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Gene Review

NPS  -  neuropeptide S

Homo sapiens

Synonyms: Neuropeptide S
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Disease relevance of NPS

  • In the mouse macrophage RAW 264.7 cell line, NPS-stimulated Galphas- and Galphaq-dependent phagocytosis of Escherichia coli [1].
  • Clearance experiments were performed and the effect of bolus, 1 mg/kg body weight i.v. of NPS 2143 on MAP in the presence and absence of thyroparathyroidectomy (TPTX) was monitored continuously [2].
  • Effect of the calcimimetic NPS R-467 on furosemide-induced nephrocalcinosis in the young rat [3].
  • Nail Patella Syndrome (NPS; OMIM #161200) is a pleiotropic condition, with a classical clinical tetrad of involvement of the nails, knees, elbows and the presence of iliac horns [4].
  • In-patients with MS nocturnal spasms (NPS) occur frequently, primarily during the night and may influence the ability to and/or quality of sleep [5].

Psychiatry related information on NPS

  • However, the stimulatory effect of hNPS given intracerebroventricularly on mouse locomotor activity was not fully mimicked by hNPS-(1-10), suggesting that the C-terminal region of the peptide maintains importance for in vivo activity [6].
  • Neuropeptide S (NPS) is a recently discovered bioactive peptide that has shed new light on the neurobiology of sleep/wakefulness regulation and anxiety-like behavior [7].
  • This unique pharmacological profile of NPS offers significant potential for developing new drugs for the treatment of sleep and/or anxiety disorders [7].

High impact information on NPS

  • We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS R-467, increased the concentration of cytoplasmic Ca2+ ([Ca2+]i) in bovine parathyroid cells and inhibited PTH secretion at nanomolar concentrations [8].
  • The results show that GPR154 is upregulated in macrophages after antigen challenge and that NPS is capable of inducing phagocytosis of unopsonized bacteria [1].
  • Here, we characterized the mRNA expression of NPS and GPR154 by using real-time RT-PCR in fractionated human blood cells and in peripheral blood mononuclear cells (PBMCs) with monocyte or T cell activation [1].
  • However, the expression profile of GPR154 in leukocytes and the cellular functions of the receptor and its endogenous agonist neuropeptide S (NPS) have remained unidentified [1].
  • In biochemical assays 11-13-mer NPS oligonucleotides demonstrated sequence- and dose-dependent inhibition of telomerase with IC(50) values <1 nM [9].

Biological context of NPS


Anatomical context of NPS

  • The NPS precursor mRNA is highly expressed in a previously undescribed group of neurons located between the locus coeruleus (LC) and Barrington's nucleus [10].
  • Finally, we demonstrate that GPRA and NPS are co-expressed in bronchial epithelium [12].
  • Addition of the calcimimetic NPS R-467 or exposure to high extracellular Ca2+ or Mg2+ levels elicited actin stress fiber assembly and process retraction in otherwise stellate cells [13].
  • Our results showed that acute caffeine treatment induces a marked decrease in the mRNA levels of NPS in the brainstem, whilst the expression levels NPS-R are increased in both hypothalamus and brainstem after caffeine treatment [14].
  • We conclude that NPS 2143 is responsible for increased blood pressure in rats in the presence of parathyroid glands [2].

Associations of NPS with chemical compounds

  • Overall, these data suggest a possible role for the NPS system in mediating some of the behavioral effects of caffeine [14].
  • SELECTION CRITERIA: We included all RCTs of any calcimimetic agent, cinacalcet HCl (AMG-073, Sensipar), NPS R-467 or NPS R-568 administered to patients with CKD for the treatment of SHPT [15].
  • The phenylalkylamine compound, NPS 568, identified as a positive allosteric modulator of the Ca(2+) receptor can selectively potentiate the actions of Ca(2+) and other polycationic agonists on the T903-Rhoc receptor [16].
  • 10 mm l-phenylalanine and 1 microm NPS R-467, submaximal doses of the two agents, each elicited similar modulation of R185Q [17].
  • In addition, calcium, magnesium, strontium, aluminum, gadolinium, and the calcimimetic NPS 568 resulted in a dose-dependent stimulation of GPRC6A overexpressed in human embryonic kidney cells 293 cells [18].

Regulatory relationships of NPS

  • Taken together, these data suggest that both 4 mm Ca(2+) and NPS R-467/CaCl(2) activate ERK1/2 via distinguishable pathways in HEK-hCaR cells and may represent a nexus to differentially regulate differentiation versus proliferation via CaR activation [19].
  • In contrast, inhibiting MEK1 only transiently inhibited the activation of this K+ channel by NPS R-467, despite the continued presence of the antagonist [20].
  • NPS R-467 potentiated the calcium-stimulated increase in involucrin promoter activity unlike NPS S-467 or vehicle [21].
  • NPS activates an orphan G protein-coupled receptor that is expressed throughout the central nervous system, including brain centers that regulate sleep/wakefulness and anxiety [22].

Other interactions of NPS

  • In particular, we will discuss the modulatory roles of the hypocretins/orexins and of neuropeptide S in sleep and awakening and those of ghrelin and melanin concentrating hormone in food intake [23].
  • In this study we show that the CaR agonist NPS R-467 (1 microm), which does not activate the CaR by itself, robustly activates ERK1/2 in the presence of a low concentration of Ca(2+) (0.5 mm CaCl(2)) in human embryonic kidney (HEK) cells permanently expressing the human CaR (HEK-hCaR) [19].
  • A three-dimensional model of the human extracellular Ca(2+)-sensing receptor (CaSR) has been used to identify specific residues implicated in the recognition of two negative allosteric CaSR modulators of different chemical structure, NPS 2143 and Calhex 231 [24].
  • ICV NPS significantly increased plasma ACTH and corticosterone 10 and 40 min after injection, respectively [25].
  • Here we show that NOS-2 expression in the activated astrocytes requires that the culture medium contain 1.8 mM Ca2+, but it is unaffected by inhibiting calcium-sensing receptors (CASRs) with NPS 89636 [26].

Analytical, diagnostic and therapeutic context of NPS


  1. Neuropeptide S and G protein-coupled receptor 154 modulate macrophage immune responses. Pulkkinen, V., Majuri, M.L., Wang, G., Holopainen, P., Obase, Y., Vendelin, J., Wolff, H., Rytilä, P., Laitinen, L.A., Haahtela, T., Laitinen, T., Alenius, H., Kere, J., Rehn, M. Hum. Mol. Genet. (2006) [Pubmed]
  2. Hypertensive effect of calcilytic NPS 2143 administration in rats. Rybczynska, A., Lehmann, A., Jurska-Jasko, A., Boblewski, K., Orlewska, C., Foks, H., Drewnowska, K. J. Endocrinol. (2006) [Pubmed]
  3. Effect of the calcimimetic NPS R-467 on furosemide-induced nephrocalcinosis in the young rat. Pattaragarn, A., Fox, J., Alon, U.S. Kidney Int. (2004) [Pubmed]
  4. Nail patella syndrome revisited: 50 years after linkage. McIntosh, I., Dunston, J.A., Liu, L., Hoover-Fong, J.E., Sweeney, E. Ann. Hum. Genet. (2005) [Pubmed]
  5. Gabapentin is effective in treating nocturnal painful spasms in multiple sclerosis. Solaro, C., Uccelli, M.M., Guglieri, P., Uccelli, A., Mancardi, G.L. Mult. Scler. (2000) [Pubmed]
  6. Structure-activity studies on neuropeptide S: identification of the amino acid residues crucial for receptor activation. Roth, A.L., Marzola, E., Rizzi, A., Arduin, M., Trapella, C., Corti, C., Vergura, R., Martinelli, P., Salvadori, S., Regoli, D., Corsi, M., Cavanni, P., Caló, G., Guerrini, R. J. Biol. Chem. (2006) [Pubmed]
  7. Neuropeptide S and its receptor: a newly deorphanized G protein-coupled receptor system. Reinscheid, R.K., Xu, Y.L. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. (2005) [Pubmed]
  8. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Nemeth, E.F., Steffey, M.E., Hammerland, L.G., Hung, B.C., Van Wagenen, B.C., DelMar, E.G., Balandrin, M.F. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  9. A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Asai, A., Oshima, Y., Yamamoto, Y., Uochi, T.A., Kusaka, H., Akinaga, S., Yamashita, Y., Pongracz, K., Pruzan, R., Wunder, E., Piatyszek, M., Li, S., Chin, A.C., Harley, C.B., Gryaznov, S. Cancer Res. (2003) [Pubmed]
  10. Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain. Xu, Y.L., Gall, C.M., Jackson, V.R., Civelli, O., Reinscheid, R.K. J. Comp. Neurol. (2007) [Pubmed]
  11. Structure-function relationships in the neuropeptide S receptor: molecular consequences of the asthma-associated mutation N107I. Bernier, V., Stocco, R., Bogusky, M.J., Joyce, J.G., Parachoniak, C., Grenier, K., Arget, M., Mathieu, M.C., O'Neill, G.P., Slipetz, D., Crackower, M.A., Tan, C.M., Therien, A.G. J. Biol. Chem. (2006) [Pubmed]
  12. Characterization of GPRA, a novel G protein-coupled receptor related to asthma. Vendelin, J., Pulkkinen, V., Rehn, M., Pirskanen, A., Räisänen-Sokolowski, A., Laitinen, A., Laitinen, L.A., Kere, J., Laitinen, T. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  13. Ca2+-sensing receptor induces Rho kinase-mediated actin stress fiber assembly and altered cell morphology, but not in response to aromatic amino acids. Davies, S.L., Gibbons, C.E., Vizard, T., Ward, D.T. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  14. Caffeine treatment regulates neuropeptide S system expression in the rat brain. Lage, R., Di??guez, C., L??pez, M. Neurosci. Lett. (2006) [Pubmed]
  15. Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients. Strippoli, G.F., Tong, A., Palmer, S.C., Elder, G., Craig, J.C. Cochrane database of systematic reviews (Online) (2006) [Pubmed]
  16. Evidence for distinct cation and calcimimetic compound (NPS 568) recognition domains in the transmembrane regions of the human Ca2+ receptor. Ray, K., Northup, J. J. Biol. Chem. (2002) [Pubmed]
  17. L-phenylalanine and NPS R-467 synergistically potentiate the function of the extracellular calcium-sensing receptor through distinct sites. Zhang, Z., Jiang, Y., Quinn, S.J., Krapcho, K., Nemeth, E.F., Bai, M. J. Biol. Chem. (2002) [Pubmed]
  18. Identification of a novel extracellular cation-sensing G-protein-coupled receptor. Pi, M., Faber, P., Ekema, G., Jackson, P.D., Ting, A., Wang, N., Fontilla-Poole, M., Mays, R.W., Brunden, K.R., Harrington, J.J., Quarles, L.D. J. Biol. Chem. (2005) [Pubmed]
  19. Calcium-sensing receptor-mediated ERK1/2 activation requires Galphai2 coupling and dynamin-independent receptor internalization. Holstein, D.M., Berg, K.A., Leeb-Lundberg, L.M., Olson, M.S., Saunders, C. J. Biol. Chem. (2004) [Pubmed]
  20. Regulation of a Ca2+-activated K+ channel by calcium-sensing receptor involves p38 MAP kinase. Ye, C.P., Yano, S., Tfelt-Hansen, J., MacLeod, R.J., Ren, X., Terwilliger, E., Brown, E.M., Chattopadhyay, N. J. Neurosci. Res. (2004) [Pubmed]
  21. Effects of a calcium receptor activator on the cellular response to calcium in human keratinocytes. Tu, C.L., Oda, Y., Bikle, D.D. J. Invest. Dermatol. (1999) [Pubmed]
  22. Neuropeptide s: a new player in the modulation of arousal and anxiety. Reinscheid, R.K., Xu, Y.L., Civelli, O. Molecular interventions. (2005) [Pubmed]
  23. Orphan neuropeptides Novel neuropeptides modulating sleep or feeding. Chung, S., Civelli, O. Neuropeptides (2006) [Pubmed]
  24. Positive and negative allosteric modulators of the Ca2+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain. Petrel, C., Kessler, A., Dauban, P., Dodd, R.H., Rognan, D., Ruat, M. J. Biol. Chem. (2004) [Pubmed]
  25. Neuropeptide S stimulates the hypothalamo-pituitary-adrenal axis and inhibits food intake. Smith, K.L., Patterson, M., Dhillo, W.S., Patel, S.R., Semjonous, N.M., Gardiner, J.V., Ghatei, M.A., Bloom, S.R. Endocrinology (2006) [Pubmed]
  26. Roles of Ca2+ and the Ca2+-sensing receptor (CASR) in the expression of inducible NOS (nitric oxide synthase)-2 and its BH4 (tetrahydrobiopterin)-dependent activation in cytokine-stimulated adult human astrocytes. Dal Pra, I., Chiarini, A., Nemeth, E.F., Armato, U., Whitfield, J.F. J. Cell. Biochem. (2005) [Pubmed]
  27. Downstream target genes of the neuropeptide S-NPSR1 pathway. Vendelin, J., Bruce, S., Holopainen, P., Pulkkinen, V., Rytilä, P., Pirskanen, A., Rehn, M., Laitinen, T., Laitinen, L.A., Haahtela, T., Saarialho-Kere, U., Laitinen, A., Kere, J. Hum. Mol. Genet. (2006) [Pubmed]
  28. NPS@: network protein sequence analysis. Combet, C., Blanchet, C., Geourjon, C., Deléage, G. Trends Biochem. Sci. (2000) [Pubmed]
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