Preferential β-arrestin signalling at low receptor density revealed by functional characterization of the human FSH receptor A189V mutation

Thibaud Tranchant , Guillaume Durand , Christophe Gauthier , Pascale Crépieux , Alfredo Ulloa-Aguirre (1) , Dominique Royère , Eric Reiter

1 LE STUDIUM Institute for Advanced Studies

The A189V inactivating mutation of the human FSH receptor (FSHR) leads to subfertility in men and primary ovarian failure in women. This mutation has previously been associated with intracellular retention of the FSHR and impaired cAMP production. Here, we show that the A189V FSHR stably expressed in HEK293N cells provoked ERK MAP kinases phosphorylation through β-arrestins, independently of the canonical cAMP/PKA pathway. Interesting, both the A189V and wild-type (Wt) FSHRs selectively activated cAMP-independent ERK phosphorylation when expressed at low plasma membrane densities. These data indicate that the selective intracellular signalling triggered by the A189V FSHR resulted from reduced membrane expression rather than by switching receptor coupling. Hence, receptor density at the plasma membrane might control the balance between distinct signal transduction mechanisms. Furthermore, our results help to clarify why mutations of FSHβ are more deleterious to human fertility than the FSHR A189V mutation which preserves parts of receptor signalling repertoire.

Mots clés: FSH; FSH receptor; A189V mutation; β-arrestin; selective signalling

Thibaud Tranchant, Guillaume Durand, Christophe Gauthier, Pascale Crépieux, Alfredo Ulloa-Aguirre, et al.. Preferential β-arrestin signalling at low receptor density revealed by functional characterization of the human FSH receptor A189V mutation. Molecular and Cellular Endocrinology, 2010, 331 (1), pp.109. ⟨10.1016/j.mce.2010.08.016⟩. ⟨hal-00639767⟩