Neuropeptide S

Neuropeptide S (NPS) is a neuropeptide found in human and mammalian brain, mainly produced by neurons in the amygdala and between Barrington's nucleus and the locus coeruleus, although NPS-responsive neurons extend projections into many other brain areas.^[5][6][7] NPS binds specifically to a G protein-coupled receptor, NPSR.^[8][9] Animal studies show that NPS suppresses anxiety and appetite, induces wakefulness and hyperactivity, including hyper-sexuality, and plays a significant role in the extinction of conditioned fear.^{[10][11][12][13][14][15][16]} It has also been shown to significantly enhance dopamine activity in the mesolimbic pathway,^[16] and inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans.^[17]

NPS
Identifiers
Aliases	NPS, neuropeptide S
External IDs	OMIM: 609513 MGI: 3642232 HomoloGene: 106066 GeneCards: NPS
Gene location (Human) Chr. Chromosome 10 (human)^[1] Band 10q26.2 Start 127,549,309 bp^[1] End 127,553,540 bp^[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)^[2] Band 7|7 F3 Start 134,860,432 bp^[2] End 134,874,671 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans prefrontal cortex substantia nigra hypothalamus temporal lobe amygdala Top expressed in spermatocyte testicle hypothalamus cerebellar cortex spermatid More reference expression data BioGPS n/a
Orthologs Species Human Mouse Entrez 594857 100043254 Ensembl ENSG00000214285 ENSMUSG00000073804 UniProt P0C0P6 P0C0P8 RefSeq (mRNA) NM_001030013 NM_001163611 RefSeq (protein) NP_001025184 NP_001157083 Location (UCSC) Chr 10: 127.55 – 127.55 Mb Chr 7: 134.86 – 134.87 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Synthetic ligands

The non-peptide NPS receptor antagonist SHA-68 blocks the effects of NPS in animals and is anxiogenic.^[18] Several peptide derived NPS agonists and antagonists have also been developed.^{[19][20][21][22][23]}

Peptide sequence

Below are the sequences of mature neuropeptide S in several representative species in which it is expressed:

Neuropeptide S Identifiers Symbol Neuropeptide_S Pfam PF14993 InterPro IPR028138 Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

species	sequence	MW
human	SFRNGVGTGMKKTSFQRAKS	2187.5
rat	SFRNGVGSGVKKTSFRRAKQ	2210.5
mouse	SFRNGVGSGAKKTSFRRAKQ	2182.5
dog, chimp	SFRNGVGTGMKKTSFRRAKS	2215.6
chicken	SFRNGVGSGIKKTSFRRAKS	2183.5
consensus	SFRNGVGxGXKKTSFxRAKx	N/A

According to Pfam's HMM logo, there is a conserved "KR" cleave site immediately N-terminal to the C-terminal mature peptide.

References

1. GRCh38: Ensembl release 89: ENSG00000214285 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000073804 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Xu YL, Gall CM, Jackson VR, Civelli O, Reinscheid RK (Jan 2007). "Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain". The Journal of Comparative Neurology. 500 (1): 84–102. doi:10.1002/cne.21159. PMID 17099900. S2CID 23864785.
6. Jüngling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu YL, Reinscheid RK, Pape HC (Jul 2008). "Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala". Neuron. 59 (2): 298–310. doi:10.1016/j.neuron.2008.07.002. PMC 2610688. PMID 18667157.
7. Meis S, Bergado-Acosta JR, Yanagawa Y, Obata K, Stork O, Munsch T (2008). Grothe B (ed.). "Identification of a neuropeptide S responsive circuitry shaping amygdala activity via the endopiriform nucleus". PLOS ONE. 3 (7): e2695. Bibcode:2008PLoSO...3.2695M. doi:10.1371/journal.pone.0002695. PMC 2442874. PMID 18628994.  
8. Reinscheid RK, Xu YL (Dec 2005). "Neuropeptide S and its receptor: a newly deorphanized G protein-coupled receptor system". The Neuroscientist. 11 (6): 532–8. doi:10.1177/1073858405276405. PMID 16282594. S2CID 30579961.
9. Reinscheid RK (2008). "Neuropeptide S: Anatomy, Pharmacology, Genetics and Physiological Functions". Orphan G Protein-Coupled Receptors and Novel Neuropeptides. Results and Problems in Cell Differentiation. Vol. 46. pp. 145–58. doi:10.1007/400_2007_051. ISBN 978-3-540-78350-3. PMID 18204825.
10. Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher FA, Zeng J, Ly NK, Henriksen SJ, de Lecea L, Civelli O (Aug 2004). "Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects". Neuron. 43 (4): 487–97. doi:10.1016/j.neuron.2004.08.005. PMID 15312648. S2CID 15601843.
11. Reinscheid RK, Xu YL (Nov 2005). "Neuropeptide S as a novel arousal promoting peptide transmitter". The FEBS Journal. 272 (22): 5689–93. doi:10.1111/j.1742-4658.2005.04982.x. PMID 16279934. S2CID 42586325.
12. Okamura N, Reinscheid RK (Aug 2007). "Neuropeptide S: a novel modulator of stress and arousal". Stress. 10 (3): 221–6. doi:10.1080/10253890701248673. PMID 17613937. S2CID 39068808.
13. Leonard SK, Dwyer JM, Sukoff Rizzo SJ, Platt B, Logue SF, Neal SJ, Malberg JE, Beyer CE, Schechter LE, Rosenzweig-Lipson S, Ring RH (May 2008). "Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders". Psychopharmacology. 197 (4): 601–11. doi:10.1007/s00213-008-1080-4. PMID 18311561. S2CID 21120092.
14. Rizzi A, Vergura R, Marzola G, Ruzza C, Guerrini R, Salvadori S, Regoli D, Calo G (May 2008). "Neuropeptide S is a stimulatory anxiolytic agent: a behavioural study in mice". British Journal of Pharmacology. 154 (2): 471–9. doi:10.1038/bjp.2008.96. PMC 2442439. PMID 18376418.
15. Vitale G, Filaferro M, Ruggieri V, Pennella S, Frigeri C, Rizzi A, Guerrini R, Calò G (Dec 2008). "Anxiolytic-like effect of neuropeptide S in the rat defensive burying". Peptides. 29 (12): 2286–91. doi:10.1016/j.peptides.2008.08.014. hdl:11380/610466. PMID 18793688. S2CID 207356961.
16. Mochizuki T, Kim J, Sasaki K (May 2010). "Microinjection of neuropeptide S into the rat ventral tegmental area induces hyperactivity and increases extracellular levels of dopamine metabolites in the nucleus accumbens shell". Peptides. 31 (5): 926–31. doi:10.1016/j.peptides.2010.02.006. PMID 20156501. S2CID 19981059.
17. Wan Saudi WS, Halim MA, Rudholm-Feldreich T, Gillberg L, Rosenqvist E, Tengholm A, Sundbom M, Karlbom U, Näslund E, Webb DL, Sjöblom M, Hellström PM (Oct 2015). "Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide". Am J Physiol Gastrointest Liver Physiol. 309 (9): G625-34. doi:10.1152/ajpgi.00104.2015. PMID 26206857. S2CID 5560949.
18. Okamura N, Habay SA, Zeng J, Chamberlin AR, Reinscheid RK (Jun 2008). "Synthesis and pharmacological in vitro and in vivo profile of 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68), a selective antagonist of the neuropeptide S receptor". The Journal of Pharmacology and Experimental Therapeutics. 325 (3): 893–901. doi:10.1124/jpet.107.135103. PMC 2583099. PMID 18337476.
19. Roth AL, 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 (Jul 2006). "Structure-activity studies on neuropeptide S: identification of the amino acid residues crucial for receptor activation" (PDF). The Journal of Biological Chemistry. 281 (30): 20809–16. doi:10.1074/jbc.M601846200. PMID 16720571.
20. Camarda V, Trapella C, Calo G, Guerrini R, Rizzi A, Ruzza C, Fiorini S, Marzola E, Reinscheid RK, Regoli D, Salvadori S (Feb 2008). "Synthesis and biological activity of human neuropeptide S analogues modified in position 2". Journal of Medicinal Chemistry. 51 (3): 655–8. doi:10.1021/jm701204n. PMID 18181564.
21. Camarda V, Trapella C, Calo' G, Guerrini R, Rizzi A, Ruzza C, Fiorini S, Marzola E, Reinscheid RK, Regoli D, Salvadori S (Oct 2008). "Structure-activity study at positions 3 and 4 of human neuropeptide S". Bioorganic & Medicinal Chemistry. 16 (19): 8841–5. doi:10.1016/j.bmc.2008.08.073. PMID 18793857.
22. Guerrini R, Camarda V, Trapella C, Calò G, Rizzi A, Ruzza C, Fiorini S, Marzola E, Reinscheid RK, Regoli D, Salvadori S (Jan 2009). "Synthesis and biological activity of human neuropeptide S analogues modified in position 5: identification of potent and pure neuropeptide S receptor antagonists". Journal of Medicinal Chemistry. 52 (2): 524–9. doi:10.1021/jm8012294. PMC 2653091. PMID 19113861.
23. Camarda V, Rizzi A, Ruzza C, Zucchini S, Marzola G, Marzola E, Guerrini R, Salvadori S, Reinscheid RK, Regoli D, Calò G (Feb 2009). "In vitro and in vivo pharmacological characterization of the neuropeptide s receptor antagonist [D-Cys(tBu)5]neuropeptide S". The Journal of Pharmacology and Experimental Therapeutics. 328 (2): 549–55. doi:10.1124/jpet.108.143867. PMC 2630366. PMID 18971372.