The neuropeptide S receptor (NPS, provisional nomenclature [4]) responds to the 20 amino-acid peptide neuropeptide S derived from a precursor (NPS, P0C0P6).

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 (Asn¹⁰⁷Ile). The human NPS receptor Asn¹⁰⁷Ile displayed similar binding affinity but higher NPS potency (by approx. 10-fold) than human NPS receptor Asn107 [12]. Several epidemiological studies reported an association between Asn¹⁰⁷Ile receptor variant and susceptibility to panic disorders [2-3,10-11]. The SNP Asn¹⁰⁷Ile has also been linked to sleep behavior [5], inflammatory bowel disease [1], schizophrenia [9], increased impulsivity and ADHD symptoms [7]. Interestingly, a carboxy-terminal splice variant of human NPS receptor was found to be overexpressed in asthmatic patients [8].

* 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: 279-288. [PMID:15914470]

* 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]

* 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. (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron, 43: 487-497. [PMID:15312648]

1. 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]

2. 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]

3. 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]

4. 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: 279-288. [PMID:15914470]

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. 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. U.S.A., 101: 1508-1513. [PMID:14757815]

7. 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]

8. Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P, Makela S, Rehn M, Pirskanen A, Rautanen A, Zucchelli M, Gullsten H, Leino M, Alenius H, Petays T, Haahtela T, Laitinen A, Laprise C, Hudson TJ, Laitinen LA, Kere J. (2004) Characterization of a common susceptibility locus for asthma-related traits. Science, 304: 300-304. [PMID:15073379]

9. 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]

10. 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]

11. 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]

12. 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: 1338-1345. [PMID:16144971]

13. 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]

14. 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]

15. Thorsell A, Tapocik JD, Liu K, Zook M, Bell L, Flanigan M, Patnaik S, Marugan J, Damadzic R, Dehdashti SJ et al.. (2013) A novel brain penetrant NPS receptor antagonist, NCGC00185684, blocks alcohol-induced ERK-phosphorylation in the central amygdala and decreases operant alcohol self-administration in rats. J. Neurosci., 33 (24): 10132-42. [PMID:23761908]

16. 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]

17. 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. (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron, 43: 487-497. [PMID:15312648]

18. Zhang Y, Gilmour BP, Navarro HA, Runyon SP. (2008) Identifying structural features on 1,1-diphenyl-hexahydro-oxazolo[3,4-a]pyrazin-3-ones critical for Neuropeptide S antagonist activity. Bioorg. Med. Chem. Lett., 18 (14): 4064-7. [PMID:18555684]

Subcommittee members: Girolamo Caló (Chairperson) Section of Pharmacology Department of Medical Sciences University of Ferrara via Fossato di Mortara 19 44121 Ferrara Italy Chiara Ruzza, PhD Section of Pharmacology Department of Medical Sciences University of Ferrara via Fossato di Mortara 19 44121 Ferrara Italy

Other contributors: Olivier Civelli University of California at Irvine Department of Pharmacology Medical Surgery II 369 Med Surge II Irvine CA 92697-4625 USA Rainer K. Reinscheid (Past chairperson) Department of Pharmacology University of California at Irvine CA 92697-4625 USA