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Partially deglycosylated equine LH preferentially activates beta-arrestin-dependent signaling at the follicle-stimulating hormone receptor.
- Source :
-
Molecular endocrinology (Baltimore, Md.) [Mol Endocrinol] 2010 Mar; Vol. 24 (3), pp. 561-73. Date of Electronic Publication: 2010 Jan 27. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Animals
Blotting, Western
Cattle
Cell Line
Cyclic AMP-Dependent Protein Kinases metabolism
Enzyme Activation drug effects
Female
Horses
Humans
Immunoprecipitation
Luteinizing Hormone chemistry
Luteinizing Hormone metabolism
Luteinizing Hormone pharmacology
Mice
Phosphorylation drug effects
Protein Binding
Protein Transport drug effects
RNA, Small Interfering
Receptors, FSH agonists
Receptors, FSH antagonists & inhibitors
Ribosomal Protein S6 metabolism
Swine
beta-Arrestins
Arrestins metabolism
Luteinizing Hormone analogs & derivatives
Receptors, FSH metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1944-9917
- Volume :
- 24
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular endocrinology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 20107152
- Full Text :
- https://doi.org/10.1210/me.2009-0347