{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeuropeptide FF receptor 2 (NPFFR2) is a G protein‐coupled receptor that has emerged as a key modulator of opioid signaling in neuronal systems. Studies using neuroblastoma cell models co‐expressing mu‐opioid and NPFFR2 have shown that receptor activation by NPFF analogs leads to strong inhibition of cyclic AMP production, modulation of N‐type Ca²⁺ channel activity, and heterologous phosphorylation of the mu‐opioid receptor via GRK2. Furthermore, the use of selective ligands – including competitive antagonists and “super‐agonists” – has refined our understanding of NPFFR2’s acute desensitization and signal regulation, underscoring its antiopioid function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical antiopioid role, NPFFR2 is responsive to a diverse range of RFamide peptides. For example, kisspeptins – which share a C‐terminal RFamide motif with NPFF – have been shown to activate NPFFR2, albeit with lesser efficacy compared with NPFF itself, suggesting the receptor’s participation in central autonomic regulation and nociceptive processing. In addition, studies in neuroblastoma cells endogenously expressing NPFFR2 reveal that receptor activation couples to Gi/o proteins, triggers receptor internalization, reorganizes the actin cytoskeleton, and stimulates mitogen‐activated protein kinase cascades. Comparative analyses also indicate that alternative splicing and species‐specific ligand binding contribute to the molecular diversity and fine‐tuning of NPFFR2 signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNPFFR2 also appears to play a role in metabolic regulation. Genetic association studies have identified NPFFR2 haplotypes that correlate strongly with body mass index, indicating that this receptor may either confer protection against or predispose to obesity. In addition, preliminary pharmacogenomic findings suggest that NPFFR2 genetic variants might influence the therapeutic response to anti‐TNF drugs, highlighting the receptor’s potential as a biomarker in inflammatory and metabolic conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Catherine Mollereau, Honoré Mazarguil, Jean-Marie Zajac, et al. 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