NPS

Summary

NPS (neuropeptide S, HGNC:33940) is a protein-coding gene on chromosome 10q26.2, encoding Neuropeptide S (P0C0P6). Ligand for NPSR1.

Predicted to be involved in positive regulation of GABAergic synaptic transmission; positive regulation of action potential; and positive regulation of glutamatergic synaptic transmission. Predicted to act upstream of or within visual learning. Predicted to be located in extracellular region.

Source: NCBI Gene 594857 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 8 total
• Druggable target: yes
• MANE Select transcript: NM_001030013

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33940
Approved symbol	NPS
Name	neuropeptide S
Location	10q26.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000214285
Ensembl biotype	protein_coding
OMIM	609513
Entrez	594857

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000398023

RefSeq mRNA: 1 — MANE Select: NM_001030013 NM_001030013

CCDS: CCDS41577

Canonical transcript exons

ENST00000398023 — 3 exons

Exon	Start	End
ENSE00001531214	127552460	127553540
ENSE00001531215	127549489	127549570
ENSE00001531216	127549309	127549376

Expression profiles

Bgee: expression breadth broad, 11 present calls, max score 80.23.

Top tissues by expression

129 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.23	gold quality
bone marrow cell	CL:0002092	38.46	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
granulocyte	CL:0000094	36.75	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
islet of Langerhans	UBERON:0000006	33.51	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
bone marrow	UBERON:0002371	32.92	gold quality
muscle tissue	UBERON:0002385	32.21	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
prefrontal cortex	UBERON:0000451	30.27	silver quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
leukocyte	CL:0000738	29.30	gold quality
monocyte	CL:0000576	28.85	gold quality
liver	UBERON:0002107	28.64	gold quality
substantia nigra	UBERON:0002038	28.37	gold quality
duodenum	UBERON:0002114	28.14	gold quality
urinary bladder	UBERON:0001255	27.80	gold quality
lymph node	UBERON:0000029	27.57	gold quality
superior frontal gyrus	UBERON:0002661	27.13	gold quality
tonsil	UBERON:0002372	27.05	gold quality
pancreas	UBERON:0001264	26.94	gold quality
vermiform appendix	UBERON:0001154	26.42	gold quality
uterine cervix	UBERON:0000002	26.27	gold quality
blood	UBERON:0000178	26.04	gold quality
hypothalamus	UBERON:0001898	26.03	gold quality
gall bladder	UBERON:0002110	25.98	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 14)

• NPS has a novel role in the stimulation of the hypothalamo-pituitary-adrenal axis (PMID:16574794)
• the C-terminal region of neuropeptide S maintains importance for in vivo activity (PMID:16720571)
• the key residues of NPS involved in NPSR activation and suggest a molecular basis for the functional effects of the N107I mutation and for its putative pathophysiological link with asthma (PMID:16790440)
• Because remodeling of airway epithelium is a feature of chronic asthma, the up-regulation of MMP10 and TIMP3 by NPS-NPSR1 signaling may be of relevance in the pathogenesis of asthma. (PMID:16926187)
• NPS acts as a novel modulator of arousal and anxiety-related behaviours by promoting a unique pattern of effects: stimulation associated with anxiolysis. (PMID:18376418)
• The available information regarding NPS and its receptor and the biological actions modulated by the NPS-NPSR system, is summarized. (PMID:19824051)
• NPS-NPSR1 signaling is likely involved in anxiety (PMID:20705147)
• NPS is able to stimulate human monocyte chemotaxis and that this effect is entirely due to selective NPSR activation. (PMID:23142110)
• A SNP within the neuropeptide s gene is associated with decreased bioactivity. (PMID:24386135)
• SNPs modify asthma risk (PMID:28463995)
• analgesic effects of NPS are linked with dopaminergic neurotransmission mainly through dopamine D2-like receptor signaling (PMID:31326375)
• Neandertal introgression and accumulation of hypomorphic mutations in the neuropeptide S (NPS) system promote attenuated functionality. (PMID:33556445)
• Further refining the critical region of 10q26 microdeletion syndrome: A possible involvement of INSYN2 and NPS in the cognitive phenotype. (PMID:34252586)
• Sphingosine 1-phosphate signaling axis mediates neuropeptide S-induced invasive phenotype of endometriotic cells. (PMID:38287231)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nps	ENSMUSG00000073804
rattus_norvegicus	Nps	ENSRNOG00000036653

Protein

Protein identifiers

Neuropeptide S — P0C0P6 (reviewed: P0C0P6)

All UniProt accessions (1): P0C0P6

UniProt curated annotations — full annotation on UniProt →

Function. Ligand for NPSR1. Binds to its receptor with nanomolar affinity and initiates a G(q)/GNAQ-dependent phospholipase C-activating signaling pathway. This results in Ca(2+) mobilization from intracellular stores and increased intracellular Ca(2+) levels. In addition to this pathway, NPS binding to its receptor activates cAMP/PKA signal transduction. Finally, both pathways converge to activate ERK1/ERK2 phosphorylation and signaling cascade. Modulates arousal and anxiety. May play an important anorexigenic role.

Subcellular location. Secreted.

RefSeq proteins (1): NP_001025184* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028138	Neuropeptide_S	Family

Pfam: PF14993

UniProt features (11 total): mutagenesis site 6, sequence variant 2, signal peptide 1, propeptide 1, peptide 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0C0P6-F1	65.34	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (6):

Position	Phenotype
80–89	does not affect receptor activation and ca(2+) intracellular increase.
70–79	loss of receptor activation and lack of ca(2+) intracellular increase.
70–71	loss of receptor activation and lack of ca(2+) intracellular increase.
70	does not affect receptor activation and ca(2+) intracellular increase.
71	loss of receptor activation and lack of ca(2+) intracellular increase.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 47 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_ASSOCIATIVE_LEARNING, GOBP_POSITIVE_REGULATION_OF_ACTION_POTENTIAL, GOBP_POSITIVE_REGULATION_OF_BEHAVIOR, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_CIRCADIAN_RHYTHM, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_REGULATION_OF_BEHAVIOR, GOBP_LEARNING, GOBP_RESPONSE_TO_RADIATION, GOBP_POSITIVE_REGULATION_OF_CIRCADIAN_RHYTHM

GO Biological Process (7): neuropeptide signaling pathway (GO:0007218), visual learning (GO:0008542), positive regulation of circadian sleep/wake cycle, wakefulness (GO:0010841), positive regulation of synaptic transmission, GABAergic (GO:0032230), synaptic transmission, glutamatergic (GO:0035249), positive regulation of action potential (GO:0045760), positive regulation of synaptic transmission, glutamatergic (GO:0051968)

GO Molecular Function (0):

GO Cellular Component (2): extracellular region (GO:0005576), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR downstream signalling	2
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of synaptic transmission	2
G protein-coupled receptor signaling pathway	1
visual behavior	1
associative learning	1
regulation of circadian sleep/wake cycle, wakefulness	1
circadian sleep/wake cycle, wakefulness	1
positive regulation of circadian rhythm	1
positive regulation of behavior	1
regulation of synaptic transmission, GABAergic	1
synaptic transmission, GABAergic	1
chemical synaptic transmission	1
action potential	1
positive regulation of biological process	1
regulation of action potential	1
synaptic transmission, glutamatergic	1
regulation of synaptic transmission, glutamatergic	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

542 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPS	NPSR1	Q6W5P4	999
NPS	HCRT	O43612	775
NPS	RLN3	Q8WXF3	646
NPS	NMU	P48645	631
NPS	CRHR1	P34998	594
NPS	POMC	P01189	592
NPS	CRH	P06850	586
NPS	OXT	P01178	583
NPS	NMS	Q5H8A3	583
NPS	NPY	P01303	580
NPS	CCK	P06307	561
NPS	PNOC	Q13519	545
NPS	PRLH	P81277	531
NPS	BDNF	P23560	524
NPS	AVPR1B	P47901	500

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ORF37	RPP40	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A023PXJ3, A6X970, A8CL69, B2KKR4, E1ZXU8, E1ZZF9, E2AYH6, G2TRL8, G2TRN1, G5CKU5, O13533, O13536, P0C0P5, P0C0P6, P0C0P7, P0C0P8, P0DW17, P13999, P14200, P20382, P38296, P40211, P47012, P48332, P51922, Q01031, Q03418, Q07509, Q12225, Q12307, Q26377, Q30KL5, Q3E821, Q5T3Y7, Q5W1L4, Q5W1L5, Q7LIF2, Q8JIM3, Q8N8P6, Q8STB2

Diamond homologs: P0C0P5, P0C0P6, P0C0P7, P0C0P8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

8 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	7
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

354 predictions. Top by Δscore:

Variant	Effect	Δscore
10:127549566:CTAAG:C	donor_loss	0.9900
10:127549571:G:GC	donor_loss	0.9900
10:127549572:T:G	donor_loss	0.9900
10:127552446:ATCT:A	acceptor_gain	0.9500
10:127549571:G:GG	donor_gain	0.9400
10:127552442:A:AG	acceptor_gain	0.9400
10:127552443:C:G	acceptor_gain	0.9300
10:127552077:G:GA	donor_gain	0.9200
10:127552449:T:A	acceptor_gain	0.9100
10:127552447:T:G	acceptor_gain	0.8600
10:127550434:T:G	acceptor_gain	0.8000
10:127552076:T:TA	donor_gain	0.7800
10:127552056:G:GT	donor_gain	0.7600
10:127550421:T:TA	acceptor_gain	0.7500
10:127552446:A:AG	acceptor_gain	0.7400
10:127552457:CA:C	acceptor_loss	0.7300
10:127552459:G:A	acceptor_loss	0.7300
10:127549384:GC:G	donor_gain	0.7000
10:127549573:A:AG	donor_loss	0.7000
10:127552494:T:A	acceptor_gain	0.7000
10:127552428:T:G	acceptor_loss	0.6700
10:127551946:A:AG	acceptor_gain	0.6500
10:127549488:GCTCA:G	acceptor_gain	0.6400
10:127552459:GGT:G	acceptor_gain	0.6300
10:127552113:T:TA	donor_gain	0.6100
10:127552501:C:G	acceptor_gain	0.6100
10:127550518:A:G	donor_gain	0.6000
10:127552009:TTC:T	donor_gain	0.5900
10:127550512:T:A	donor_gain	0.5800
10:127552427:A:AG	acceptor_loss	0.5700

AlphaMissense

575 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:127552580:T:C	F71L	0.962
10:127552582:T:A	F71L	0.962
10:127552582:T:G	F71L	0.962
10:127552583:C:A	R72S	0.956
10:127552584:G:C	R72P	0.932
10:127552609:A:C	K80N	0.883
10:127552609:A:T	K80N	0.883
10:127552587:A:T	N73I	0.882
10:127552596:G:A	G76D	0.882
10:127552588:T:A	N73K	0.881
10:127552588:T:G	N73K	0.881
10:127552608:A:T	K80I	0.850
10:127552581:T:G	F71C	0.848
10:127552581:T:C	F71S	0.842
10:127552587:A:C	N73T	0.828
10:127552627:A:C	R86S	0.824
10:127552627:A:T	R86S	0.824
10:127552590:G:A	G74E	0.821
10:127552584:G:T	R72L	0.818
10:127552595:G:C	G76R	0.818
10:127552601:G:T	G78W	0.813
10:127552576:G:C	R69S	0.809
10:127552576:G:T	R69S	0.809
10:127552595:G:T	G76C	0.796
10:127552590:G:T	G74V	0.792
10:127552583:C:G	R72G	0.791
10:127552602:G:A	G78E	0.789
10:127552573:A:C	K68N	0.782
10:127552573:A:T	K68N	0.782
10:127552593:T:A	V75D	0.780

dbSNP variants (sampled 300 via entrez): RS1000011465 (10:127549805 A>G), RS1000570816 (10:127551621 T>C), RS1001410866 (10:127550734 G>A), RS1001555809 (10:127552216 A>T), RS1001626522 (10:127552027 C>T), RS1001788380 (10:127547345 T>G), RS1001901399 (10:127547494 TA>T), RS1002015313 (10:127551737 A>G), RS1002387325 (10:127552048 T>A,C), RS1002950171 (10:127553267 G>T), RS1003173243 (10:127548615 T>C), RS1003302097 (10:127553254 T>C), RS1003634780 (10:127548830 G>A), RS1004839691 (10:127551227 G>A), RS1004893932 (10:127550328 A>T)

Disease associations

OMIM: gene MIM:609513 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007576_253	Chronotype	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3596086 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

1 total (human), top 1 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3599005	Binding	Binding affinity to neuropeptide-S (unknown origin) at 200 uM incubated for 2 hrs irradiated with UV light for 10 mins by MALDI-TOF-MS method	Covalent modifier-type aggregation inhibitor of amyloid-β based on a cyclo-KLVFF motif. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.