title: The actions of relaxin family peptides on signal transduction pathways activated by the relaxin family peptide receptor RXFP4.
abstract: The relaxin family peptide receptor 4 (RXFP4) is a G protein-coupled receptor (GPCR) expressed in the colorectum with emerging roles in metabolism and appetite regulation. It is activated by its cognate ligand insulin-like peptide 5 (INSL5) that is expressed in enteroendocrine L cells in the gut. Whether other evolutionarily related peptides such as relaxin-2, relaxin-3, or INSL3 activate RXFP4 signal transduction mechanisms with a pattern similar to or distinct from INSL5 is still unclear. In this study, we compare the signaling pathways activated by various relaxin family peptides to INSL5. We found that, like INSL5, relaxin-3 activated ERK1/2, p38MAPK, Akt, and S6RP phosphorylations leading to increased cell proliferation and also caused GRK and β-arrestin-mediated receptor internalization. Interestingly, relaxin-3 was slightly more potent than INSL5 in ERK1/2 and Akt phosphorylations, but both peptides were almost equipotent in adenylyl cyclase inhibition, S6RP phosphorylation, and cell proliferation. In addition, relaxin-3 showed greater efficacy only in Akt phosphorylation but not in the other pathways investigated. In contrast, no signaling activity or receptor internalization mechanisms were observed following relaxin-2 and INSL3. In conclusion, relaxin-3 is a high-efficacy agonist at RXFP4 with a comparable signal transduction profile to INSL5.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
authors.forename: Sheng Y
authors.initials: SY
authors.lastname: Ang
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.|Department of Pharmacology, Monash University, Clayton, VIC, Australia.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Hutchinson
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: Evans
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Hossain
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Nitin
authors.initials: N
authors.lastname: Patil
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.|Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Ross A D
authors.initials: RA
authors.lastname: Bathgate
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Martina
authors.initials: M
authors.lastname: Kocan
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. roger.summers@monash.edu.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Summers
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008024:Ligands; D010766:Phosphorylation; D021381:Protein Transport; D011506:Proteins / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012065:Relaxin / Q000494:pharmacology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D000071557:beta-Arrestins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007328:Insulin; C084797:Leydig insulin-like protein; D008024:Ligands; D011506:Proteins; C095068:RLN2 protein, human; C480238:RLN3 protein, human; C480239:RXFP4 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D000071557:beta-Arrestins; D012065:Relaxin; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000262:Adenylyl Cyclases
keywords: Insulin-like peptide 3; Insulin-like peptide 5; Relaxin family peptide receptor 4; Relaxin-2; Relaxin-3; Signal transduction