Neuropeptide S Explained

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.[1] [2] [3] NPS binds specifically to a G protein-coupled receptor, NPSR.[4] [5] Animal studies show that NPS suppresses anxiety and appetite, induces wakefulness[6] and hyperactivity, including hyper-sexuality, and plays a significant role in the extinction of conditioned fear.[7] [8] [9] [10] [11] [12] [13] It has also been shown to significantly enhance dopamine activity in the mesolimbic pathway, and inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans.[14]

Synthetic ligands

The non-peptide NPS receptor antagonist SHA-68 blocks the effects of NPS in animals and is anxiogenic.[15] Several peptide derived NPS agonists and antagonists have also been developed.[16] [17] [18] [19] [20]

Peptide sequence

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

Symbol:Neuropeptide_S
Neuropeptide S
Pfam:PF14993
Interpro:IPR028138
speciessequenceMW
humanSFRNGVGTGMKKTSFQRAKS2187.5
ratSFRNGVGSGVKKTSFRRAKQ2210.5
mouseSFRNGVGSGAKKTSFRRAKQ2182.5
dog, chimpSFRNGVGTGMKKTSFRRAKS2215.6
chickenSFRNGVGSGIKKTSFRRAKS2183.5
consensusSFRNGVGxGXKKTSFxRAKxN/A
According to Pfam's HMM logo, there is a conserved "KR" cleave site immediately N-terminal to the C-terminal mature peptide.

Notes and References

  1. Xu YL, Gall CM, Jackson VR, Civelli O, Reinscheid RK . 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 . Jan 2007 . 17099900 . 10.1002/cne.21159 . 23864785 .
  2. Jüngling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu YL, Reinscheid RK, Pape HC . Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala . Neuron . 59 . 2 . 298–310 . Jul 2008 . 18667157 . 2610688 . 10.1016/j.neuron.2008.07.002 .
  3. Meis S, Bergado-Acosta JR, Yanagawa Y, Obata K, Stork O, Munsch T . Identification of a neuropeptide S responsive circuitry shaping amygdala activity via the endopiriform nucleus . PLOS ONE . 3 . 7 . e2695 . 2008 . 18628994 . 2442874 . 10.1371/journal.pone.0002695 . 2008PLoSO...3.2695M . Grothe B . free .
  4. Reinscheid RK, Xu YL . Neuropeptide S and its receptor: a newly deorphanized G protein-coupled receptor system . The Neuroscientist . 11 . 6 . 532–8 . Dec 2005 . 16282594 . 10.1177/1073858405276405 . 30579961 .
  5. Book: Reinscheid RK . Orphan G Protein-Coupled Receptors and Novel Neuropeptides . Neuropeptide S: Anatomy, Pharmacology, Genetics and Physiological Functions . Results and Problems in Cell Differentiation . 46 . 145–58 . 2008 . 18204825 . 10.1007/400_2007_051 . 978-3-540-78350-3 .
  6. Chauveau F, Claverie D, Lardant E, Varin C, Hardy E, Walter A, Canini F, Rouach N, Rancillac A . Neuropeptide S promotes wakefulness through the inhibition of sleep-promoting ventrolateral preoptic nucleus neurons . Sleep . 43 . 1 . January 2020 . 31403694 . 10.1093/sleep/zsz189 .
  7. 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 . Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects . Neuron . 43 . 4 . 487–97 . Aug 2004 . 15312648 . 10.1016/j.neuron.2004.08.005 . 15601843 . free .
  8. Reinscheid RK, Xu YL . Neuropeptide S as a novel arousal promoting peptide transmitter . The FEBS Journal . 272 . 22 . 5689–93 . Nov 2005 . 16279934 . 10.1111/j.1742-4658.2005.04982.x . 42586325 . free .
  9. Okamura N, Reinscheid RK . Neuropeptide S: a novel modulator of stress and arousal . Stress . 10 . 3 . 221–6 . Aug 2007 . 17613937 . 10.1080/10253890701248673 . 39068808 .
  10. Leonard SK, Dwyer JM, Sukoff Rizzo SJ, Platt B, Logue SF, Neal SJ, Malberg JE, Beyer CE, Schechter LE, Rosenzweig-Lipson S, Ring RH . John Dwyer (medicine) . Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders . Psychopharmacology . 197 . 4 . 601–11 . May 2008 . 18311561 . 10.1007/s00213-008-1080-4 . 21120092 .
  11. Rizzi A, Vergura R, Marzola G, Ruzza C, Guerrini R, Salvadori S, Regoli D, Calo G . Neuropeptide S is a stimulatory anxiolytic agent: a behavioural study in mice . British Journal of Pharmacology . 154 . 2 . 471–9 . May 2008 . 18376418 . 2442439 . 10.1038/bjp.2008.96 .
  12. Vitale G, Filaferro M, Ruggieri V, Pennella S, Frigeri C, Rizzi A, Guerrini R, Calò G . Anxiolytic-like effect of neuropeptide S in the rat defensive burying . Peptides . 29 . 12 . 2286–91 . Dec 2008 . 18793688 . 10.1016/j.peptides.2008.08.014 . 11380/610466 . 207356961 . free .
  13. Mochizuki T, Kim J, Sasaki K . 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 . May 2010 . 20156501 . 10.1016/j.peptides.2010.02.006 . 19981059 .
  14. 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 . Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide . Am J Physiol Gastrointest Liver Physiol . 309 . 9 . G625-34 . Oct 2015 . 26206857 . 10.1152/ajpgi.00104.2015 . 5560949 . free .
  15. Okamura N, Habay SA, Zeng J, Chamberlin AR, Reinscheid RK . 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 . Jun 2008 . 18337476 . 2583099 . 10.1124/jpet.107.135103 .
  16. 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 . Structure-activity studies on neuropeptide S: identification of the amino acid residues crucial for receptor activation . The Journal of Biological Chemistry . 281 . 30 . 20809–16 . Jul 2006 . 16720571 . 10.1074/jbc.M601846200 . free .
  17. Camarda V, Trapella C, Calo G, Guerrini R, Rizzi A, Ruzza C, Fiorini S, Marzola E, Reinscheid RK, Regoli D, Salvadori S . Synthesis and biological activity of human neuropeptide S analogues modified in position 2 . Journal of Medicinal Chemistry . 51 . 3 . 655–8 . Feb 2008 . 18181564 . 10.1021/jm701204n .
  18. Camarda V, Trapella C, Calo' G, Guerrini R, Rizzi A, Ruzza C, Fiorini S, Marzola E, Reinscheid RK, Regoli D, Salvadori S . Structure-activity study at positions 3 and 4 of human neuropeptide S . Bioorganic & Medicinal Chemistry . 16 . 19 . 8841–5 . Oct 2008 . 18793857 . 10.1016/j.bmc.2008.08.073 .
  19. Guerrini R, Camarda V, Trapella C, Calò G, Rizzi A, Ruzza C, Fiorini S, Marzola E, Reinscheid RK, Regoli D, Salvadori S . 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 . Jan 2009 . 19113861 . 2653091 . 10.1021/jm8012294 .
  20. Camarda V, Rizzi A, Ruzza C, Zucchini S, Marzola G, Marzola E, Guerrini R, Salvadori S, Reinscheid RK, Regoli D, Calò G . 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 . Feb 2009 . 18971372 . 2630366 . 10.1124/jpet.108.143867 .

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