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Gene Review

Npy4r  -  neuropeptide Y receptor Y4

Mus musculus

Synonyms: NPY4-R, NPYR-D, NYYR-D, Neuropeptide Y receptor type 4, PP1, ...
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Disease relevance of Ppyr1

  • Y4(-/-) mice displayed lower body weight and reduced white adipose tissue mass accompanied by increased plasma levels of pancreatic polypeptide (PP) [1].
  • However, a synergistic interaction between Y2 and Y4 pathways seems to regulate bone volume and adiposity and could have important implications for possible interventions in obesity and for anabolic treatment of osteoporotic bone loss [2].
  • Surprisingly, despite significant hyperphagia, Y2(-/-) Y4(-/-) mice retained a markedly lean phenotype, with reduced body weight, white adipose tissue mass, leptinemia, and insulinemia [2].
  • Furthermore, we and others have demonstrated that the growth of mouse RAS-induced sarcomas allografts in mice is almost completely suppressed by either FK228 or a combination of two complimentary Tyr-kinase inhibitors, PP1 and AG 879, all of which block the RAS-induced activation of PAK1 [3].
  • Also, this PP1/GL-2003 combination therapy has been proven to be very effective to suppress the estrogen-independent growth of an NF1-deficient multidrug/FK228-resistant human breast cancer (MDA-MB-231) xenograft in mice [3].

High impact information on Ppyr1

  • In COS-7 cells, cotransfection of hm1 or hm2 receptors with Ras-GRF conferred carbachol-dependent increases in exchange-factor activity, whereas cotransfection with G-protein beta gamma subunits caused a constitutive activation that was sensitive to PP1 [4].
  • These data suggest that central Y4 receptor signaling specifically inhibits reproductive function under conditions of elevated central NPY-ergic tonus [1].
  • Development of the mammary ducts and lobuloalveoli was significantly enhanced in pregnant Y4(-/-) and Y4(-/-),ob/ob females [1].
  • In contrast, pretreatment of cells with the Src-specific tyrosine kinase inhibitor PP1 strengthened promotion of apoptosis by GADD34 [5].
  • Differential display analysis of mRNA derived from hypoxic epithelia revealed a specific and time-dependent repression of protein phosphatase 1 (PP1), a serine phosphatase important in CREB dephosphorylation [6].

Chemical compound and disease context of Ppyr1

  • Hydroxyproline release, an indicator of degradation of type-I collagen, and F-actin ring formation, a structure linked to osteoclastic bone resorption, were suppressed by PP1, cytochalasin B or wortmannin [7].
  • It is found that the replacement of the non-polar amino acid l-leucine at the second position of these heptacyclic peptide toxins by a polar l-arginine reduces their mouse toxicities and inhibitory activities against PP-1 and PP-2A to different extends [8].
  • The loss of a methyl group on the common methylaspartic acid (MeAsp) at the third position of MC-FR, -WR, and -RR does not alter their toxicity levels, but dominantly reduces their activities in PP-1 inhibition compared to other substitutions or modifications [8].
  • Reduction of the methyldehydroalanine (Mdha) residue of MCYST-LR with ethanethiol totally abolished the covalent binding of the toxin to PP1, but retained its inhibitory toxicity on PP1 [9].

Biological context of Ppyr1

  • Y4 receptor-knockout mice, anaesthetised with sodium pentobarbitone, displayed slower heart rate, indicated by a higher pulse interval and lower blood pressure compared to control mice [10].
  • Murine marrow cells from Lyn-deficient mice or wild-type mice cultured in the presence of the Src inhibitor, PP1, yielded a greater number of mature megakaryocytes and increased nuclear ploidy [11].
  • Rapid apoptosis induction required inhibition of both PP1 and PP2A, and the apoptosis was preceded by increased phosphorylation of several proteins, including myosin light chain [12].
  • Therefore, deletion of Y2 and Y4 receptors synergistically protects against diet-induced obesity, at least partially via changes in food intake and hypothalamic proopiomelanocortin expression [13].
  • [125I] [Leu31,Pro34]PYY (total Y1-like; Y1, Y4, and Y5) and [125I]PYY3-36 (total Y2-like; Y2 and possibly Y5) binding sites were discretely but similarly distributed in the rat and mouse brain, each having its unique pattern [14].

Anatomical context of Ppyr1


Associations of Ppyr1 with chemical compounds

  • We propose that the reduced vasoconstrictor and vagal inhibitory activity evoked by NPY in Y4 receptor-knockout mice is due to a lack of adrenergic tone bought about by a proposed reduction in sympathetic activity, possibly resulting from altered NPY activity secondarily affecting adrenergic transmission [10].
  • Treatment with PP1, a specific inhibitor of the non-receptor tyrosine-kinase c-Src, which is a negative regulator of osteoblast differentiation, showed that the activity of this kinase inhibits the F promoter [18].
  • Interestingly, the increased AMPAR response after reelin application was not blocked by PP1 but was blocked by the phosphoinositide-3' kinase (PI3K) inhibitors wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] [19].
  • The endogenous Y4 agonist PP depressed the activity of GABA-expressing neurons mainly by presynaptic attenuation of glutamate release [20].
  • When the incubation was stopped with EGTA the Src inhibitors PP1 and PP2 reduced PMN-platelet adhesion, while the inactive analog PP3 was ineffective [21].

Other interactions of Ppyr1


Analytical, diagnostic and therapeutic context of Ppyr1


  1. Y4 receptor knockout rescues fertility in ob/ob mice. Sainsbury, A., Schwarzer, C., Couzens, M., Jenkins, A., Oakes, S.R., Ormandy, C.J., Herzog, H. Genes Dev. (2002) [Pubmed]
  2. Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. Sainsbury, A., Baldock, P.A., Schwarzer, C., Ueno, N., Enriquez, R.F., Couzens, M., Inui, A., Herzog, H., Gardiner, E.M. Mol. Cell. Biol. (2003) [Pubmed]
  3. Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). Hirokawa, Y., Levitzki, A., Lessene, G., Baell, J., Xiao, Y., Zhu, H., Maruta, H. Cancer Lett. (2007) [Pubmed]
  4. Phosphorylation-dependent activation of the Ras-GRF/CDC25Mm exchange factor by muscarinic receptors and G-protein beta gamma subunits. Mattingly, R.R., Macara, I.G. Nature (1996) [Pubmed]
  5. Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis. Grishin, A.V., Azhipa, O., Semenov, I., Corey, S.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  6. Phosphorylation-dependent targeting of cAMP response element binding protein to the ubiquitin/proteasome pathway in hypoxia. Taylor, C.T., Furuta, G.T., Synnestvedt, K., Colgan, S.P. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  7. Regulation of collagenolytic protease secretion through c-Src in osteoclasts. Furuyama, N., Fujisawa, Y. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  8. Comparison of protein phosphatase inhibition activities and mouse toxicities of microcystins. Chen, Y.M., Lee, T.H., Lee, S.J., Huang, H.B., Huang, R., Chou, H.N. Toxicon (2006) [Pubmed]
  9. Monitoring of microcystin-protein phosphatase adduct formation with immunochemical methods. Liu, B.H., Yu, F.Y., Huang, X., Chu, F.S. Toxicon (2000) [Pubmed]
  10. Cardiac function in neuropeptide Y Y4 receptor-knockout mice. Smith-White, M.A., Herzog, H., Potter, E.K. Regul. Pept. (2002) [Pubmed]
  11. Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors. Lannutti, B.J., Drachman, J.G. Blood (2004) [Pubmed]
  12. Ultrarapid caspase-3 dependent apoptosis induction by serine/threonine phosphatase inhibitors. Fladmark, K.E., Brustugun, O.T., Hovland, R., Boe, R., Gjertsen, B.T., Zhivotovsky, B., Døskeland, S.O. Cell Death Differ. (1999) [Pubmed]
  13. Y2Y4 receptor double knockout protects against obesity due to a high-fat diet or Y1 receptor deficiency in mice. Sainsbury, A., Bergen, H.T., Boey, D., Bamming, D., Cooney, G.J., Lin, S., Couzens, M., Stroth, N., Lee, N.J., Lindner, D., Singewald, N., Karl, T., Duffy, L., Enriquez, R., Slack, K., Sperk, G., Herzog, H. Diabetes (2006) [Pubmed]
  14. Species differences in the expression and distribution of the neuropeptide Y Y1, Y2, Y4, and Y5 receptors in rodents, guinea pig, and primates brains. Dumont, Y., Jacques, D., Bouchard, P., Quirion, R. J. Comp. Neurol. (1998) [Pubmed]
  15. Cloning and characterization of a novel receptor to pancreatic polypeptide, a member of the neuropeptide Y receptor family. Gregor, P., Millham, M.L., Feng, Y., DeCarr, L.B., McCaleb, M.L., Cornfield, L.J. FEBS Lett. (1996) [Pubmed]
  16. Temporal and spatial expression of tissue inhibitors of metalloproteinases during the natural ovulatory cycle of the mouse. Inderdeo, D.S., Edwards, D.R., Han, V.K., Khokha, R. Biol. Reprod. (1996) [Pubmed]
  17. Endogenous neuropeptide Y depresses the afferent signaling of gastric acid challenge to the mouse brainstem via neuropeptide Y type Y2 and Y4 receptors. Wultsch, T., Painsipp, E., Thoeringer, C.K., Herzog, H., Sperk, G., Holzer, P. Neuroscience (2005) [Pubmed]
  18. Modulation of human estrogen receptor alpha F promoter by a protein kinase C/c-Src-dependent mechanism in osteoblast-like cells. Longo, M., Peruzzi, B., Fortunati, D., De Luca, V., Denger, S., Caselli, G., Migliaccio, S., Teti, A. J. Mol. Endocrinol. (2006) [Pubmed]
  19. Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus. Qiu, S., Zhao, L.F., Korwek, K.M., Weeber, E.J. J. Neurosci. (2006) [Pubmed]
  20. Mechanisms of neuropeptide Y, peptide YY, and pancreatic polypeptide inhibition of identified green fluorescent protein-expressing GABA neurons in the hypothalamic neuroendocrine arcuate nucleus. Acuna-Goycolea, C., Tamamaki, N., Yanagawa, Y., Obata, K., van den Pol, A.N. J. Neurosci. (2005) [Pubmed]
  21. Role of P-selectin, beta2-integrins, and Src tyrosine kinases in mouse neutrophil-platelet adhesion. Evangelista, V., Manarini, S., Coller, B.S., Smyth, S.S. J. Thromb. Haemost. (2003) [Pubmed]
  22. Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. Zhou, H.R., Jia, Q., Pestka, J.J. Toxicol. Sci. (2005) [Pubmed]
  23. Identification and distribution of mRNA encoding the Y1, Y2, Y4, and Y5 receptors for peptides of the PP-fold family in the rat intestine and colon. Goumain, M., Voisin, T., Lorinet, A.M., Laburthe, M. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  24. Cell cycle-dependent phosphorylation of mammalian protein phosphatase 1 by cdc2 kinase. Kwon, Y.G., Lee, S.Y., Choi, Y., Greengard, P., Nairn, A.C. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  25. Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities. Li, D.W., Liu, J.P., Schmid, P.C., Schlosser, R., Feng, H., Liu, W.B., Yan, Q., Gong, L., Sun, S.M., Deng, M., Liu, Y. Oncogene (2006) [Pubmed]
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