Neuropeptide S
experimentalAlso known as: NPS, P0C0P6
Neuropeptide S (NPS) is a 20-amino-acid peptide that acts as the endogenous ligand for the NPS receptor (NPSR1), a G protein-coupled receptor. Upon binding with nanomolar affinity, NPS activates a Gαq/GNAQ-dependent signaling cascade, leading to phospholipase C activation, inositol trisphosphate production, and subsequent calcium mobilization from intracellular stores. This signaling pathway underlies NPS's ability to modulate neuronal excitability and neurotransmitter release in key brain regions, including the amygdala, hypothalamus, and brainstem. Preclinical research has demonstrated that central administration of NPS produces robust arousal-promoting, anxiolytic-like, and pro-cognitive effects in rodent models. Specifically, NPS increases wakefulness and locomotor activity, reduces anxiety-like behavior in elevated plus-maze and open-field tests, and enhances fear extinction and spatial memory. These effects are mediated primarily through NPSR1 activation in the amygdala and locus coeruleus. Notably, NPS also exhibits bidirectional modulation of stress responses, with low doses reducing and high doses potentiating stress-induced behaviors. Despite its promising preclinical profile, NPS remains in the experimental stage, with no clinical trials completed in humans. Its potential therapeutic relevance lies in disorders involving arousal dysregulation, anxiety, and cognitive impairment, such as post-traumatic stress disorder, narcolepsy, and Alzheimer's disease. However, the translational gap persists due to challenges in peptide stability, blood-brain barrier permeability, and the complex dose-dependent effects of NPS on stress and arousal systems. For research purposes only — not medical advice.
Key data
MISSVKLNLILVLSLSTMHVFWCYPVPSSKVSGKSDYFLILLNSCPTRLDRSKELAFLKPILEKMFVKRSFRNGVGTGMKKTSFQRAKSC93H155N31O28SMechanism of action
Ligand for NPSR1 (PubMed:15312648, PubMed:15947423, PubMed:16720571, PubMed:16790440). 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 (PubMed:15312648, PubMed:15947423, PubMed:16720571, PubMed:16790440, PubMed:25714705, PubMed:26865629). In addition to this pathway, NPS binding to its receptor activates cAMP/PKA signal transduction (PubMed:26865629). Finally, both pathways converge to activate ERK1/ERK2 phosphorylation and signaling cascade (PubMed:26865629). Modulates arousal and anxiety. May play an important anorexigenic role (By similarity)
Research & studies
NPS infusion (0.5-2 nmol) facilitated ICSS behavior in rats.; SHA-68 pretreatment dose-dependently blocked nicotine-induced ICSS facilitation.; Single nicotine injection activated NPS neurons in the pericoerulear area and increased NPS protein in the lateral hypothalamus.; Repeated nicotine administration elevated NPS mRNA in the pericoerulear area and protein levels in multiple brain regions.
NPS+ neurons in the LPBA, but not peri-LC or DMT, showed increased activity before wakefulness and decreased activity during REM sleep.; Activation of LPBA NPS+ neurons increased wakefulness and reduced REM sleep, recapitulating broad NPS system effects.; LPBA NPS+ neuron activation also increased respiratory rate, linking arousal and breathing regulation.; Brain-wide mapping revealed distinct input/output patterns for each NPS+ cluster, with NPSR1 expression patterns characterized.
Cognitive impairment in PD includes subjective cognitive decline, mild cognitive impairment, and PD dementia, significantly impacting quality of life and caregiver burden.; Current pharmacological treatments have only partial efficacy and do not stop disease progression.; Over 20 emerging agents are under investigation, targeting mechanisms like α-synuclein aggregation, mitochondrial function, synaptic plasticity, and neurotransmission.; Potential mechanisms also involve the gut-brain axis, neuroinflammation, and upregulation of neurotrophic factors.
Frequently asked questions
What is Neuropeptide S?
Neuropeptide S (NPS) is a 20-amino-acid peptide that acts as the endogenous ligand for the NPS receptor (NPSR1), a G protein-coupled receptor. Upon binding with nanomolar affinity, NPS activates a Gαq/GNAQ-dependent signaling cascade, leading to phospholipase C activation, inositol trisphosphate production, and subsequ
How does Neuropeptide S work?
Ligand for NPSR1 (PubMed:15312648, PubMed:15947423, PubMed:16720571, PubMed:16790440). 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 (PubMed:15312648, PubMed:15947423, PubMed:16720571, PubMed:16790440, PubMed:25714
What is the research status of Neuropeptide S?
Neuropeptide S is currently classified as experimental, with 419 research references on record. This is for research purposes only and is not medical advice.
What is the molecular weight of Neuropeptide S?
Neuropeptide S has a molecular weight of approximately 2187.5 g/mol (formula C93H155N31O28S).
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