An intracellular VHH targeting the Luteinizing Hormone receptor modulates G protein-dependent signaling and steroidogenesis
Résumé
Luteinizing hormone (LH) is essential for reproduction, controlling ovulation and steroidogenesis. Its receptor
(LHR) recruits various transducers leading to the activation of a complex signaling network. We recently identified iPRC1, the first variable fragment from heavy-chain-only antibody (VHH) interacting with intracellular
loop 3 (ICL3) of the follicle-stimulating hormone receptor (FSHR). Because of the high sequence similarity of the
human FSHR and LHR (LHCGR), here we examined the ability of the iPRC1 intra-VHH to modulate LHCGR
activity. In this study, we demonstrated that iPRC1 binds LHCGR, to a greater extent when the receptor was
stimulated by the hormone. In addition, it decreased LH-induced cAMP production, cAMP-responsive elementdependent transcription, progesterone and testosterone production. These impairments are not due to Gs nor
β-arrestin recruitment to the LHCGR. Consequently, iPRC1 is the first intra-VHH to bind and modulate LHCGR
biological activity, including steroidogenesis. It should help further understand signaling mechanisms elicited at
this receptor and their outcomes on reproduction
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