Heteromerization of G Protein-coupled Estrogen Receptor With the LH Receptor Biases G Protein Signaling

LH/choriogonadotropin (hCG) receptor (LHCGR) and the G protein-coupled estrogen receptor (GPER) are coexpressed in the ovary and support reproduction. The latter is involved in pathophysiological conditions and has been suggested as a potential therapeutic target. However, its role is still controversial, and several studies reported GPER to form heterocomplexes with other class A G protein-coupled receptors, modulating their signaling cascades. We evaluated if GPER interacts with LHCGR and impacts ligand-mediated pathways. In HEK293, LHCGR-GPER heteromers allosterically modulate LH/hCG-mediated signaling by preventing receptor coupling with Gq protein, leading to inhibition of phospholipase C pathway, and related transcriptional and mitogenic functions. This effect is prevented by mutant GPER unable to form heteromers with LHCGR. Interestingly, GPER expression has no effect on LH/hCG-induced Gs/cAMP/protein kinase A pathway activation, demonstrating selective inhibition of Gq pathway. These results were not recapitulated in cells displaying insufficient endogenous Gq protein expression levels, whereas they are recovered under exogenous Gq overexpression. Our data strengthen the concept that GPER may act as a modulator of other membrane G protein-coupled receptors, and a potential new target for treatment of tumors displaying Gq signalling.