Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors

Abstract Human luteinizing hormone (LH) and chorionic gonadotropin (hCG) have been considered biologically equivalent because of their structural similarities and their binding to the same receptor; the LH/CGR. However, accumulating evidence suggest that LH/CGR differentially responds to the two hor...

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Autores principales:	Laura Riccetti, Romain Yvinec, Danièle Klett, Nathalie Gallay, Yves Combarnous, Eric Reiter, Manuela Simoni, Livio Casarini, Mohammed Akli Ayoub
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/14e0a3cfe6c446ad86d633c372aa2fef
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spelling	oai:doaj.org-article:14e0a3cfe6c446ad86d633c372aa2fef2021-12-02T12:31:46ZHuman Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors10.1038/s41598-017-01078-82045-2322https://doaj.org/article/14e0a3cfe6c446ad86d633c372aa2fef2017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01078-8https://doaj.org/toc/2045-2322Abstract Human luteinizing hormone (LH) and chorionic gonadotropin (hCG) have been considered biologically equivalent because of their structural similarities and their binding to the same receptor; the LH/CGR. However, accumulating evidence suggest that LH/CGR differentially responds to the two hormones triggering differential intracellular signaling and steroidogenesis. The mechanistic basis of such differential responses remains mostly unknown. Here, we compared the abilities of recombinant rhLH and rhCG to elicit cAMP, β-arrestin 2 activation, and steroidogenesis in HEK293 cells and mouse Leydig tumor cells (mLTC-1). For this, BRET and FRET technologies were used allowing quantitative analyses of hormone activities in real-time and in living cells. Our data indicate that rhLH and rhCG differentially promote cell responses mediated by LH/CGR revealing interesting divergences in their potencies, efficacies and kinetics: rhCG was more potent than rhLH in both HEK293 and mLTC-1 cells. Interestingly, partial effects of rhLH were found on β-arrestin recruitment and on progesterone production compared to rhCG. Such a link was further supported by knockdown experiments. These pharmacological differences demonstrate that rhLH and rhCG act as natural biased agonists. The discovery of novel mechanisms associated with gonadotropin-specific action may ultimately help improve and personalize assisted reproduction technologies.Laura RiccettiRomain YvinecDanièle KlettNathalie GallayYves CombarnousEric ReiterManuela SimoniLivio CasariniMohammed Akli AyoubNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Laura Riccetti Romain Yvinec Danièle Klett Nathalie Gallay Yves Combarnous Eric Reiter Manuela Simoni Livio Casarini Mohammed Akli Ayoub Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors
description	Abstract Human luteinizing hormone (LH) and chorionic gonadotropin (hCG) have been considered biologically equivalent because of their structural similarities and their binding to the same receptor; the LH/CGR. However, accumulating evidence suggest that LH/CGR differentially responds to the two hormones triggering differential intracellular signaling and steroidogenesis. The mechanistic basis of such differential responses remains mostly unknown. Here, we compared the abilities of recombinant rhLH and rhCG to elicit cAMP, β-arrestin 2 activation, and steroidogenesis in HEK293 cells and mouse Leydig tumor cells (mLTC-1). For this, BRET and FRET technologies were used allowing quantitative analyses of hormone activities in real-time and in living cells. Our data indicate that rhLH and rhCG differentially promote cell responses mediated by LH/CGR revealing interesting divergences in their potencies, efficacies and kinetics: rhCG was more potent than rhLH in both HEK293 and mLTC-1 cells. Interestingly, partial effects of rhLH were found on β-arrestin recruitment and on progesterone production compared to rhCG. Such a link was further supported by knockdown experiments. These pharmacological differences demonstrate that rhLH and rhCG act as natural biased agonists. The discovery of novel mechanisms associated with gonadotropin-specific action may ultimately help improve and personalize assisted reproduction technologies.
format	article
author	Laura Riccetti Romain Yvinec Danièle Klett Nathalie Gallay Yves Combarnous Eric Reiter Manuela Simoni Livio Casarini Mohammed Akli Ayoub
author_facet	Laura Riccetti Romain Yvinec Danièle Klett Nathalie Gallay Yves Combarnous Eric Reiter Manuela Simoni Livio Casarini Mohammed Akli Ayoub
author_sort	Laura Riccetti
title	Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors
title_short	Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors
title_full	Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors
title_fullStr	Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors
title_full_unstemmed	Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors
title_sort	human luteinizing hormone and chorionic gonadotropin display biased agonism at the lh and lh/cg receptors
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/14e0a3cfe6c446ad86d633c372aa2fef
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Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors

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