AI Article Synopsis
- Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) both activate the LH receptor/cAMP signaling pathway to trigger ovulation, but Org 43553 is a newly developed orally active low molecular weight LHR agonist that interacts differently with the LH receptor.
- Org 43553 binds to the endodomain of the receptor and inhibits LH-induced phospholipase C (PLC) activity while also stimulating cAMP production, suggesting a selective signaling mechanism.
- The study concludes that Org 43553 is an allosteric LHR agonist that may induce a similar receptor conformation to LH, which is crucial for activating physiological responses typically mediated by LH.
Article Abstract
Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) activate the LH receptor/cyclic AMP (cAMP) signaling pathway to induce ovulation. As an alternative to parenterally administered hCG to treat anovulatory infertility, orally active low molecular weight (LMW) LHR agonists have been developed at Organon. In this paper, we present the mechanism of action of a prototypic, nanomolar potent and almost full LHR agonist, Org 43553. Org 43553 interacts with the endodomain of the LHR, whereas LH acts via the N-terminal exodomain. LH stimulates the cAMP pathway with an EC50 of 35 pM, but this stimulation is not antagonized by simultaneous incubation with Org 43553. At nanomolar concentrations, LH also stimulates phospholipase C (PLC), but Org 43553 is hardly able to do so. In contrast, Org 43553 inhibits LH-induced PLC (IC50 approximately 10 nM). While Org 43553 stimulates dissociation of [125I]hCG from the LHR and reduces [125I]hCG binding, LH reduces specific [3H]Org 43553 binding. We conclude that Org 43553 is a signaling-selective, allosteric LHR agonist. We hypothesize that Org 43553 and LH induce a similar LHR conformation necessary for activating adenylyl cyclase, which initiates most, if not all, physiological responses of LH.
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