{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRXFP3, formerly known as GPCR135, is a G protein–coupled receptor that has been firmly established as the cognate receptor for the neuropeptide relaxin‐3. Initial studies demonstrated that relaxin‐3 is the only member of the relaxin/insulin superfamily capable of binding with high affinity to RXFP3, with receptor expression localized to key regions in the central nervous system involved in brainstem–hypothalamus circuitry. These pioneering findings highlighted that both the rat and porcine brain extracts can activate RXFP3 by stimulating GTP binding and inhibiting cAMP accumulation, setting the stage for understanding its neurophysiological roles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSubsequent molecular and structure–activity studies have clarified that the relaxin‐3 B‐chain is the principal ligand determinant for interaction with RXFP3. Biochemical analyses using engineered peptides and chimeric analogs have revealed that truncations or substitutions of the A‐chain of relaxin‐3 minimally affect RXFP3 binding whereas the B‐chain retains full activation capability. Functional assays in receptor‐expressing cell lines confirmed that stimulation with H3 relaxin robustly inhibits forskolin-induced cAMP production while activating downstream ERK1/2 signaling, underscoring a Gi/o-mediated signaling mechanism. These studies also identified key electrostatic and hydrophobic interactions between conserved arginine residues in the relaxin‐3 B‐chain and acidic residues in the receptor’s extracellular and transmembrane domains that are critical for efficient signal transduction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdvanced ligand‐receptor interaction studies using chimeric peptides—where modifications such as A‐chain replacement and peptide stapling were employed—have further refined our understanding of RXFP3 pharmacology. These investigations showed that exchanging key determinants can convert a ligand’s efficacy from agonism to antagonism and provided evidence for the existence of distinct binding sites on the receptor that differentially accommodate various relaxin family peptides. Assays leveraging novel platforms, such as NanoBiT‐based homogeneous binding systems, have elucidated both hydrophobic contacts (for example, interactions involving large aliphatic residues) and electrostatic interactions that contribute to receptor affinity and activation, firmly establishing the structural basis for selective RXFP3 modulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFunctionally, RXFP3 activation by relaxin‐3 has been implicated in modulating a broad array of behavioral and physiological responses encompassing arousal, stress regulation, appetite, and even aspects of cognitive function. Preclinical approaches and systematic reviews have provided compelling evidence that RXFP3 signaling can suppress depressive‐ and anxiety-like behaviors and exert pronounced orexigenic effects. Although candidate gene studies in large human cohorts have yet to consistently associate genetic variants in the relaxin‐3/RXFP3 pathway with neuropsychiatric outcomes, the preclinical data robustly position RXFP3 as a potential therapeutic target for disorders related to stress, feeding, and mood regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Changlu Liu, Elo Eriste, Steven Sutton, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M308995200"}], "href": "https://doi.org/10.1074/jbc.M308995200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14522968"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14522968"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Changlu Liu, Jingcai Chen, Chester Kuei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Relaxin-3/insulin-like peptide 5 chimeric peptide, a selective ligand for G protein-coupled receptor (GPCR)135 and GPCR142 over leucine-rich repeat-containing G protein-coupled receptor 7."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.104.006700"}], "href": "https://doi.org/10.1124/mol.104.006700"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15465925"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15465925"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mohammed Akhter Hossain, K Johan Rosengren, Linda M Haugaard-Jönsson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The A-chain of human relaxin family peptides has distinct roles in the binding and activation of the different relaxin family peptide receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M801911200"}], "href": "https://doi.org/10.1074/jbc.M801911200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18434306"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18434306"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Emma T Van der Westhuizen, Patrick M Sexton, Ross A D Bathgate, et al. 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