{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRelaxin‐3 (RLN3) is a member of the insulin/relaxin peptide superfamily that has been molecularly characterized as a two‐chain hormone held together by disulfide bonds, with a unique conformation revealed by nuclear magnetic resonance studies. Early biochemical studies identified RLN3 as the endogenous ligand for orphan G protein–coupled receptors such as GPCR135 (RXFP3) and GPCR142, and extensive structure–activity work—including the use of chimeric peptides and A‐chain substitutions—has elucidated that conserved residues (for example, key arginines and hydrophobic motifs within its B‐chain) are critical for high‐affinity receptor binding and for triggering efficient signal transduction. Detailed mutagenesis experiments further established the importance of complementary electrostatic and hydrophobic interactions between RLN3 and its receptors, and structural comparisons have differentiated its interactions with RXFP3/GPCR135 versus other related receptors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the central nervous system RLN3 is predominantly expressed in discrete brainstem nuclei – notably the nucleus incertus – with extensive projections to hypothalamic and limbic regions. Functional neuropharmacological studies have demonstrated that central administration of RLN3 robustly increases food intake and modulates arousal, stress responses, and emotional behaviors through activation of RXFP3, engaging inhibitory G protein pathways and downstream MAPK signaling cascades. Moreover, pharmacological tools such as selective antagonists and biased agonists have refined our understanding of its receptor–mediated effects, while studies in primate tissue and ex vivo preparations underline neuroprotective actions and a potential role in the modulation of depressive‐ and anxiety‐like behaviors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central neuromodulatory roles, RLN3 has been implicated in a range of peripheral physiological processes. Experimental studies have shown that RLN3 can exert antifibrotic effects in cardiac fibroblasts by antagonizing profibrotic signals via RXFP1, and its circulating levels have been associated with acute heart failure. Moreover, clinical investigations have linked RLN3 with metabolic regulation and components of the metabolic syndrome, while genetic and hormonal studies have suggested roles in reproductive development and even in the timing of puberty. However, candidate gene approaches exploring associations with neuropsychiatric outcomes have produced mixed results, highlighting the need for further research on this pleiotropic peptide."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Changlu Liu, Jingcai Chen, Steven Sutton, et al. 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