Signalling profiles of H3 relaxin, H2 relaxin and R3(B?23-27)R/I5 acting at the relaxin family peptide receptor 3 (RXFP3).

ABSTRACT: BACKGROUND AND PURPOSE: Relaxin family peptide receptor 3 (RXFP3) is expressed in brain areas important for processing sensory information and feeding, suggesting that it may be a target for anti-anxiety and anti-obesity drugs. We examined the effects of H3 relaxin, the biased agonist H2 relaxin and the antagonist, R3(B?23-27)R/I5, on RXFP3 signalling to establish their suitability as tools to assess the physiological roles of RXFP3. EXPERIMENTAL APPROACH: The signalling profile of the RXFP3 ligands was determined using reporter gene assays, multiplexed signalling assays and direct examination of receptor-G protein and receptor-?-arrestin interactions using BRET. KEY RESULTS: H2 relaxin activated p38MAPK and ERK1/2 with lower efficacy than H3 relaxin, but had similar efficacy for JNK1/2 phosphorylation. H2 or H3 relaxin activation of p38MAPK, JNK1/2 or ERK1/2 involved Pertussis toxin-sensitive G-proteins. R3(B?23-27)R/I5 blocked H3 relaxin AP-1 reporter gene activation, but not H2 relaxin AP-1 activation or H3 relaxin NF-?B activation. R3(B?23-27)R/I5 activated the SRE reporter, but did not inhibit either H2 or H3 relaxin SRE activation. R3(B?23-27)R/I5 blocked H3 relaxin-stimulated p38MAPK and ERK1/2 phosphorylation, but was a weak partial agonist for p38MAPK and ERK1/2 signalling. p38MAPK activation by R3(B?23-27)R/I5 was G protein-independent. H3 relaxin-activated RXFP3 interacts with G?i2 , G?i3 , G?o A and G?o B whereas H2 relaxin or R3(B?23-27)R/I5 induce interactions only with G?i2 or G?o B . Only H3 relaxin promoted RXFP3/?-arrestin interactions that were blocked by R3(B?23-27)R/I5. CONCLUSION AND IMPLICATIONS: Understanding signalling profile of drugs acting at RXFP3 is essential for development of therapies targeting this receptor.

SUBMITTER: Kocan M 

PROVIDER: S-EPMC4243858 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature