Neuropeptide S receptor: Introduction


Neuropeptide S (NPS) was named for its amino-terminal serine residue that is conserved across all species where NPS sequences have been found at the genomic level. NPS was isolated as a ligand of an orphan GPCR and first disclosed in a patent in 2002 [40]. Similar to other neuropeptides, NPS is encoded by a precursor protein that contains a pair of basic amino acid residues immediately preceding the immature peptide which will likely serve as processing sites for proteolytic cleavage. The NPS precursor is divided into at least three exons and is located on human Chr. 10. The NPS peptide is located at the carboxy-terminal end of the protein. Thus far, DNA sequences encoding NPS have been found in a number of vertebrate species with the exception of fish [36]. A comparison of the amino acid sequences of NPS has revealed that the peptide has been well conserved throughout evolution. This degree of conservation is indicative of the importance of the amino-terminal sequence for biological activity (Fig. 1). Structure-activity studies at the NPS sequence identified the N-terminus of NPS as the bioactive core of the molecule, with the sequence Phe2-Arg3-Asn4 acting as message domain, crucial for receptor binding and activation, and the sequence Gly5-Val6-Gly7 shaping the bioactive conformation of the peptide [12].

NPS precursor is expressed mainly in the brain [44]. In mouse and rat NPS precursor mRNA is highly expressed in a cluster of cells located between the locus coeruleus and Barrington's nucleus in the pontine brain stem [5,43]. In rat NPS precursor expression was also found in the lateral parabrachial nucleus, the principle 5 nucleus of the brainstem and in a few scattered neurons in the amygdala and hypothalamus [43]. In mouse NPS precursor mRNA is also expressed in the Kölliker-Fuse nucleus [5]. In human, the majority of NPS mRNA positive neurons are located in the parabrachial area, in particular in the extension of the medial and lateral parabrachial nuclei, in the Kölliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, only very few NPS positive cells were found close to the locus coeruleus [1]. NPS appears to be colocalized with other excitatory neurotransmitters. In the pericoerulear region, NPS-synthesizing cells were found to coexpress vesicular glutamate transporters and are thus glutamatergic neurons [43]. A few cells in this region might be cholinergic neurons. NPS-expressing cells in the lateral parabrachial nucleus also express corticotropine-releasing factor while all NPS-expressing cells in the principle 5 nucleus are glutamatergic. In the Kölliker-Fuse nucleus NPS is co-expressed with galanin [26]. Overall, the expression of NPS precursor is rather restricted in the brain. Peripheral sites expressing NPS precursor include mostly endocrine tissues such as thyroid, mammary gland, salivary gland and testis.

NPS was found to promote arousal in mice and is able to suppress all stages of sleep in rats [44]. Nanomolar doses of NPS administered centrally induce hyperlocomotion [4,38,44]. In addition, NPS appears to produce anxiolytic- and panicolytic like behavior in rodents [23,27,34,38,42,44]. This pharmacological spectrum is quite unique since classical psychostimulants either increase anxiety-like behavior or do not affect emotionality. On the other hand, typical anxiolytics normally reduce locomotion and cause sedation. Central administration of NPS was reported to facilitate the extinction of fear [17], suppress feeding [10,32,41], modulate HPA axis activity [41], facilitate memory [15,29], reduce pain transmission [25,33], inhibit colonic transit [14], increase alcohol and cocaine seeking [3,18,31], and reduce aggressiveness [2,39]. Interestingly, the anxiolytic and analgesic effects of NPS are reported also after intranasal administration of the peptide [7,16,27-28].

   Figure 1 The amino acid sequence of neuropeptide S
   Amino acids which differ between species are shown in red.

NPS receptor

The NPS receptor is a typical GPCR, also known as GPR154, vasopressin-receptor related receptor 1 (VRR1) [13], or GPRA [21]. The receptor gene contains at least 9 exons and is located on human Chr 7p14. NPS receptor was found mainly expressed in the central nervous system of rats by using in-situ hybridization [43-44] and and immunohistochemistry [24]. NPS receptor mRNA is widely distributed in many brain areas with high expression levels in cortex, hypothalamus, amygdala and multiple midline thalamic nuclei. Many of these areas have been functionally associated with arousal and processing of emotional behavior. In the human pons NPSR mRNA-expressing neurons are located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray [1].

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 AsnIle107 displayed similar binding affinity but higher NPS potency (by approx. 10-fold) than human NPS receptor Asn107 [37]. Several epidemiological studies reported an association between Asn107Ile receptor variant and susceptibility to panic disorders [8-9,30,35]. The SNP Asn107Ile has also been linked to sleep behavior [11], inflammatory bowel disease [6], schizophrenia [22], increased impulsivity and ADHD symptoms [19-20]. Interestingly, a carboxy-terminal splice variant of human NPS receptor was found to be over-expressed in asthmatic patients [21].


Show »

1. Adori C, Barde S, Bogdanovic N, Uhlén M, Reinscheid RR, Kovacs GG, Hökfelt T. (2015) Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons. Front Neuroanat, 9: 126. [PMID:26441556]

2. Beiderbeck DI, Lukas M, Neumann ID. (2014) Anti-aggressive effects of neuropeptide S independent of anxiolysis in male rats. Front Behav Neurosci, 8: 185. [PMID:24910598]

3. Cannella N, Economidou D, Kallupi M, Stopponi S, Heilig M, Massi M, Ciccocioppo R. (2009) Persistent increase of alcohol-seeking evoked by neuropeptide S: an effect mediated by the hypothalamic hypocretin system. Neuropsychopharmacology, 34 (9): 2125-34. [PMID:19322167]

4. Castro AA, Moretti M, Casagrande TS, Martinello C, Petronilho F, Steckert AV, Guerrini R, Calo' G, Dal Pizzol F, Quevedo J et al.. (2009) Neuropeptide S produces hyperlocomotion and prevents oxidative stress damage in the mouse brain: a comparative study with amphetamine and diazepam. Pharmacol Biochem Behav, 91 (4): 636-42. [PMID:19022279]

5. Clark SD, Duangdao DM, Schulz S, Zhang L, Liu X, Xu YL, Reinscheid RK. (2011) Anatomical characterization of the neuropeptide S system in the mouse brain by in situ hybridization and immunohistochemistry. J Comp Neurol, 519 (10): 1867-93. [PMID:21452235]

6. 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]

7. Dine J, Ionescu IA, Avrabos C, Yen YC, Holsboer F, Landgraf R, Schmidt U, Eder M. (2015) Intranasally applied neuropeptide S shifts a high-anxiety electrophysiological endophenotype in the ventral hippocampus towards a "normal"-anxiety one. PLoS ONE, 10 (4): e0120272. [PMID:25830625]

8. 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]

9. 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]

10. Fedeli A, Braconi S, Economidou D, Cannella N, Kallupi M, Guerrini R, Calò G, Cifani C, Massi M, Ciccocioppo R. (2009) The paraventricular nucleus of the hypothalamus is a neuroanatomical substrate for the inhibition of palatable food intake by neuropeptide S. Eur J Neurosci, 30 (8): 1594-602. [PMID:19821837]

11. 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]

12. 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]

13. 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]

14. Han RW, Chang M, Peng YL, Qiao LY, Yin XQ, Li W, Wang R. (2009) Central Neuropeptide S inhibits distal colonic transit through activation of central Neuropeptide S receptor in mice. Peptides, 30 (7): 1313-7. [PMID:19540430]

15. Han RW, Yin XQ, Chang M, Peng YL, Li W, Wang R. (2009) Neuropeptide S facilitates spatial memory and mitigates spatial memory impairment induced by N-methyl-D-aspartate receptor antagonist in mice. Neurosci Lett, 455 (1): 74-7. [PMID:19429110]

16. Ionescu IA, Dine J, Yen YC, Buell DR, Herrmann L, Holsboer F, Eder M, Landgraf R, Schmidt U. (2012) Intranasally administered neuropeptide S (NPS) exerts anxiolytic effects following internalization into NPS receptor-expressing neurons. Neuropsychopharmacology, 37 (6): 1323-37. [PMID:22278093]

17. Jüngling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu YL, Reinscheid RK et al.. (2008) Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala. Neuron, 59 (2): 298-310. [PMID:18667157]

18. Kallupi M, Cannella N, Economidou D, Ubaldi M, Ruggeri B, Weiss F, Massi M, Marugan J, Heilig M, Bonnavion P et al.. (2010) Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system. Proc Natl Acad Sci USA, 107 (45): 19567-72. [PMID:20974945]

19. Laas K, Eensoo D, Paaver M, Lesch KP, Reif A, Harro J. (2015) Further evidence for the association of the NPSR1 gene A/T polymorphism (Asn107Ile) with impulsivity and hyperactivity. J Psychopharmacol (Oxford), 29 (8): 878-83. [PMID:25744621]

20. 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]

21. 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]

22. 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]

23. Leonard SK, Dwyer JM, Sukoff Rizzo SJ, Platt B, Logue SF, Neal SJ, Malberg JE, Beyer CE, Schechter LE, Rosenzweig-Lipson S et al.. (2008) Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders. Psychopharmacology (Berl.), 197 (4): 601-11. [PMID:18311561]

24. Leonard SK, Ring RH. (2011) Immunohistochemical localization of the neuropeptide S receptor in the rat central nervous system. Neuroscience, 172: 153-63. [PMID:20950671]

25. Li W, Chang M, Peng YL, Gao YH, Zhang JN, Han RW, Wang R. (2009) Neuropeptide S produces antinociceptive effects at the supraspinal level in mice. Regul Pept, 156 (1-3): 90-5. [PMID:19345242]

26. Liu X, Zeng J, Zhou A, Theodorsson E, Fahrenkrug J, Reinscheid RK. (2011) Molecular fingerprint of neuropeptide S-producing neurons in the mouse brain. J Comp Neurol, 519 (10): 1847-66. [PMID:21452230]

27. Lukas M, Neumann ID. (2012) Nasal application of neuropeptide S reduces anxiety and prolongs memory in rats: social versus non-social effects. Neuropharmacology, 62 (1): 398-405. [PMID:21871467]

28. Medina G, Ji G, Grégoire S, Neugebauer V. (2014) Nasal application of neuropeptide S inhibits arthritis pain-related behaviors through an action in the amygdala. Mol Pain, 10: 32. [PMID:24884567]

29. Okamura N, Garau C, Duangdao DM, Clark SD, Jüngling K, Pape HC, Reinscheid RK. (2011) Neuropeptide S enhances memory during the consolidation phase and interacts with noradrenergic systems in the brain. Neuropsychopharmacology, 36 (4): 744-52. [PMID:21150909]

30. 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]

31. Pañeda C, Huitron-Resendiz S, Frago LM, Chowen JA, Picetti R, de Lecea L, Roberts AJ. (2009) Neuropeptide S reinstates cocaine-seeking behavior and increases locomotor activity through corticotropin-releasing factor receptor 1 in mice. J Neurosci, 29 (13): 4155-61. [PMID:19339610]

32. Peng YL, Han RW, Chang M, Zhang L, Zhang RS, Li W, Han YF, Wang R. (2010) Central Neuropeptide S inhibits food intake in mice through activation of Neuropeptide S receptor. Peptides, 31 (12): 2259-63. [PMID:20800637]

33. Peng YL, Zhang JN, Chang M, Li W, Han RW, Wang R. (2010) Effects of central neuropeptide S in the mouse formalin test. Peptides, 31 (10): 1878-83. [PMID:20603169]

34. Pulga A, Ruzza C, Rizzi A, Guerrini R, Calo G. (2012) Anxiolytic- and panicolytic-like effects of Neuropeptide S in the mouse elevated T-maze. Eur J Neurosci, 36 (11): 3531-7. [PMID:22928868]

35. 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]

36. Reinscheid RK. (2007) Phylogenetic appearance of neuropeptide S precursor proteins in tetrapods. Peptides, 28 (4): 830-7. [PMID:17293003]

37. 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]

38. Rizzi A, Vergura R, Marzola G, Ruzza C, Guerrini R, Salvadori S, Regoli D, Calo G. (2008) Neuropeptide S is a stimulatory anxiolytic agent: a behavioural study in mice. Br J Pharmacol, 154 (2): 471-9. [PMID:18376418]

39. 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]

40. Sato, Suli et al.. (2002) Novel G protein-coupled receptor protein and DNA thereof. Patent number: WO0231145. Assignee: Takeda. Priority date: 13/10/2000. Publication date: 01/01/2002.

41. Smith KL, Patterson M, Dhillo WS, Patel SR, Semjonous NM, Gardiner JV, Ghatei MA, Bloom SR. (2006) Neuropeptide S stimulates the hypothalamo-pituitary-adrenal axis and inhibits food intake. Endocrinology, 147 (7): 3510-8. [PMID:16574794]

42. Vitale G, Filaferro M, Ruggieri V, Pennella S, Frigeri C, Rizzi A, Guerrini R, Calò G. (2008) Anxiolytic-like effect of neuropeptide S in the rat defensive burying. Peptides, 29 (12): 2286-91. [PMID:18793688]

43. Xu YL, Gall CM, Jackson VR, Civelli O, Reinscheid RK. (2007) Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain. J Comp Neurol, 500 (1): 84-102. [PMID:17099900]

44. 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]

How to cite this page

To cite this family introduction, please use the following:

Database page citation (select format):