ArticleFrontiers in endocrinology2015
Activation of Relaxin Family Receptor 1 from Different Mammalian Species by Relaxin Peptide and Small-Molecule Agonist ML290.
Article in Frontiers in endocrinology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Anti-apoptotic and Matrix Remodeling Actions of a Small Molecule Agonist of the Human Relaxin Receptor, ML290 in Mice With Unilateral Ureteral Obstruction.Frontiers in physiology · 2021Article
- Characterizing relaxin receptor expression and exploring relaxin's effect on tissue remodeling/fibrosis in the human bladder.BMC urology · 2020Article
- Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Targeting the relaxin/insulin-like family peptide receptor 1 and 2 with small molecule compounds.Molecular and cellular endocrinology · 2019Review
- Multi-Component Mechanism of H2 Relaxin Binding to RXFP1 through NanoBRET Kinetic Analysis.iScience · 2019Article
- Heart Disease and Relaxin: New Actions for an Old Hormone.Trends in endocrinology and metabolism: TEM · 2018Review
- In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis.Scientific reports · 2017Article
- ML290 is a biased allosteric agonist at the relaxin receptor RXFP1.Scientific reports · 2017Article
- Human Relaxin Receptor Is Fully Functional in Humanized Mice and Is Activated by Small Molecule Agonist ML290.Journal of the Endocrine Society · 2017Article
- Relaxin-like peptides in male reproduction - a human perspective.British journal of pharmacology · 2017Review
- Synthetic non-peptide low molecular weight agonists of the relaxin receptor 1.British journal of pharmacology · 2017Review
- Protection from cigarette smoke-induced vascular injury by recombinant human relaxin-2 (serelaxin).Journal of cellular and molecular medicine · 2016Article
- Structural Insights into the Activation of Human Relaxin Family Peptide Receptor 1 by Small-Molecule Agonists.Biochemistry · 2016Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Relaxin peptide (RLN), which signals through the relaxin family peptide 1 (RXFP1) GPCR receptor, has shown therapeutic effects in an acute heart failure clinical trial. We have identified a small-molecule agonist of human RXFP1, ML290; however, it does not activate the mouse receptor. To find a suitable animal model for ML290 testing and to gain mechanistic insights into the interaction of various ligands with RXFP1, we have cloned rhesus macaque, pig, rabbit, and guinea pig RXFP1s and analyzed their activation by RLN and ML290. HEK293T cells expressing macaque or pig RXFP1 responded to relaxin and ML290 treatment as measured by an increase of cAMP production. Guinea pig RXFP1 responded to relaxin but had very low response to ML290 treatment only at highest concentrations used. The rabbit RXFP1 amino acid sequence was the most divergent, with a number of unique substitutions within the ectodomain and the seven-transmembrane domain (7TM). Two splice variants of rabbit RXFP1 derived through alternative splicing of the fourth exon were identified. In contrast to the other species, rabbit RXFP1s were activated by ML290, but not with human, pig, mouse, or rabbit RLNs. Using FLAG-tagged constructs, we have shown that both rabbit RXFP1 variants are expressed on the cell surface. No binding of human Eu-labeled RLN to rabbit RXFP1 was detected, suggesting that in this species, RXFP1 might be non-functional. We used chimeric rabbit-human and guinea pig-human constructs to identify regions important for RLN or ML290 receptor activation. Chimeras with the human ectodomain and rabbit 7TM domain were activated by RLN, whereas substitution of part of the guinea pig 7TM domain with the human sequence only partially restored ML290 activation, confirming the allosteric mode of action for the two ligands. Our data demonstrate that macaque and pig models can be used for ML290 testing.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.