General

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].

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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]

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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]

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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]

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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]

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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]

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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]

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