Endocrine Abstracts

The classical model of GPCR activation entails the binding of a single ligand to a single receptor molecule, followed by transmembrane signal transduction to the appropriate G protein(s). The possibility of GPCRs functioning as dimers or oligomers still remains controversial, and is largely based on in vitro studies on transfected cells. The glycoprotein hormone receptors, including that of LH (LHCGR), differ from most GPCRs by their large extracellular ligand-binding domain distinct from the transmembrane signaling domain. Therefore, numerous LHCGR mutants are specifically devoid of either ligand binding or intracellular signaling. If such mutants are coexpressed in transfected cells, they can partially rescue ligand-evoked signaling, providing compelling evidence for functional complementation (or intermolecular co-operation) possibly through dimerization. We tested the physiological significance of this mode of receptor activation by co-expressing in BAC transgenic mice either a binding- or signaling deficient mutant of LHCGR, crossed into the LHCGR null background. Either of the mutant LHCGRs singularly expressed did not alter the hypogonadal phenotype of LHCGR knockout (KO) mice. However, when both mutants were coexpressed in the KO background, the eugonadal and fertile wild-type phenotype of male mice was restored. Interestingly, female mice co-expressing the two mutant receptors in the KO background remained hypogonadal and infertile. These findings indicate that binding- and signaling-deficient LHCGRs are able to partially recover the signaling that is sufficient for Leydig cell activation and fertility in male mice. Functional complementation in females is not sufficient to revert the hypogonadal KO phenotype, probably due to the higher receptor activation required (ovulatory LH peak), but it is also possible that only selected signaling pathways (biased agonism) are activated upon LHCGR functional complementation.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Declaration of funding

This work was supported by the Wellcome Trust Programme Grant 082101/Z/07/Z, the BBSCR Project Grant BB/1008004/1 and a grant from The Academy of Finland.