RXFP3
RXFP3 is the cognate receptor for relaxin-3, an abundant brain neuropeptide that acts through a class-A GPCR system to regulate neural network signaling[1][2]. Mechanistically, RXFP3 couples mainly to Gαᵢ/Gαₒ proteins and engages MAPK pathways including ERK1/2, p38MAPK, and JNK1/2 after ligand activation[2][3]. In brain systems, relaxin-3/RXFP3 signaling modulates stress responses, anxiety-related behavior, motivated behavior, circadian rhythms, learning, and memory[1]. In experimental models, central RXFP3 activation disrupted social recognition and increased ERK phosphorylation in specific GABAergic amygdala neurons[4]. RXFP3-expressing cells in the zona incerta/lateral hypothalamus also projected to stress and arousal centers, and chemogenetic activation increased behavioral arousal in RXFP3-Cre mice[5]. Compared with related isoforms, RXFP3 differs from RXFP1/RXFP2 systems because relaxin-3 is primarily a neuropeptide, while RXFP3 and RXFP4 share Gαᵢ/Gαₒ coupling[2]. RXFP3 also differs from RXFP4 because relaxin-3 selectively activates RXFP3, whereas INSL5 is the cognate ligand for RXFP4[1]. For experimental applications, RXFP3 ligands include peptide agonists, antagonists, biased agonists, and an allosteric modulator, supporting pathway-selective studies and drug-design research[2][3][6].
References:
- [1]. Ma S, et al. Distribution, physiology and pharmacology of relaxin-3/RXFP3 systems in brain. Br J Pharmacol. 2017 May;174(10):1034-1048. [Content Brief]
- [2]. Halls ML, et al. International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides. Pharmacol Rev. 2015;67(2):389-440. [Content Brief]
- [3]. Kocan M, et al. Signalling profiles of H3 relaxin, H2 relaxin and R3(BΔ23-27)R/I5 acting at the relaxin family peptide receptor 3 (RXFP3). Br J Pharmacol. 2014 Jun;171(11):2827-41. [Content Brief]
- [4]. Albert-Gasco H, et al. Central relaxin-3 receptor (RXFP3) activation impairs social recognition and modulates ERK-phosphorylation in specific GABAergic amygdala neurons. Brain Struct Funct. 2019 Jan;224(1):453-469. [Content Brief]
- [5]. Richards BK, et al. Relaxin family peptide receptor 3 (RXFP3) expressing cells in the zona incerta/lateral hypothalamus augment behavioural arousal. J Neurochem. 2025 Jan;169(1):e16217. [Content Brief]
- [6]. Wong LLL, et al. Distinct but overlapping binding sites of agonist and antagonist at the relaxin family peptide 3 (RXFP3) receptor. J Biol Chem. 2018 Oct 12;293(41):15777-15789. [Content Brief]
