The neuropeptide S receptor (NPS receptor) responds to the 20 amino-acid peptide neuropeptide S derived from a precursor (NPS, P0C0P6). NPS activates its receptor at low nanomolar concentrations elevating intracellular cAMP and calcium levels [14]. Currently, some peptidic and small molecule NPS receptor antagonists are available as research tools [1,6,11,15]. No NPS receptor ligands are currently used clinically.

Multiple single-nucleotide polymorphisms (SNP) and several splice variants have been identified in the human NPS receptor. The most interesting of these is an Asn-Ile exchange at position 107 (Ile107Asn, rs324981). The human NPS receptor Ile107Asn displayed similar binding affinity but higher NPS potency (by approx. 10-fold) than human NPS receptor Asn107 [14]. Several epidemiological studies reported an association between the Ile107Asn receptor variant and susceptibility to panic disorders [3-4,12-13]. The SNP Ile107Asn (rs324981) has also been linked to sleep behavior [5], inflammatory bowel disease [2], schizophrenia [10], increased impulsivity and ADHD symptoms [8]. Interestingly, a carboxy-terminal splice variant of human NPS receptor was found to be overexpressed in asthmatic patients [9]. Additionally, the gain-of-function variant Tyr206His has been described in a single family where it appears to dramatically reduce total sleep time [19].

* Key recommended reading is highlighted with an asterisk

Cannella N, Kallupi M, Ruggeri B, Ciccocioppo R, Ubaldi M. (2013) The role of the neuropeptide S system in addiction: focus on its interaction with the CRF and hypocretin/orexin neurotransmission. Prog Neurobiol, 100: 48-59. [PMID:23041581]

Dal Ben D, Antonini I, Buccioni M, Lambertucci C, Marucci G, Thomas A, Volpini R, Cristalli G. (2011) Neuropeptide S receptor: recent updates on nonpeptide antagonist discovery. ChemMedChem, 6 (7): 1163-71. [PMID:21452188]

Dal Ben D, Antonini I, Buccioni M, Lambertucci C, Marucci G, Vittori S, Volpini R, Cristalli G. (2010) Molecular modeling studies on the human neuropeptide S receptor and its antagonists. ChemMedChem, 5 (3): 371-83. [PMID:20087922]

Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

Grund T, Neumann ID. (2019) Brain neuropeptide S: via GPCR activation to a powerful neuromodulator of socio-emotional behaviors. Cell Tissue Res, 375 (1): 123-132. [PMID:30112573]

* Guerrini R, Salvadori S, Rizzi A, Regoli D, Calo' G. (2010) Neurobiology, pharmacology, and medicinal chemistry of neuropeptide S and its receptor. Med Res Rev, 30 (5): 751-77. [PMID:19824051]

Pape HC, Jüngling K, Seidenbecher T, Lesting J, Reinscheid RK. (2010) Neuropeptide S: a transmitter system in the brain regulating fear and anxiety. Neuropharmacology, 58 (1): 29-34. [PMID:19523478]

Reinscheid RK. (2008) Neuropeptide S: anatomy, pharmacology, genetics and physiological functions. Results Probl Cell Differ, 46: 145-58. [PMID:18204825]

* Reinscheid RK, Ruzza C. (2021) Pharmacology, Physiology and Genetics of the Neuropeptide S System. Pharmaceuticals (Basel), 14 (5). [PMID:33922620]

* Reinscheid RK, Xu YL, Okamura N, Zeng J, Chung S, Pai R, Wang Z, Civelli O. (2005) Pharmacological characterization of human and murine neuropeptide s receptor variants. J Pharmacol Exp Ther, 315 (3): 1338-45. [PMID:16144971]

* Ruzza C, Asth L, Guerrini R, Trapella C, Gavioli EC. (2015) Neuropeptide S reduces mouse aggressiveness in the resident/intruder test through selective activation of the neuropeptide S receptor. Neuropharmacology, 97: 1-6. [PMID:25979487]

* Ruzza C, Calò G, Di Maro S, Pacifico S, Trapella C, Salvadori S, Preti D, Guerrini R. (2017) Neuropeptide S receptor ligands: a patent review (2005-2016). Expert Opin Ther Pat, 27 (3): 347-362. [PMID:27788040]

* Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher FA, Zeng J, Ly NK, Henriksen SJ et al.. (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron, 43 (4): 487-97. [PMID:15312648]

1. Camarda V, Rizzi A, Ruzza C, Zucchini S, Marzola G, Marzola E, Guerrini R, Salvadori S, Reinscheid RK, Regoli D et al.. (2009) In vitro and in vivo pharmacological characterization of the neuropeptide s receptor antagonist [D-Cys(tBu)5]neuropeptide S. J Pharmacol Exp Ther, 328 (2): 549-55. [PMID:18971372]

2. D'Amato M, Bruce S, Bresso F, Zucchelli M, Ezer S, Pulkkinen V, Lindgren C, Astegiano M, Rizzetto M, Gionchetti P et al.. (2007) Neuropeptide s receptor 1 gene polymorphism is associated with susceptibility to inflammatory bowel disease. Gastroenterology, 133 (3): 808-17. [PMID:17854592]

3. Domschke K, Reif A, Weber H, Richter J, Hohoff C, Ohrmann P, Pedersen A, Bauer J, Suslow T, Kugel H et al.. (2011) Neuropeptide S receptor gene -- converging evidence for a role in panic disorder. Mol Psychiatry, 16 (9): 938-48. [PMID:20603625]

4. Donner J, Haapakoski R, Ezer S, Melén E, Pirkola S, Gratacòs M, Zucchelli M, Anedda F, Johansson LE, Söderhäll C et al.. (2010) Assessment of the neuropeptide S system in anxiety disorders. Biol Psychiatry, 68 (5): 474-83. [PMID:20705147]

5. Gottlieb DJ, O'Connor GT, Wilk JB. (2007) Genome-wide association of sleep and circadian phenotypes. BMC Med Genet, 8 Suppl 1: S9. [PMID:17903308]

6. Guerrini R, Camarda V, Trapella C, Caló G, Rizzi A, Ruzza C, Fiorini S, Marzola E, Reinscheid RK, Regoli D et al.. (2009) Further studies at neuropeptide s position 5: discovery of novel neuropeptide S receptor antagonists. J Med Chem, 52 (13): 4068-71. [PMID:19473027]

7. Gupte J, Cutler G, Chen JL, Tian H. (2004) Elucidation of signaling properties of vasopressin receptor-related receptor 1 by using the chimeric receptor approach. Proc Natl Acad Sci USA, 101: 1508-1513. [PMID:14757815]

8. Laas K, Reif A, Kiive E, Domschke K, Lesch KP, Veidebaum T, Harro J. (2014) A functional NPSR1 gene variant and environment shape personality and impulsive action: a longitudinal study. J Psychopharmacol (Oxford), 28 (3): 227-36. [PMID:23325374]

9. Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P, Mäkelä S, Rehn M, Pirskanen A, Rautanen A et al.. (2004) Characterization of a common susceptibility locus for asthma-related traits. Science, 304 (5668): 300-4. [PMID:15073379]

10. Lennertz L, Quednow BB, Schuhmacher A, Petrovsky N, Frommann I, Schulze-Rauschenbach S, Landsberg MW, Steinbrecher A, Höfels S, Pukrop R et al.. (2012) The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response. Int J Neuropsychopharmacol, 15 (9): 1205-15. [PMID:22078257]

11. Okamura N, Habay SA, Zeng J, Chamberlin AR, Reinscheid RK. (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. J Pharmacol Exp Ther, 325 (3): 893-901. [PMID:18337476]

12. Okamura N, Hashimoto K, Iyo M, Shimizu E, Dempfle A, Friedel S, Reinscheid RK. (2007) Gender-specific association of a functional coding polymorphism in the Neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry, 31 (7): 1444-8. [PMID:17669576]

13. Raczka KA, Gartmann N, Mechias ML, Reif A, Büchel C, Deckert J, Kalisch R. (2010) A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing. Mol Psychiatry, 15 (11): 1045, 1067-74. [PMID:20628342]

14. Reinscheid RK, Xu YL, Okamura N, Zeng J, Chung S, Pai R, Wang Z, Civelli O. (2005) Pharmacological characterization of human and murine neuropeptide s receptor variants. J Pharmacol Exp Ther, 315 (3): 1338-45. [PMID:16144971]

15. Ruzza C, Rizzi A, Camarda V, Pulga A, Marzola G, Filaferro M, Novi C, Ruggieri V, Marzola E, Vitale G et al.. (2012) [tBu-D-Gly5]NPS, a pure and potent antagonist of the neuropeptide S receptor: in vitro and in vivo studies. Peptides, 34 (2): 404-11. [PMID:22342393]

16. Ruzza C, Rizzi A, Malfacini D, Pulga A, Pacifico S, Salvadori S, Trapella C, Reinscheid RK, Calo G, Guerrini R. (2015) In vitro and in vivo pharmacological characterization of a neuropeptide S tetrabranched derivative. Pharmacol Res Perspect, 3 (1): e00108. [PMID:25692025]

17. Ruzza C, Rizzi A, Trapella C, Pela' M, Camarda V, Ruggieri V, Filaferro M, Cifani C, Reinscheid RK, Vitale G et al.. (2010) Further studies on the pharmacological profile of the neuropeptide S receptor antagonist SHA 68. Peptides, 31 (5): 915-25. [PMID:20172007]

18. Vendelin J, Pulkkinen V, Rehn M, Pirskanen A, Räisänen-Sokolowski A, Laitinen A, Laitinen LA, Kere J, Laitinen T. (2005) Characterization of GPRA, a novel G protein-coupled receptor related to asthma. Am J Respir Cell Mol Biol, 33 (3): 262-70. [PMID:15947423]

19. Xing L, Shi G, Mostovoy Y, Gentry NW, Fan Z, McMahon TB, Kwok PY, Jones CR, Ptáček LJ, Fu YH. (2019) Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation. Sci Transl Med, 11 (514). [PMID:31619542]

20. Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher FA, Zeng J, Ly NK, Henriksen SJ et al.. (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron, 43 (4): 487-97. [PMID:15312648]

Subcommittee members: Girolamo Caló (Chairperson) Section of Pharmacology Department of Pharmaceutical and Pharmacological Sciences University of Padova Largo Meneghetti, 2 35131 Padova Italy Rainer K. Reinscheid Institute of Pharmacology and Toxicology University Hospital Jena D-07747 Jena Germany Chiara Ruzza, PhD Section of Pharmacology Department of Biomedical and Specialty Surgical Sciences University of Ferrara 44121 Ferrara Italy

Other contributors: Olivier Civelli School of Pharmaceutical Sciences and Pharmacy University of California, Irvine Department of Pharmacology Irvine, CA 92697-4625 USA