Endocrine Abstracts

G protein-coupled receptors (GPCRs) are one of the largest families of the mammalian genome, mediating the effects of approximately 40% of prescribed drugs. Until recently, accepted dogma stated that GPCRs exist as monomers, however, it is becoming evident that GPCRs can form higher order dimer/oligomer complexes which provide important mechanisms for the diversification of receptor function. The LHCGR is a class A family GPCR, primarily coupling to the G_αs pathway to mediate its reproductive functions. We have recently reported the first in vivo evidence showing the physiological importance of LHCGR dimerisation. Using BAC clones, we showed that co-expression of transgenic binding deficient LHCGR (LHCGR^LH-) and signalling deficient LHCGR (LHCGR^cAMP-) in an LHCGR null background could rescue the hypogonadism and infertility of male LHCGR deficient mice, restoring wild type (wt) reproductive functionality. As the physiological events mediated by LHCGRs require the activation of multiple intracellular signals, the present study aimed to investigate in vitro whether co-expression of LHCGR^LH- and LHCGR^cAMP- was sufficient to mimic wt LHCGR signalling properties, and whether any bias in signalling pathway activation existed between the endogenous ligands of the LHCGR, luteinising hormone (LH) and human chorionic gonadotrophin (hCG). We first investigated LHCGR G-protein coupling; dose responses to hCG and LH showed comparable G_αs-cAMP responses in both wt LHCGR and LHCGR^LH-/cAMP- cell lines, however ligand-mediated differences were observed in G_αq/11 inositol phosphate and calcium responses. Conductance of a phospho-kinase proteome array revealed differences in signalling pathways activated by wt LHCGR and LHCGR^LH-/cAMP- cell lines but only few ligand differences were observed. Novel signalling targets of LHCGR were also identified. These results show that LHCGR dimerisation can result in diversification of ligand-activated signal transduction and suggests mechanisms by which one receptor subtype can facilitate multiple physiological functions.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.