{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have established that the chemerin receptor now known as CMKLR2 (historically linked to GPR1) is a multifunctional G protein‐coupled receptor that binds the adipokine chemerin to regulate a spectrum of biological processes. Structural analyses have revealed that upon binding chemerin or its active C‑terminal peptide, CMKLR2 engages Gi proteins via a “two‑site” binding mechanism in which a short peptide fragment is sufficient for receptor activation, while an extended interaction with full‑length chemerin further stabilizes the complex. This molecular arrangement underlies downstream MAP kinase signaling cascades and contributes to diverse cellular responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its signaling properties, CMKLR2 plays critical roles in metabolic homeostasis and pathophysiological conditions. Its activation has been implicated in vascular tone regulation and vasoconstriction, and alterations in receptor expression are observed in metabolic conditions such as gestational diabetes, where CMKLR2 signaling is linked to impaired carbohydrate and lipid metabolism during pregnancy. Similarly, distinct chemerin isoforms that engage CMKLR2 have been shown to modulate hepatocyte migration, suggesting a potential protective role against tumor metastasis in hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional evidence highlights diverse facets of CMKLR2 function in immunological and developmental contexts. The receptor has been linked to anti-viral functions, as synthetic peptides derived from its N‑terminal region can inhibit HIV‑1 infection by interacting with envelope glycoproteins, underscoring the importance of its extracellular determinants. Genomic and epigenetic studies have further identified CMKLR2 (referred to by its gene symbol GPR1) as an imprinted gene in both human and mouse tissues, with variants showing significant associations with neurological disorders such as Alzheimer’s disease. Moreover, comparative analyses reveal species‐specific variations in CMKLR2 coupling to β‑arrestins, which influence receptor internalization and trafficking properties."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}, {"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Atsushi Jinno-Oue, Nobuaki Shimizu, Yasushi Soda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The synthetic peptide derived from the NH2-terminal extracellular region of an orphan G protein-coupled receptor, GPR1, preferentially inhibits infection of X4 HIV-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M500195200"}], "href": "https://doi.org/10.1074/jbc.M500195200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15919664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15919664"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Aijun Liu, Yezhou Liu, Geng Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of G protein-coupled receptor GPR1 bound to full-length chemerin adipokine reveals a chemokine-like reverse binding mode."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Biol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pbio.3002838"}], "href": "https://doi.org/10.1371/journal.pbio.3002838"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39466725"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39466725"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Amanda J Kennedy, Peiran Yang, Cai Read, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chemerin Elicits Potent Constrictor Actions via Chemokine-Like Receptor 1 (CMKLR1), not G-Protein-Coupled Receptor 1 (GPR1), in Human and Rat Vasculature."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Heart Assoc (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/JAHA.116.004421"}], "href": "https://doi.org/10.1161/JAHA.116.004421"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27742615"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27742615"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Binbin Huang, Chen Huang, Huashan Zhao, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Chemerin Isoform-Specific Effects on Hepatocyte Migration and Immune Cell Inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms21197205"}], "href": "https://doi.org/10.3390/ijms21197205"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33003572"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33003572"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hitoshi Hiura, Atsushi Sugawara, Hidehiko Ogawa, et al. 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