Neuropeptide S

Chemical Identity

Property	Value
Name	Neuropeptide S
Sequence	Ser-Asp-Arg-Leu-Ala-Phe-Leu-Gly-Arg-Arg-Ala-Phe-Leu-Gly-Gly-Gly-Gln-Gln-Phe-NH₂
Length	20 amino acids
Chemical Formula	C₉₅H₁₅₅N₂₇O₂₄
MW	2041.5 Da
N-terminal	Serine (critical for activity)
PDB Structures	2BCF (NMR)

Distribution

Central Nervous System

• Locus coeruleus (LC): Primary site — NPS neurons project widely
• Hypothalamus: Lateral hypothalamic area
• Amygdala: Central and basolateral nuclei
• Brainstem: Periaqueductal gray, parabrachial nucleus

Receptor

NPSR1 (GPR154)

• Type: Class A G-protein coupled receptor (orphan receptor)
• Expression: LC, amygdala, cortex, olfactory bulb
• G-protein: Gαs → cAMP → PKA
• Genetic variants: rs324981 (T/T genotype) linked to asthma, anxiety, IBS

Physiological Functions

Wakefulness

NPS neurons (LC) → NPS release → NPSR1 (LC, thalamus, cortex)
    → ↑ Histamine (TMN)
    → ↑ Norepinephrine (LC)
    → Wakefulness promotion
    → Arousal during stress

Anxiety and Fear

• Anxiolytic: NPS reduces fear and anxiety in animal models
• Mechanism: Attenuates amygdala activity, reduces fear conditioning
• Human studies: NPSR1 variants associated with anxiety traits

Other Functions

• Feeding: NPS stimulates food intake (potent orexigenic)
• Locomotion: Increases locomotor activity
• Memory: Enhances spatial memory
• Pain: Modulates nociceptive signaling

Clinical Significance

NPSR1 Genetic Variants

• rs324981: Common variant linked to:
  • Bronchial hyperresponsiveness (asthma)
  • Anxiety disorders
  • Irritable bowel syndrome (IBS)
  • Panic disorder

Therapeutic Potential

• Anxiety: NPSR1 antagonists could treat anxiety
• Asthma: NPSR1 antagonists could reduce airway hyperresponsiveness
• Pain: NPS modulates pain processing

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• C-terminal amidation: Required for activity
• Purification: RP-HPLC
• Characterization: Mass spectrometry, NMR

References

1. Xu YL, et al. “Neuropeptide S is a novel anxiolytic.” Nature 428:702-705, 2004. doi:10.1038/nature02355
2. Reinscheid RK, et al. “Neuropeptide S and its receptor.” Journal of Biological Chemistry 280:15060-15067, 2005.
3. Zhou M, et al. “NPSR1 polymorphisms and anxiety.” Human Molecular Genetics 17:3000-3006, 2008.
4. Laitinen T, et al. “NPSR1 variants and asthma.” Journal of Allergy and Clinical Immunology 123:644-651, 2009.
5. Ensign SH, et al. “Neuropeptide S and arousal.” Trends in Neurosciences 28:634-638, 2005.