EYES2023 ESE Young Endocrinologists and Scientists (EYES) 2023 Oral communication 5: Reproductive Endocrinology (9 abstracts)
Luteinizing hormone/choriogonadotropin receptor (LHCGR)/G protein-coupled estrogen receptor (GPER) heteromers impact on reproductive signals
Clara Lazzaretti 1 , Elia Paradiso 2 , Samantha Sperduti 3 , Niamh Sayers 4 , Ginevra Pelagatti 5 , Sara D’Alessandro 6 , Carmela Perri 7 , Lara Baschieri 8 , Manuela Simoni 9 , Aylin Carla Hanyaloglu 4 & Livio Casarini 10
1University of Modena and Reggio Emilia, Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia. Baggiovara Hospital, Via P. Giardini 1355, 41126 Modena, Italy., Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy; 2University of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Dept. of Biomedical Sciences, Metabolic and Neuroscience, Modena, Italy; 3Unit of Endocrinology, University of Modena and Reggio Emilia, Center for Genomic Research, University of Modena and Reggio Emilia. Via G. Campi 287, 41125 Modena, Italy., Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy; 4Imperial College London, Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, London, UK; 5University of Modena and Reggio Emilia, Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy; 6Unit of Endocrinology, University of Modena and Reggio Emilia., International Ph.D. School in Clinical and Experimental Medicine (Cem), University of Modena and Reggio Emilia., Department of Biomedical, Metabolic and Neural Sciences., Modena, Italy; 7Unit of Endocrinology, University of Modena and Reggio Emilia., Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy; 8Unit of Endocrinology, University of Modena and Reggio Emilia, International Ph.D. School in Clinical and Experimental Medicine (Cem), University of Modena and Reggio Emilia, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy; 9Department of Medicine, Endocrinology Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy; 10Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy.
Background: Follicle-stimulating hormone receptor (FSHR) and G protein-coupled estrogen receptor (GPER) are expressed on the surface of granulosa cells, where they form heteromeric complexes, shifting FSH-induced signals to survival pathways and determining the follicular fate.
Objectives: We evaluated whether GPER can interact with the luteinizing hormone (LH)/choriogonadotropin (hCG) receptor (LHCGR) and modulate the LH/hCG/dependent signalling pathways.
Methods: LHCGR-GPER heteromers were evaluated in transiently transfected HEK293 cells by bioluminescence resonance energy transfer (BRET) and photo-activated localization microscopy using photoactivatable dyes (PD-PALM). The LH/hCG-dependent signalling analyses were performed by evaluating LHCGR-coupling to G proteins, intracellular Ca2+, cAMP and inositol monophosphate (IP1) increase by BRET and homogeneous time-resolved fluorescence (HTRF). Activation of LH/hCG-dependent gene transcription was evaluated using a reporter system. Data were analysed by non-linear regression or Kruskal–Wallis test and Dunn’s post-hoc test (P<0.05; n=4 to 6), as appropriate.
Results: Super-resolution microscopy and BRET data revealed that LHCGR and GPER form heteromers and interact on the cell surface, causing a displacement of Gαq to LHCGR. Consistently, under GPER/LHCGR co-expression, hCG-induced Ca2+ response is inhibited as well as all other Gαq-dependent events, i.e. IP1 production and NFAT promoter activation, whereas LH and hCG activate the Gαq-dependent signalling in LHCGR-expressing cells. Conversely, GPER-LHCGR complexes have no impact on LH/hCG-induced cAMP/protein kinase A (PKA) pathway activation, suggesting that GPER specifically inhibits Gαq-, but not Gαs-mediated signals. Control experiments were performed using a mutant GPER (GPERmut) unable to interact with LHCGR, as confirmed by PD-PALM and BRET methods, demonstrating that LH/hCG induce IP1 accumulation and gene transcription in GPERmut/LHCGR-expressing cells.
Conclusion: GPER and LHCGR can form heteromers at the cell surface, biasing LH/hCG-induced signals via specific inhibition of Gαq-dependent cascades and suggesting their potential role in the regulation of reproductive functions in the ovary.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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