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GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo
OBJECTIVES: GPR40 (FFAR1), a clinically proven anti-diabetes target, is a Gq-coupled receptor for long chain fatty acids (LCFA) stimulating insulin secretion directly and mediating a major part of the dietary triglyceride-induced secretion of the incretins GLP-1 and GIP. In phase-II studies the GPR4...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314522/ https://www.ncbi.nlm.nih.gov/pubmed/25685685 http://dx.doi.org/10.1016/j.molmet.2014.10.002 |
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author | Hauge, Maria Vestmar, Marie A. Husted, Anna S. Ekberg, Jeppe P. Wright, Michael J. Di Salvo, Jerry Weinglass, Adam B. Engelstoft, Maja S. Madsen, Andreas N. Lückmann, Michael Miller, Michael W. Trujillo, Maria E. Frimurer, Thomas M. Holst, Birgitte Howard, Andrew D. Schwartz, Thue W. |
author_facet | Hauge, Maria Vestmar, Marie A. Husted, Anna S. Ekberg, Jeppe P. Wright, Michael J. Di Salvo, Jerry Weinglass, Adam B. Engelstoft, Maja S. Madsen, Andreas N. Lückmann, Michael Miller, Michael W. Trujillo, Maria E. Frimurer, Thomas M. Holst, Birgitte Howard, Andrew D. Schwartz, Thue W. |
author_sort | Hauge, Maria |
collection | PubMed |
description | OBJECTIVES: GPR40 (FFAR1), a clinically proven anti-diabetes target, is a Gq-coupled receptor for long chain fatty acids (LCFA) stimulating insulin secretion directly and mediating a major part of the dietary triglyceride-induced secretion of the incretins GLP-1 and GIP. In phase-II studies the GPR40 agonist TAK-875 decreased blood glucose but surprisingly without stimulating incretins. METHODS AND RESULTS: Here we find that GPR40 can signal through not only Gq and IP3 but also Gs and cAMP when stimulated with certain agonists such as AM-1638 and AM-5262 in contrast to the endogenous LCFA ligands and agonists such as TAK-875 and AM-837, which only signal through Gq. In competition binding against [3H]AM-1638 and [3H]L358 the Gq + Gs and the Gq-only agonists either competed for or showed positive cooperativity by increasing the binding of the two different radio-ligands, in opposite ways. Nevertheless, both the Gq-only and the Gq + Gs agonists all docked surprisingly well into the binding site for TAK-875 in the X-ray structure of GPR40. In murine intestinal primary cell-cultures the endogenous LCFAs and the Gq-only agonists stimulated GLP-1 secretion with rather poor efficacy as compared with the high efficacy Gq + Gs GPR40 agonists and a prototype GPR119 agonist. Similarly, in fasting both male and female mice the Gq + Gs agonists showed significantly higher efficacy than the Gq-only agonists in respect of increasing plasma GLP-1 and plasma GIP in a GPR40-dependent manner. CONCLUSIONS: It is concluded that stimulation of GPR40 by endogenous LCFAs or by Gq-only synthetic agonists result in a rather limited incretin response, whereas Gq + Gs GPR40 agonists stimulate incretin secretion robustly. |
format | Online Article Text |
id | pubmed-4314522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-43145222015-02-14 GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo Hauge, Maria Vestmar, Marie A. Husted, Anna S. Ekberg, Jeppe P. Wright, Michael J. Di Salvo, Jerry Weinglass, Adam B. Engelstoft, Maja S. Madsen, Andreas N. Lückmann, Michael Miller, Michael W. Trujillo, Maria E. Frimurer, Thomas M. Holst, Birgitte Howard, Andrew D. Schwartz, Thue W. Mol Metab Original Article OBJECTIVES: GPR40 (FFAR1), a clinically proven anti-diabetes target, is a Gq-coupled receptor for long chain fatty acids (LCFA) stimulating insulin secretion directly and mediating a major part of the dietary triglyceride-induced secretion of the incretins GLP-1 and GIP. In phase-II studies the GPR40 agonist TAK-875 decreased blood glucose but surprisingly without stimulating incretins. METHODS AND RESULTS: Here we find that GPR40 can signal through not only Gq and IP3 but also Gs and cAMP when stimulated with certain agonists such as AM-1638 and AM-5262 in contrast to the endogenous LCFA ligands and agonists such as TAK-875 and AM-837, which only signal through Gq. In competition binding against [3H]AM-1638 and [3H]L358 the Gq + Gs and the Gq-only agonists either competed for or showed positive cooperativity by increasing the binding of the two different radio-ligands, in opposite ways. Nevertheless, both the Gq-only and the Gq + Gs agonists all docked surprisingly well into the binding site for TAK-875 in the X-ray structure of GPR40. In murine intestinal primary cell-cultures the endogenous LCFAs and the Gq-only agonists stimulated GLP-1 secretion with rather poor efficacy as compared with the high efficacy Gq + Gs GPR40 agonists and a prototype GPR119 agonist. Similarly, in fasting both male and female mice the Gq + Gs agonists showed significantly higher efficacy than the Gq-only agonists in respect of increasing plasma GLP-1 and plasma GIP in a GPR40-dependent manner. CONCLUSIONS: It is concluded that stimulation of GPR40 by endogenous LCFAs or by Gq-only synthetic agonists result in a rather limited incretin response, whereas Gq + Gs GPR40 agonists stimulate incretin secretion robustly. Elsevier 2014-10-24 /pmc/articles/PMC4314522/ /pubmed/25685685 http://dx.doi.org/10.1016/j.molmet.2014.10.002 Text en © 2014 The Authors http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). |
spellingShingle | Original Article Hauge, Maria Vestmar, Marie A. Husted, Anna S. Ekberg, Jeppe P. Wright, Michael J. Di Salvo, Jerry Weinglass, Adam B. Engelstoft, Maja S. Madsen, Andreas N. Lückmann, Michael Miller, Michael W. Trujillo, Maria E. Frimurer, Thomas M. Holst, Birgitte Howard, Andrew D. Schwartz, Thue W. GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo |
title | GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo |
title_full | GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo |
title_fullStr | GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo |
title_full_unstemmed | GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo |
title_short | GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo |
title_sort | gpr40 (ffar1) – combined gs and gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314522/ https://www.ncbi.nlm.nih.gov/pubmed/25685685 http://dx.doi.org/10.1016/j.molmet.2014.10.002 |
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