{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeuropeptide Y receptor type 1 (NPY1R) is a widely expressed G‐protein–coupled receptor that mediates a broad range of physiological functions. It plays a role in regulating vascular homeostasis and angiogenesis, as evidenced by its contribution to endothelial cell migration and proliferation in the formation of new capillaries (via heteromeric interactions with Y2 and Y5 receptors)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the gastrointestinal system, NPY1R participates in modulating electrogenic ion transport in human colonic mucosa"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", while in adipose tissue it affects lipid metabolism and has been implicated in obesity and dyslipidemia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, in the central nervous system, NPY1R influences food intake, anxiety, and even seizure susceptibility, with gene transfer studies demonstrating that overexpression in the hippocampus can elicit modest anxiolytic effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, NPY1R signals predominantly via Gi/o proteins to modulate downstream pathways such as the inhibition of adenylyl cyclase, reduction of intracellular cAMP, and activation of mitogen‐activated protein kinase (MAPK) cascades. Detailed analyses in cultured cells have revealed that NPY1R activation leads to ERK1/2 phosphorylation through rapid Gβ/γ–dependent signaling that—even in the absence of β–arrestin recruitment—requires cross‐talk with insulin‐like growth factor receptors (IGFR)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Furthermore, biophysical studies using fluorescence correlation spectroscopy have demonstrated that agonist binding promotes receptor clustering and decreases lateral mobility, reflecting early events in receptor internalization mediated by a C–terminal tyrosine‐based sorting motif."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Structural elucidation and mutagenesis work have further provided a framework for developing potent and selective NPY1R antagonists for therapeutic applications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, NPY1R has emerged as an important modulator in various pathological conditions. In prostate cancer cells, its activation can differentially regulate cell proliferation depending on the cell context and associated kinetics of MAPK activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In hepatocellular carcinoma, reduced NPY1R expression correlates with enhanced proliferation, suggesting that restoration of NPY1R signaling may inhibit tumor growth through MAPK pathway inactivation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In breast cancer, NPY1R expression is highest in luminal subtypes, and its estrogen–dependent regulation is associated with attenuation of estradiol–stimulated proliferation, making it a promising biomarker for endocrine sensitivity and favorable prognosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": " Moreover, genetic association studies have linked NPY1R variants with risk for alcohol and heroin dependence as well as autonomic traits that could predispose to cardiovascular disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "19"}]}, {"type": "t", "text": " Additional studies have documented its expression in the retina, testicular tissues, and even in periodontal ligament stem cells, emphasizing its diverse roles in physiological and pathophysiological processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "22"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sharareh Movafagh, John P Hobson, Sarah Spiegel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuropeptide Y induces migration, proliferation, and tube formation of endothelial cells bimodally via Y1, Y2, and Y5 receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.05-4770fje"}], "href": "https://doi.org/10.1096/fj.05-4770fje"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16891622"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16891622"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Helen M Cox, Iain R Tough "}, {"type": "b", "children": [{"type": "t", "text": "Neuropeptide Y, Y1, Y2 and Y4 receptors mediate Y agonist responses in isolated human colon mucosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Pharmacol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjp.0704604"}], "href": "https://doi.org/10.1038/sj.bjp.0704604"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11906964"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11906964"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "J B Blumenthal, R E Andersen, B D Mitchell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel neuropeptide Y1 and Y5 receptor gene variants: associations with serum triglyceride and high-density lipoprotein cholesterol levels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1034/j.1399-0004.2002.620302.x"}], "href": "https://doi.org/10.1034/j.1399-0004.2002.620302.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12220433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12220433"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xiaoyan Feng, Ye Ding, Min Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrative Analysis of Exosomal miR-452 and miR-4713 Downregulating "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "NPY1R"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " for the Prevention of Childhood Obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dis Markers (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2022/2843353"}], "href": "https://doi.org/10.1155/2022/2843353"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35401881"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35401881"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Zhenlin Yang, Shuo Han, Max Keller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis of ligand binding modes at the neuropeptide Y Y"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "1"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": " receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-018-0046-x"}], "href": "https://doi.org/10.1038/s41586-018-0046-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29670288"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29670288"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "M V Olesen, S H Christiansen, C R Gøtzsche, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuropeptide Y Y1 receptor hippocampal overexpression via viral vectors is associated with modest anxiolytic-like and proconvulsant effects in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jnr.22770"}], "href": "https://doi.org/10.1002/jnr.22770"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21971867"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21971867"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sandra Lecat, Lazare Belemnaba, Jean-Luc Galzi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuropeptide Y receptor mediates activation of ERK1/2 via transactivation of the IGF receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2015.03.016"}], "href": "https://doi.org/10.1016/j.cellsig.2015.03.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25817573"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25817573"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Laura E Kilpatrick, Stephen J Briddon, Nicholas D Holliday "}, {"type": "b", "children": [{"type": "t", "text": "Fluorescence correlation spectroscopy, combined with bimolecular fluorescence complementation, reveals the effects of β-arrestin complexes and endocytic targeting on the membrane mobility of neuropeptide Y receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2012.03.002"}], "href": "https://doi.org/10.1016/j.bbamcr.2012.03.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22487268"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22487268"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Sandra Lecat, Moussa Ouédraogo, Thomas Cherrier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Contribution of a tyrosine-based motif to cellular trafficking of wild-type and truncated NPY Y(1) receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2010.09.007"}], "href": "https://doi.org/10.1016/j.cellsig.2010.09.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20837140"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20837140"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Max Keller, Lisa Schindler, Günther Bernhardt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toward Labeled Argininamide-Type NPY Y1 Receptor Antagonists: Identification of a Favorable Propionylation Site in BIBO3304."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Pharm (Weinheim) (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ardp.201400427"}], "href": "https://doi.org/10.1002/ardp.201400427"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25884646"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25884646"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Tatsuya Umeda, Akio Kanatani, Hisashi Iwaasa "}, {"type": "b", "children": [{"type": "t", "text": "Cloning and characterization of rabbit neuropeptide Y receptor subtypes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Peptides (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.peptides.2009.05.020"}], "href": "https://doi.org/10.1016/j.peptides.2009.05.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19481128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19481128"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Massimiliano Ruscica, Elena Dozio, Stéphane Boghossian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of the Y1 receptor by neuropeptide Y regulates the growth of prostate cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2005-0925"}], "href": "https://doi.org/10.1210/en.2005-0925"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16339211"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16339211"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Xiufang Lv, Fengbo Zhao, Xisong Huo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuropeptide Y1 receptor inhibits cell growth through inactivating mitogen-activated protein kinase signal pathway in human hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Oncol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12032-016-0785-1"}], "href": "https://doi.org/10.1007/s12032-016-0785-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27262566"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27262566"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Raksha Bhat, Hariprasad Thangavel, Noor Mazin Abdulkareem, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NPY1R exerts inhibitory action on estradiol-stimulated growth and predicts endocrine sensitivity and better survival in ER-positive breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-022-05949-7"}], "href": "https://doi.org/10.1038/s41598-022-05949-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35121782"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35121782"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Marwa M Dawoud, Khaled K-E Abdelaziz, Alshimaa M Alhanafy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical Significance of Immunohistochemical Expression of Neuropeptide Y1 Receptor in Patients With Breast Cancer in Egypt."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Appl Immunohistochem Mol Morphol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/PAI.0000000000000877"}], "href": "https://doi.org/10.1097/PAI.0000000000000877"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33086223"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33086223"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Philip J Medeiros, Sydney A Pascetta, Sarah M Kirsh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of hypoxia inducible factor-dependent neuropeptide Y receptors Y1 and Y5 sensitizes hypoxic cells to NPY stimulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2022.101645"}], "href": "https://doi.org/10.1016/j.jbc.2022.101645"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35093384"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35093384"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Leah Wetherill, Marc A Schuckit, Victor Hesselbrock, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Alcohol Clin Exp Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1530-0277.2008.00790.x"}], "href": "https://doi.org/10.1111/j.1530-0277.2008.00790.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18828811"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18828811"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Lei Wang, Fangwen Rao, Kuixing Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuropeptide Y(1) Receptor NPY1R discovery of naturally occurring human genetic variants governing gene expression in cella as well as pleiotropic effects on autonomic activity and blood pressure in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Coll Cardiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jacc.2009.05.035"}], "href": "https://doi.org/10.1016/j.jacc.2009.05.035"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19712806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19712806"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Drashti Desai, Pravin Shende "}, {"type": "b", "children": [{"type": "t", "text": "Strategic Aspects of NPY-Based Monoclonal Antibodies for Diagnosis and Treatment of Breast Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Protein Pept Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/1389203721666200918151604"}], "href": "https://doi.org/10.2174/1389203721666200918151604"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32951575"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32951575"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "M Valeria Cantó Soler, Juan E Gallo, Ricardo A Dodds, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Y1 receptor of neuropeptide Y as a glial marker in proliferative vitreoretinopathy and diseased human retina."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Glia (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/glia.10107"}], "href": "https://doi.org/10.1002/glia.10107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12203398"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12203398"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Meike Körner, Beatriche Waser, George N Thalmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High expression of NPY receptors in the human testis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2011.01.021"}], "href": "https://doi.org/10.1016/j.mce.2011.01.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21295110"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21295110"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Lewis Winning, Ikhlas A El Karim, Gerard J Linden, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential regulation of NPY and SP receptor expression in STRO-1+ve PDLSCs by inflammatory cytokines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Periodontal Res (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jre.12952"}], "href": "https://doi.org/10.1111/jre.12952"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34773642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34773642"}]}]}]}