Endocrine Abstracts

The gonadotrophin hormone receptor, LHR, is essential for reproductive functions, mediating ovarian follicle development, ovulation, steroidogenesis and corpus luteum functions. As a G protein-coupled receptor (GPCR), LHR primarily signals through the Gαs recruitment/adenylyl cyclase/cAMP canonical pathway, however, it has been shown that under conditions of heightened LH concentration and LHR expression, the LHR can activate Gαq/11, triggering intracellular calcium release. A wide array of evidence has demonstrated that GPCRs exist and function as dimers and higher-order oligomers (homomers and heteromers), which diversify signal specificity, selectivity and diversifies receptor function. Our studies have shown that the LHR primarily forms and functions as homomers, but how LHR mediates this functional and physiological diversity remains unknown. Our previous work has also shown that LHR forms and functions as homomers and with FSHR as heteromers, providing a means to fine-tune signal specificity and magnitude of response. The aim of this study was therefore to determine the effect of modulating LHR homomerisation on LH/LHR ovarian functions. Synthetic peptides were designed to target specific receptor transmembrane domains (TM1, TM2, TM4, TM5 and TM6) were used to disrupt receptor oligomerisation. Disrupting peptides were shown to inhibit LH-dependent cAMP production. Culture of mouse ovarian fragments in the presence of the disrupting peptides highlighted trends for modulating LH-dependent regulation of EGF mediated pathways, steroidogenesis and inflammatory ovulatory pathways. Additional open follicle cultures demonstrated a shorter time to germinal vesicle breakdown (GVBD), in follicles treated with the disrupting peptides, suggesting a shift towards Gq-mediated activity. Together these data suggest that different LHR homomeric forms can distinctly modulate LH-dependent functions within the ovary fine tuning the response.