The injection of equine chorionic gonadotropin (eCG) in dairy goats induces the production of anti-eCG antibodies (Abs) in some females. We have previously shown that Abs negatively modulate the LH and FSH-like bioactivities of eCG, in most cases, compromising fertility in treated females. Surprisingly, we found out that some anti-eCG Abs improved fertility and prolificity of the treated females, in vivo. These Abs, when complexed with eCG, enhanced LH and FSH ability to induce steroidogenesis on specific target cells, in vitro. In the present study, we analyzed the impact of three eCG/anti-eCG Ab-enhancing complexes on two transduction mechanisms triggered by the FSH receptor: guanine nucleotide-binding protein αS-subunit/cAMP/protein kinase A (PKA) and β-arrestin-dependent pathways, respectively. In all cases, significant enhancing effects were observed on ERK phosphorylation compared with eCG alone. However, cAMP production and PKA activation induced by eCG could be differently modulated by Abs. By using a pharmacological inhibitor of PKA and small interfering RNA-mediated knock-down of endogenous β-arrestin 1 and 2, we demonstrated that signaling bias was induced and was clearly dependent on the complexed Ab. Together, our data show that eCG/anti-eCG Ab-enhancing complexes can differentially modulate cAMP/PKA and β-arrestin pathways as a function of the complexed Ab. We hypothesize that enhancing Abs may change the eCG conformation, the immune complex acquiring new “biased” pharmacological properties ultimately leading to the physiological effects observed in vivo. The modulation of ligand pharmacological properties by Abs opens promising research avenues towards the optimization of glycoprotein hormone biological activities and, more generally, the development of new therapeutics.

Equine chorionic gonadotropin

Gonadotropin

10.1210/en.2009-0892

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Citations (28)

SESSION 32: REPRODUCTIVE ENDOCRINOLOGY 1

Human Reproduction (2012)

Rosa Vissenberg E. van den Boogaard Madelon van Wely Joris van der Post Eric Fliers

Reproductive Endocrinology

10.1093/humrep/27.s2.31

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Behaviour of ewes at parturition toward amniotic fluids from sheep, cows and goats

Applied Animal Behaviour Science (1991)

Cécile Arnould Vincent Piketty Frédéric Lévy

Domestic sheep reproduction

10.1016/s0168-1591(05)80042-5

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Absence of sexual dimorphism in pars tuberalis [¹²⁵I]‐melatonin binding sites of lambs slaughtered in June and in October1

Journal of Pineal Research (2001)

Vincent Piketty

The timing of puberty appears to be affected by photoperiod to a greater extent in female lambs than in male lambs. Melatonin, a daylength information conveyor, shows the same plasma levels in female lambs as in male lambs. We therefore tested the hypothesis that the predominant melatonin binding sites, located in the pars tuberalis (PT) of the pituitary, might display sexual dimorphism. Here, in two independent experiments, we report no difference in quantity, density or dissociation constant between female and male peripubertal lambs' PT melatonin binding sites, measured by individual saturation curves. In October, Bmax values were 19.5 +/- 1.8 and 19.6 +/- 1.2, whereas in June, they were 94.1 +/- 8.6 and 96.4 +/- 12.1 fmol/mg protein (mean +/- S.E.M.) for females and males, respectively. The Kd values were in the range of 10-20 pmol. The sexual parameters measured, i.e. presence of corpus luteum in female ovaries or testis weight in male lambs, were not linked with PT melatonin binding numbers.

Pars tuberalis

Sexual dimorphism

10.1034/j.1600-079x.2001.300107.x

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

Molecular Endocrinology (2010)

Vanessa L. Wehbi Thibaud Tranchant Guillaume Durand Astrid Musnier Jérémy Decourtye

Deglycosylated FSH is known to trigger poor Galphas 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 beta-arrestin-dependent signaling. We compared native eLH to an eLH derivative [i.e. truncated eLHbeta (Delta121-149) combined with asparagine56-deglycosylated eLHalpha (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 beta-arrestin recruitment. Both eLH and eLHdg triggered ERK and ribosomal protein (rp) S6 phosphorylation at 1 nM. The depletion of endogenous beta-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 beta-arrestin-depleted cells. Together, these results show that eLHdg has the ability to preferentially activate beta-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.

Arrestin

GNRHR

Internalization

10.1210/me.2009-0347

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Citations (53)

Physiological determinism of olfactory attraction for amniotic fluis in sheep

HAL (Le Centre pour la Communication Scientifique Directe) (1988)

Frédéric Lévy E.B. Keverne Vincent Piketty Pascal Poindron

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