Endocrine Abstracts

The gonadotrophin receptors, LH receptor (LHR) and FSH receptor (FSHR) are G-protein coupled receptors, vital in regulating reproductive functions. During the follicular phase of the ovarian cycle, FSHR and LHR are separately localised to discrete cellular compartments, granulosa and theca cells respectively, where they control steroidogenesis and follicle maturation. However, as the follicle develops, LHR expression is induced in granulosa cells, resulting in temporary co-expression of FSHR and LHR in a single cellular compartment. Remarkably, little is known about the functional significance of this co-expression. While both FSHR and LHR are known to homodimerise, the question of whether FSHR and LHR can form functional heterodimers remains to be explored. Therefore, this study aims to determine if FSHR and LHR can form heterodimers and assess the functional impact on cellular signalling. The ability of FSHR and LHR to heterodimerise in live cells was observed via bioluminescence resonance energy transfer. Flow cytometric analysis indicated that co-expression of FSHR and LHR had no effect on cell surface targeting of either receptor. Furthermore, gonadotrophin-induced Gαlphas/cAMP signalling was not altered in the LHR/FSHR heterodimer compared to cells expressing each receptor alone. Interestingly, the pattern of LHR-induced Gαlphaq/calcium signalling was significantly altered in the presence of FSHR, from an acute and rapid signal to a more sustained calcium response. The prolonged calcium signal in LH-stimulated LHR/FSHR expressing cells appears to be mediated through activation of L-type calcium channels. A Gαlphai inhibitor, pertussis toxin, had no effect on calcium signalling, indicating there may be no alteration in G protein-coupling of the heterodimer. Co-expression of FSHR with LHR also enhanced the LH-induced MAPK signalling. The mechanisms underlying this change in signalling patterns will be further assessed. Overall this study indicates that LHR/FSHR heterodimers may represent a key mechanism for generating sustained signal responses in preovulatory follicles.