English (United Kingdom)

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https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Biased signaling has recently emerged as an interesting mean to modulate thefunction of many G protein-coupled receptors (GPCRs). Previous studies reportedtwo negative allosteric modulators (NAMs) of follicle-stimulating hormonereceptor (FSHR), ADX68692 and ADX68693, with differential effects onFSHR-mediated steroidogenesis and ovulation. In this study, we attempted topharmacologically profile these NAMs on the closely relatedluteinizing/chorionic gonadotropin hormone receptor (LH/CGR) with regards toits canonical Gs/cAMP pathway as well as \beta-arrestin recruitment in HEK293cells. The NAMs effects on progesterone and testosterone production were alsoassessed in murine Leydig tumor cell line (mLTC-1). We found that both NAMsstrongly antagonized LH/CGR signaling in both HEK293 and mLTC-1 cells. ADX68693appeared more potent than ADX68692 to inhibit hCG-induced cAMP and\beta-arrestin 2 in HEK293 and mLTC-1 cells whereas no significant differencein their efficacy on hCG-promoted \beta-arrestin 2 recruitment. Interestingly,differential antagonism of the two NAMs on hCG-promoted steroidogenesis inmLTC-1 cells was observed with significant inhibition of testosterone but notprogesterone production. These observations suggest biased effects of the twoNAMs on LH/CGR-dependent pathways controlling steroidogenesis, which appearedto be different to that previously shown on FSHR. This also illustrates thecomplexity of signaling pathways controlling FSHR- and LH/CGR-mediatedsteroidogenesis, suggesting differential implication of cAMP and\beta-arrestins. Together, our data demonstrate that ADX68692 and ADX68693 areNAMs at the LH/CGR in addition to FSHR. These pharmacological characteristicsare important to consider for potential contraceptive and therapeuticapplications based on such compounds.

Profiling of FSHR Negative Allosteric Modulators on LH/CGR Reveals Biased Antagonism with Implications in Steroidogenesis