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Reinscheid, R.K. Neuropeptide S System. Encyclopedia. Available online: https://encyclopedia.pub/entry/9864 (accessed on 21 December 2025).
Reinscheid RK. Neuropeptide S System. Encyclopedia. Available at: https://encyclopedia.pub/entry/9864. Accessed December 21, 2025.
Reinscheid, Rainer K.. "Neuropeptide S System" Encyclopedia, https://encyclopedia.pub/entry/9864 (accessed December 21, 2025).
Reinscheid, R.K. (2021, May 19). Neuropeptide S System. In Encyclopedia. https://encyclopedia.pub/entry/9864
Reinscheid, Rainer K.. "Neuropeptide S System." Encyclopedia. Web. 19 May, 2021.
Neuropeptide S System
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This entry is adapted from the peer-reviewed paper 10.3390/ph14050401

The Neuropeptide S (NPS) system was discovered by a "reverse pharmacology" approach in search for the endogenous ligand of an orphan G protein-coupled receptor. Its peptide ligand and receptor are mainly found in the brain. Effects on anxiety and memory have been described for NPS, as well as genetic associations of the receptor gene with asthma and inflammatory diseases.

transmitter GPCR brainstem anxiety memory genetic variation

1. Introduction

Neuropeptide S (NPS) was discovered as a ligand of a previously orphan G protein-coupled receptor (GPCR) by using the “orphan receptor strategy”, also known as “reverse pharmacology” [1]. The receptor (previously known as GPR154 or GPRA) was stably expressed in cells that served as a bait to purify the endogenous ligand from brain extracts [2]. The ligand turned out to be a peptide of 20 amino acids that contains a perfectly conserved serine (single amino acid code “S”) at the N-terminus in all species analyzed, and was thus termed accordingly [3]. NPS is encoded as a single copy peptide by a rather small precursor protein (<90 amino acids) that occurs in the genome of all tetrapods but is absent from fish [4]. The seven N-terminal residues are identical in all tetrapods, as well as the overall 20 amino acid length, while the C-terminal half shows more variation (Figure 1).

Figure 1. Neuropeptide S (NPS) or NPS-like peptide sequences. Residues divergent from the human NPS sequence are highlighted in red. The C-terminal amide (NH2) in the Branchiostoma peptide is encoded by glycine in the precursor protein and therefore identical to the consensus.

A shortened peptide has been identified in a cephalochordate that contains the conserved amino terminal residues [5]. Together with the identification of a distantly-related GPCR from the same class of animals, this suggests a rather complex evolution of the NPS system in bilaterians, where teleost fish may have lost both genes [6].
NPSR1 is also a single-copy gene with moderate similarity to other peptide GPCRs, the closest being vasopressin 1A and oxytocin receptors. NPSR1 is found in the genomes of all tetrapods and no convincing orthologues have been identified in fish genomes [7].

2. General Pharmacology

NPSR1 couples via Gαs and Gαq to elevate intracellular cAMP and Ca2+, thus it is an excitatory GPCR [8]. Activation of mitogen-activated protein kinase (MAPK) pathways and opening of neuronal Ca2+ channels have also been described [8][9][10]. NPS activates its receptor at low nanomolar concentrations and structure-activity relationship (SAR) studies have confirmed the importance of the amino terminus for agonist activity, overlapping with the high evolutionary conservation of this part of the peptide structure [11][12][13]. Focused SAR studies performed on Gly5 lead to the identification of peptidergic NPSR1 antagonists, characterized by a D-amino acid with a short branched aliphatic side chain [14][15]. Some well-characterized NPSR1 antagonists identified in the frame of these studies are [D-Cys(t-Bu)5]NPS, [D-Val5]NPS, and [t-Bu-D-Gly5]NPS [15][16][17].
The prototype synthetic NPSR1 antagonist is SHA 68, belonging to the class of diphenyltetrahydro-1H-oxazolo [3,4-α]pyrazines [18] (Figure 2). SHA 68, and the closely related SHA 66, display nanomolar affinity for NPSR1 in vitro but only limited bioavailability in vivo, due to its high lipophilicity. Using the core structure of SHA 68, several refinements have been made to improve in vivo potency. It appears that slight increases in polarity can indeed cause an increased in vivo potency, albeit with a net loss in receptor affinity [19][20][21][22]. Additional high-throughput drug screening programs have yielded further structures with NPSR1 antagonistic profiles (Figure 2), although with lower in vitro and in vivo potency compared to SHA 68 [23][24][25]. None of these compounds has progressed beyond the preclinical stage yet.

Figure 2. Chemical structures of NPSR1 antagonists. Details about synthesis and pharmacological activities can be found in the original literature. SHA 68 [18], RTI-118 [26], PI1 [27], MLS001018695 [28], NCGC84 [23], QA1 [29], R06039-478 [30].

3. Physiological and Behavioral Effects of NPS

3.1. Modulation of Animal Behavior

In experimental animals, NPS was found to induce arousal and wakefulness [3][31], reduce fear and anxiety [3][31][32][33][34][35][36], promote learning and memory consolidation [37][38][39], accelerate fear extinction [40][41], attenuate pharmacologically-induced psychotic behaviors [42], stimulate release of stress hormones [43][44] and prefrontal dopamine [45], produce analgesia [46][47][48][49][50][51], attenuate food intake [43][52][53], counteract motor deficits in a model of Parkinson’s disease [54], and promote drug-seeking behaviors including relapse of drug seeking [55][56][57][58][59]. An overview about animal models, routes and location of drug administration, and behavioral paradigms can be found in the review by Ruzza et al. [25]. Importantly, NPS-dependent stimulation of, or relapse to, either alcohol or cocaine seeking behavior can be blocked by NPSR1 antagonists [59][26]. Hypothalamic NPSR1 appear to be critical for modulating drug seeking behaviors and may interact with orexin/hypocretin and corticotropin-releasing factor neurotransmission [55][60][61]. Notably, both central (intracerebroventricular) and intra-amygdala administration of NPS elicited acute anxiolytic-like effects [3][40], while intra-amygdala administration of SHA 68 produced increased anxiety-like behavior [40], suggesting endogenous NPS release upon stress exposure. It appears that NPS may have a unique bifurcated effect on anxiety: while acutely attenuating anxiety-like responses, it later appears to facilitate extinction of fear memories. This combination of activities could be desirable therapeutic effects in the treatment of generalized anxiety disorders, phobias, panic disorder, or post-traumatic stress disorder.
There is limited evidence for a role of NPS in mood regulation. In the high-anxiety Flinders rat model, NPS normalized anxiety-like behaviors without producing anti-depressant effects in the forced swim test [62]. However, localized NPS administrations into the nucleus accumbens (NAc) shell, but not the NAc core or the bed nucleus of the stria terminalis (BNST), were reported to induce anti-depressant effects in a learned helplessness model in rats [63]. Unexpectedly, infusions of the NPSR1 antagonist SHA 68 into the BNST, another important part of the extended amygdala network regulating mood and anxiety, also produced anti-depressant-like effects. However, knockout mouse models did not exhibit depression-like phenotypes. Further studies may be required to clarify possible functions of endogenous NPS in mood regulation.
Prominent phenotypes in knockout mouse models for NPSR1 and NPS include attenuated arousal, deficits in learning and memory including disrupted fear learning, and mildly increased anxiety [37][44][64][65][66]. While the anxiogenic and memory impairment phenotype of NPSR1 knockout mice has not been replicated in all laboratories [67], all studies showed that the stimulant, arousal-promoting, and anxiolytic effects of NPS completely disappeared in NPSR1 knockout animals, demonstrating that NPSR1 is the unique protein by which NPS exerts its biological actions [44][64][65][67].
No respiratory phenotypes were detected in NPSR1 knockout mice, including models of induced asthma [68]. However, central NPS administration can stimulate respiratory frequency in an NPSR1-dependent manner [69].

3.2. NPS and Immune Functions

A few in vitro studies have described effects of NPS on lymphocytes or macrophages [70][71][72]. In general, NPS was found to induce lymphocyte proliferation and promote macrophage phagocytosis. These effects were accompanied by upregulated expression of pro-inflammatory cytokines. Whether any immune-modulatory deficits exist in NPSR1 or NPS knockout mice has not yet been established. Increased expression of NPSR1 in eosinophils from patients with asthma or severe inflammation has been reported [73].

4. Concluding Remarks

An impressive number of physiological functions have been identified for the NPS system in the relatively short time since its discovery. Together with the plethora of genetic association data for NPSR1 variants with human disease and behaviors, increased efforts to identify therapeutic applications for this interesting transmitter system appear to be promising and warranted. The articles in this Special Issue reflect the continuing progress in our knowledge about the NPS system and its therapeutic potential.

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