Aguirre, In Vitro Impact of FSH Glycosylation Variants on FSH Receptor-stimulated Signal Transduction and Functional Selectivity, Journal of the Endocrine Society, Volume 4, no. 5, May 2020, bvaa019en_US
dc.identifier.issn2472-1972
dc.identifier.urihttps://doi.org/10.1210/jendso/bvaa019
dc.identifier.urihttps://soar.wichita.edu/handle/10057/17647
dc.description© Endocrine Society 2020. This is an Open Access article distributed under the terms of the Creative Commons AttributionNonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited.en_US
dc.description.abstractFSH exists as different glycoforms that differ in glycosylation of the hormone-specific β-subunit. Tetra-glycosylated FSH (FSH24) and hypo-glycosylated FSH (FSH18/21) are the most abundant glycoforms found in humans. Employing distinct readouts in HEK293 cells expressing the FSH receptor, we compared signaling triggered by human pituitary FSH preparations (FSH18/21 and FSH24) as well as by equine FSH (eFSH), and human recombinant FSH (recFSH), each exhibiting distinct glycosylation patterns. The potency in eliciting cAMP production was greater for eFSH than for FSH18/21, FSH24, and recFSH, whereas in the ERK1/2 activation readout, potency was highest for FSH18/21 followed by eFSH, recFSH, and FSH24. In β-arrestin1/2 CRISPR/Cas9 HEK293-KO cells, FSH18/21 exhibited a preference toward β-arrestin-mediated ERK1/2 activation as revealed by a drastic decrease in pERK during the first 15-minute exposure to this glycoform. Exposure of β-arrestin1/2 KO cells to H89 additionally decreased pERK1/2, albeit to a significantly lower extent in response to FSH18/21. Concurrent silencing of β-arrestin and PKA signaling, incompletely suppressed pERK response to FSH glycoforms, suggesting that pathways other than those dependent on Gs-protein and β-arrestins also contribute to FSH-stimulated pERK1/2. All FSH glycoforms stimulated intracellular Ca2+ (iCa2+) accumulation through both influx from Ca2+ channels and release from intracellular stores; however, iCa2+ in response to FSH18/21 depended more on the latter, suggesting differences in mechanisms through which glycoforms promote iCa2+ accumulation. These data indicate that FSH glycosylation plays an important role in defining not only the intensity but also the functional selectivity for the mechanisms leading to activation of distinct signaling cascades.en_US
dc.description.sponsorshipGrants 240619 from CONACyT (Consejo Nacional de Ciencia y Tecnología), México and the National University of Mexico (UNAM) (to A. Ulloa-Aguirre), and from grant AG029531 from the National Institutes of Health (NIH), Bethesda, Maryland (to G.R. Bousfield).en_US
dc.language.isoen_USen_US
dc.publisherOxford University Pressen_US
dc.relation.ispartofseriesJournal of the Endocrine Society;v.4:no.5:art. no.bvaa019
dc.subjectFollicle-stimulating hormoneen_US
dc.subjectFollicle-stimulating hormone receptoren_US
dc.subjectMacroheterogeneityen_US
dc.subjectGlycosylationen_US
dc.subjectSignal transductionen_US
dc.subjectFunctional selectivityen_US
dc.subjectBiased agonismen_US
dc.titleIn Vitro Impact of FSH Glycosylation Variants on FSH Receptor-stimulated Signal Transduction and Functional Selectivityen_US
dc.typeArticleen_US
dc.rights.holder© 2020, Oxford University Pressen_US


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