Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling
(1) The human luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptor (LHCGR) discriminates its two hormone ligands and differs from the murine receptor (Lhr) in amino acid residues potentially involved in qualitative discerning of LH and hCG. The latter gonadotropin is absent in rodents. The...
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doaj-8b0e044ac1bc4d6c95484f09798acbec2020-12-26T00:03:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-012215115110.3390/ijms22010151Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific SignalingClara Lazzaretti0Valentina Secco1Elia Paradiso2Samantha Sperduti3Claudia Rutz4Annika Kreuchwig5Gerd Krause6Manuela Simoni7Livio Casarini8Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41126 Modena, ItalyUnit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41126 Modena, ItalyUnit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41126 Modena, ItalyUnit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41126 Modena, ItalyLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, GermanyLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, GermanyLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, GermanyUnit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41126 Modena, ItalyUnit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41126 Modena, Italy(1) The human luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptor (LHCGR) discriminates its two hormone ligands and differs from the murine receptor (Lhr) in amino acid residues potentially involved in qualitative discerning of LH and hCG. The latter gonadotropin is absent in rodents. The aim of the study is to identify LHCGR residues involved in hCG/LH discrimination. (2) Eight LHCGR cDNAs were developed, carrying “murinizing” mutations on aminoacidic residues assumed to interact specifically with LH, hCG, or both. HEK293 cells expressing a mutant or the wild type receptor were treated with LH or hCG and the kinetics of cyclic adenosine monophosphate (cAMP) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) activation was analyzed by bioluminescence resonance energy transfer (BRET). (3) Mutations falling within the receptor leucine reach repeat 9 and 10 (LRR9 and LRR10; K225S +T226I and R247T), of the large extracellular binding domain, are linked to loss of hormone-specific induced cAMP increase, as well as hCG-specific pERK1/2 activation, leading to a Lhr-like modulation of the LHCGR-mediated intracellular signaling pattern. These results support the hypothesis that LHCGR LRR domain is the interaction site of the hormone β-L2 loop, which differs between LH and hCG, and might be fundamental for inducing gonadotropin-specific signals. (4) Taken together, these data identify LHCGR key residues likely evolved in the human to discriminate LH/hCG specific binding.https://www.mdpi.com/1422-0067/22/1/151luteinizing hormone (LH)human chorionic gonadotropin (hCG)LH/hCG receptor (LHCGR)mutationcAMPERK1/2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Clara Lazzaretti Valentina Secco Elia Paradiso Samantha Sperduti Claudia Rutz Annika Kreuchwig Gerd Krause Manuela Simoni Livio Casarini |
spellingShingle |
Clara Lazzaretti Valentina Secco Elia Paradiso Samantha Sperduti Claudia Rutz Annika Kreuchwig Gerd Krause Manuela Simoni Livio Casarini Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling International Journal of Molecular Sciences luteinizing hormone (LH) human chorionic gonadotropin (hCG) LH/hCG receptor (LHCGR) mutation cAMP ERK1/2 |
author_facet |
Clara Lazzaretti Valentina Secco Elia Paradiso Samantha Sperduti Claudia Rutz Annika Kreuchwig Gerd Krause Manuela Simoni Livio Casarini |
author_sort |
Clara Lazzaretti |
title |
Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling |
title_short |
Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling |
title_full |
Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling |
title_fullStr |
Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling |
title_full_unstemmed |
Identification of Key Receptor Residues Discriminating Human Chorionic Gonadotropin (hCG)- and Luteinizing Hormone (LH)-Specific Signaling |
title_sort |
identification of key receptor residues discriminating human chorionic gonadotropin (hcg)- and luteinizing hormone (lh)-specific signaling |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-12-01 |
description |
(1) The human luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptor (LHCGR) discriminates its two hormone ligands and differs from the murine receptor (Lhr) in amino acid residues potentially involved in qualitative discerning of LH and hCG. The latter gonadotropin is absent in rodents. The aim of the study is to identify LHCGR residues involved in hCG/LH discrimination. (2) Eight LHCGR cDNAs were developed, carrying “murinizing” mutations on aminoacidic residues assumed to interact specifically with LH, hCG, or both. HEK293 cells expressing a mutant or the wild type receptor were treated with LH or hCG and the kinetics of cyclic adenosine monophosphate (cAMP) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) activation was analyzed by bioluminescence resonance energy transfer (BRET). (3) Mutations falling within the receptor leucine reach repeat 9 and 10 (LRR9 and LRR10; K225S +T226I and R247T), of the large extracellular binding domain, are linked to loss of hormone-specific induced cAMP increase, as well as hCG-specific pERK1/2 activation, leading to a Lhr-like modulation of the LHCGR-mediated intracellular signaling pattern. These results support the hypothesis that LHCGR LRR domain is the interaction site of the hormone β-L2 loop, which differs between LH and hCG, and might be fundamental for inducing gonadotropin-specific signals. (4) Taken together, these data identify LHCGR key residues likely evolved in the human to discriminate LH/hCG specific binding. |
topic |
luteinizing hormone (LH) human chorionic gonadotropin (hCG) LH/hCG receptor (LHCGR) mutation cAMP ERK1/2 |
url |
https://www.mdpi.com/1422-0067/22/1/151 |
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