Partially Deglycosylated Equine LH Preferentially Activates β-Arrestin-Dependent Signaling at the Follicle-Stimulating Hormone Receptor

Author:

Wehbi Vanessa1,Tranchant Thibaud1,Durand Guillaume1,Musnier Astrid1,Decourtye Jérémy1,Piketty Vincent1,Butnev Vladimir Y.2,Bousfield George R.2,Crépieux Pascale1,Maurel Marie-Christine1,Reiter Eric1

Affiliation:

1. From BIOS Group (V.W., T.T., G.D., A.M., J.D., V.P., P.C., M.-C.M., E.R.), Institut National de la Recherche Agronomique, Unité Mixte de Recherche (UMR) 85, Unité Physiologie de la Reproduction et des Comportements; Centre National de la Recherche Scientifique, UMR 6175; and Haras Nationaux, F-37380 Nouzilly, France; Université François Rabelais, F-37041 Tours, France

2. Department of Biological Sciences (V.Y.B., G.R.B.), Wichita State University, Wichita, Kansas 67260

Abstract

AbstractDeglycosylated FSH is known to trigger poor Gαs coupling while efficiently binding its receptor. In the present study, we tested the possibility that a deglycosylated equine LH (eLHdg) might be able to selectively activate β-arrestin-dependent signaling. We compared native eLH to an eLH derivative [i.e. truncated eLHβ (Δ121-149) combined with asparagine56-deglycosylated eLHα (eLHdg)] previously reported as an antagonist of cAMP accumulation at the FSH receptor (FSH-R). We confirmed that, when used in conjunction with FSH, eLHdg acted as an antagonist for cAMP accumulation in HEK-293 cells stably expressing the FSH-R. Furthermore, when used alone at concentrations up to 1 nm, eLHdg had no detectable agonistic activity on cAMP accumulation, protein kinase A activity or cAMP-responsive element-dependent transcriptional activity. At higher concentrations, however, a weak agonistic action was observed with eLHdg, whereas eLH led to robust responses whatever the concentration. Both eLH and eLHdg triggered receptor internalization and led to β-arrestin recruitment. Both eLH and eLHdg triggered ERK and ribosomal protein (rp) S6 phosphorylation at 1 nm. The depletion of endogenous β-arrestins had only a partial effect on eLH-induced ERK and rpS6 phosphorylation. In contrast, ERK and rpS6 phosphorylation was completely abolished at all time points in β-arrestin-depleted cells. Together, these results show that eLHdg has the ability to preferentially activate β-arrestin-dependent signaling at the FSH-R. This finding provides a new conceptual and experimental framework to revisit the physiological meaning of gonadotropin structural heterogeneity. Importantly, it also opens a field of possibilities for the development of selective modulators of gonadotropin receptors.

Publisher

The Endocrine Society

Subject

Endocrinology,Molecular Biology,General Medicine

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