{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have identified QRFPR (also known as GPR103) as a critical G protein‐coupled receptor activated by endogenous RF‐amide peptides, such as QRFP/26RFa, that play key roles in neuroendocrine regulation. In the central nervous system, QRFP is expressed in hypothalamic nuclei and its receptor is distributed in distinct brain areas. Activation of QRFPR influences feeding behavior, locomotor activity, and cardiovascular functions, and its expression and ligand activity are modulated by metabolic cues such as fasting and obesity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond the brain, QRFPR is implicated in a novel RF‐amide neuroendocrine system. Studies using predictive peptide mining and ligand characterization have uncovered novel endogenous peptides that selectively activate QRFPR, which is expressed in brain as well as in peripheral tissues such as heart, kidney, and reproductive organs. Such findings underscore the receptor’s potential role in integrating central and peripheral signals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, activation of QRFPR in adipocyte models contributes to the regulation of lipid metabolism. In differentiated adipocytes, stimulation with QRFP peptides increases triglyceride accumulation and fatty acid uptake while attenuating isoproterenol-induced lipolysis. These actions, linked to the upregulation of genes involved in lipid uptake and adipogenesis, suggest that QRFPR functions in an autocrine/paracrine manner to fine-tune peripheral metabolic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the signaling level, QRFPR exhibits dual coupling to Gαq and Gαi/o proteins. Detailed investigation into naturally occurring receptor mutations has revealed that alterations in QRFPR can bias signaling toward distinct intracellular pathways—affecting either calcium mobilization or ERK1/2 activation. Such biased signaling highlights the receptor’s complex regulation and functional versatility, which may underlie its diverse physiological roles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer biology, particularly in prostate cancer models, QRFPR activation has been shown to promote signaling via ERK1/2, p38, JNK, and Akt pathways. These signaling events are associated with enhanced cell migration, invasion, and increased expression of matrix metalloproteinases, linking QRFPR activity to tumor progression and suggesting a potential mechanistic link between adiposity and aggressive cancer phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shinobu Takayasu, Takeshi Sakurai, Satoshi Iwasaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0602371103"}], "href": "https://doi.org/10.1073/pnas.0602371103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16648250"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16648250"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Huanzheng Li, Ran Lou, Xueqin Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The variations in human orphan G protein-coupled receptor QRFPR affect PI3K-AKT-mTOR signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Lab Anal (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcla.23822"}], "href": "https://doi.org/10.1002/jcla.23822"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34018631"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34018631"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ying Jiang, Lin Luo, Eric L Gustafson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and characterization of a novel RF-amide peptide ligand for orphan G-protein-coupled receptor SP9155."}]}, {"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.M302945200"}], "href": "https://doi.org/10.1074/jbc.M302945200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12714592"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12714592"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mukandila Mulumba, Christian Jossart, Riccarda Granata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GPR103b functions in the peripheral regulation of adipogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2010-0010"}], "href": "https://doi.org/10.1210/me.2010-0010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20534693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20534693"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Qiang Ma, Zheng Cao, Huanzheng Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Two naturally occurring mutations of human GPR103 define distinct G protein selection bias."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Cell Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2021.119046"}], "href": "https://doi.org/10.1016/j.bbamcr.2021.119046"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33872671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33872671"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Mohamed Ab Kawan, Ioannis Kyrou, Manjunath Ramanjaneya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of the glutamine RF‑amide peptide and its cognate receptor GPR103 in prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2018.6893"}], "href": "https://doi.org/10.3892/or.2018.6893"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30483810"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30483810"}]}]}]}