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The actions of relaxin family peptides on signal transduction pathways activated by the relaxin family peptide receptor RXFP4

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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.

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Acknowledgements

This work is supported by an Australian National Health and Medical Research Council (NHMRC) program grant (1055134; RJS). DSH is supported by a NHMRC Career Development Fellowship (545952). SYA is supported by a Faculty of Pharmacy and Pharmaceutical Sciences, Monash University Postgraduate Scholarship. Research at the Florey was supported by an ARC Linkage grant to RADB and MAH (LP120100654) and by the Victorian Government Operational Infrastructure Support Program. RADB is supported by an NHMRC Research Fellowship (1042650).

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Authors and Affiliations

  1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia

    Sheng Y. Ang, Dana S. Hutchinson, Bronwyn A. Evans & Roger J. Summers

  2. Department of Pharmacology, Monash University, Clayton, VIC, Australia

    Dana S. Hutchinson

  3. The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia

    Mohammed A. Hossain, Nitin Patil, Ross A. D. Bathgate & Martina Kocan

  4. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia

    Ross A. D. Bathgate

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  1. Sheng Y. Ang
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  2. Dana S. Hutchinson
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  3. Bronwyn A. Evans
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  4. Mohammed A. Hossain
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  5. Nitin Patil
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  6. Ross A. D. Bathgate
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  7. Martina Kocan
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  8. Roger J. Summers
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Correspondence to Roger J. Summers.

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Ang, S.Y., Hutchinson, D.S., Evans, B.A. et al. The actions of relaxin family peptides on signal transduction pathways activated by the relaxin family peptide receptor RXFP4. Naunyn-Schmiedeberg's Arch Pharmacol 390, 105–111 (2017). https://doi.org/10.1007/s00210-016-1321-8

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  • DOI: https://doi.org/10.1007/s00210-016-1321-8

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