Activation of Relaxin Family Receptor 1 from Different Mammalian Species by Relaxin Peptide and Small-Molecule Agonist ML290

Frontiers in Endocrinology
Zaohua HuangAlexander I Agoulnik

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 RXFP...Continue Reading

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Citations

Oct 25, 2016·British Journal of Pharmacology·Alexander I AgoulnikJuan Marugan
Dec 10, 2016·British Journal of Pharmacology·Richard IvellRavinder Anand-Ivell
Aug 17, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Elena M KaftanovskayaAlexander I Agoulnik
Jun 9, 2017·Scientific Reports·Martina KocanRoger J Summers
Mar 13, 2018·Trends in Endocrinology and Metabolism : TEM·Teja Devarakonda, Fadi N Salloum

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Datasets Mentioned

BETA
KT149378
KT149379
KT149380

Methods Mentioned

BETA
PCR
transfection
transfections
saturation binding

Software Mentioned

Blast2seq
GraphPad PRISM
GraphPad
BLAST
MUSCLE
Ensembl

Related Concepts

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