ML290 is a biased allosteric agonist at the relaxin receptor RXFP1

Abstract Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molecule RXFP1 agonist with simple structure, long half-life and high stability. Here we demonstrate that ML290 is a biased agonist in human cells expressing RXFP1 wi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Martina Kocan, Mohsin Sarwar, Sheng Y. Ang, Jingbo Xiao, Juan J. Marugan, Mohammed A. Hossain, Chao Wang, Dana S. Hutchinson, Chrishan S. Samuel, Alexander I. Agoulnik, Ross A. D. Bathgate, Roger J. Summers
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dd60bf90c42d4a01bd40b123afd44a23
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:dd60bf90c42d4a01bd40b123afd44a23
record_format	dspace
spelling	oai:doaj.org-article:dd60bf90c42d4a01bd40b123afd44a232021-12-02T11:40:23ZML290 is a biased allosteric agonist at the relaxin receptor RXFP110.1038/s41598-017-02916-52045-2322https://doaj.org/article/dd60bf90c42d4a01bd40b123afd44a232017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02916-5https://doaj.org/toc/2045-2322Abstract Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molecule RXFP1 agonist with simple structure, long half-life and high stability. Here we demonstrate that ML290 is a biased agonist in human cells expressing RXFP1 with long-term beneficial actions on markers of fibrosis in human cardiac fibroblasts (HCFs). ML290 did not directly compete with orthosteric relaxin binding and did not affect binding kinetics, but did increase binding to RXFP1. In HEK-RXFP1 cells, ML290 stimulated cAMP accumulation and p38MAPK phosphorylation but not cGMP accumulation or ERK1/2 phosphorylation although prior addition of ML290 increased p-ERK1/2 responses to relaxin. In human primary vascular endothelial and smooth muscle cells that endogenously express RXFP1, ML290 increased both cAMP and cGMP accumulation but not p-ERK1/2. In HCFs, ML290 increased cGMP accumulation but did not affect p-ERK1/2 and given chronically activated MMP-2 expression and inhibited TGF-β1-induced Smad2 and Smad3 phosphorylation. In vascular cells, ML290 was 10x more potent for cGMP accumulation and p-p38MAPK than for cAMP accumulation. ML290 caused strong coupling of RXFP1 to Gαs and GαoB but weak coupling to Gαi3. ML290 exhibited signalling bias at RXFP1 possessing a signalling profile indicative of vasodilator and anti-fibrotic properties.Martina KocanMohsin SarwarSheng Y. AngJingbo XiaoJuan J. MaruganMohammed A. HossainChao WangDana S. HutchinsonChrishan S. SamuelAlexander I. AgoulnikRoss A. D. BathgateRoger J. SummersNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Martina Kocan Mohsin Sarwar Sheng Y. Ang Jingbo Xiao Juan J. Marugan Mohammed A. Hossain Chao Wang Dana S. Hutchinson Chrishan S. Samuel Alexander I. Agoulnik Ross A. D. Bathgate Roger J. Summers ML290 is a biased allosteric agonist at the relaxin receptor RXFP1
description	Abstract Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molecule RXFP1 agonist with simple structure, long half-life and high stability. Here we demonstrate that ML290 is a biased agonist in human cells expressing RXFP1 with long-term beneficial actions on markers of fibrosis in human cardiac fibroblasts (HCFs). ML290 did not directly compete with orthosteric relaxin binding and did not affect binding kinetics, but did increase binding to RXFP1. In HEK-RXFP1 cells, ML290 stimulated cAMP accumulation and p38MAPK phosphorylation but not cGMP accumulation or ERK1/2 phosphorylation although prior addition of ML290 increased p-ERK1/2 responses to relaxin. In human primary vascular endothelial and smooth muscle cells that endogenously express RXFP1, ML290 increased both cAMP and cGMP accumulation but not p-ERK1/2. In HCFs, ML290 increased cGMP accumulation but did not affect p-ERK1/2 and given chronically activated MMP-2 expression and inhibited TGF-β1-induced Smad2 and Smad3 phosphorylation. In vascular cells, ML290 was 10x more potent for cGMP accumulation and p-p38MAPK than for cAMP accumulation. ML290 caused strong coupling of RXFP1 to Gαs and GαoB but weak coupling to Gαi3. ML290 exhibited signalling bias at RXFP1 possessing a signalling profile indicative of vasodilator and anti-fibrotic properties.
format	article
author	Martina Kocan Mohsin Sarwar Sheng Y. Ang Jingbo Xiao Juan J. Marugan Mohammed A. Hossain Chao Wang Dana S. Hutchinson Chrishan S. Samuel Alexander I. Agoulnik Ross A. D. Bathgate Roger J. Summers
author_facet	Martina Kocan Mohsin Sarwar Sheng Y. Ang Jingbo Xiao Juan J. Marugan Mohammed A. Hossain Chao Wang Dana S. Hutchinson Chrishan S. Samuel Alexander I. Agoulnik Ross A. D. Bathgate Roger J. Summers
author_sort	Martina Kocan
title	ML290 is a biased allosteric agonist at the relaxin receptor RXFP1
title_short	ML290 is a biased allosteric agonist at the relaxin receptor RXFP1
title_full	ML290 is a biased allosteric agonist at the relaxin receptor RXFP1
title_fullStr	ML290 is a biased allosteric agonist at the relaxin receptor RXFP1
title_full_unstemmed	ML290 is a biased allosteric agonist at the relaxin receptor RXFP1
title_sort	ml290 is a biased allosteric agonist at the relaxin receptor rxfp1
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/dd60bf90c42d4a01bd40b123afd44a23
work_keys_str_mv	AT martinakocan ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT mohsinsarwar ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT shengyang ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT jingboxiao ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT juanjmarugan ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT mohammedahossain ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT chaowang ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT danashutchinson ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT chrishanssamuel ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT alexanderiagoulnik ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT rossadbathgate ml290isabiasedallostericagonistattherelaxinreceptorrxfp1 AT rogerjsummers ml290isabiasedallostericagonistattherelaxinreceptorrxfp1
_version_	1718395675396276224

ML290 is a biased allosteric agonist at the relaxin receptor RXFP1

Ejemplares similares