Partially deglycosylated equine LH preferentially activates beta-arrestin-dependent signaling at the follicle-stimulating hormone receptor

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Wehbi, Vanessa
Tranchant, Thibaud
Durand, Guillaume
Musnier, Astrid
Decourtye, Jérémy
Piketty, Vincent
Butnev, Vladimir Y.
Bousfield, George R.
Crépieux, Pascale
Maurel, Marie-Christine
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Deglycosylated 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.

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Vanessa Wehbi, Thibaud Tranchant, Guillaume Durand, Astrid Musnier, Jérémy Decourtye, Vincent Piketty, Vladimir Y. Butnev, George R. Bousfield, Pascale Crépieux, Marie-Christine Maurel, Eric Reiter; Partially Deglycosylated Equine LH Preferentially Activates β-Arrestin-Dependent Signaling at the Follicle-Stimulating Hormone Receptor;Mol Endocrinol. 2010 March; 24(3): 561–573; doi: 10.1210/me.2009-0347
The Endocrine Society
PubMed ID
0888-8809 (Print)
1944-9917 (Electronic)