NPS

Official Full Name

neuropeptide S

Organism

Homo sapiens

GeneID

594857

Background

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. [provided by Alliance of Genome Resources, Feb 2025]

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Detailed Information

Neuropeptide S (NPS) was identified as an endogenous ligand of the orphan receptor GPR154 (also known as GPRA, VRR1) by a reverse pharmacological strategy in 2002, consisting of 20 amino acids. Because its amino-terminal residues are serine (S) in the tested species, it is named neuropeptide S. NPS functions through its receptor NPSR, which is a G protein coupled receptor (GPCR), mainly Gs and Gq proteins. NPS and its receptors constitute a new neuropeptide system that regulates a number of important physiological and pathological processes such as arousal and sleep, anxiety and depression, learning and memory, food and energy metabolism, neuroendocrine, immunity and antioxidant.

Nps Figure 1. Representative scheme of neuronal neuropeptide S receptor (NPSR)-coupled signaling cascades summarizing finding. (Thomas, G., et al. 2018)

NPS Receptor

NPS receptors were originally identified as orphan receptor GPR154, vasopressin receptor-related receptor-1 (VRR1), asthma-susceptible G protein-coupled receptors, and so on. NPSR is a typical G protein-coupled receptor with moderate degree of homology to other peptide receptors. In particular, the vasopressin receptors V1a and V2, but only 21% to 23% of the amino acid residues are the same. After activation of NPSR, Ca²⁺ increases in cells, indicating that it is mainly an excitatory effect at the cellular level, and cAMP levels in cells are increased, which indicates that the NPSR-coupled G proteins are mainly Gs and Gq proteins.

NPSR mRNA is expressed in stress-related brain regions such as the apricot kernel, hypothalamus, mesial nucleus group, and ventral tegmental area. The NPS system may interact with other neurotransmitters (5-hydroxytryptamine, dopamine, etc.) to regulate anxiety and stress responses. Studies have found that NPSR may regulate the pathophysiology of asthma by increasing expression in the bronchial epithelium and inhibiting cell proliferation. Researchers have explored downstream genes of the NPS-NPSR pathway and found that a series of asthma-related genes have significantly increased expression, such as matrix metallopeptidase 10 (MMP10), inhibin alpha subunit gene (INHBA), and interleukin (IL8), suggesting that the NPS system is involved in the development of asthma.

NPS Physiological Function

NPS and its receptors are widely distributed in the nervous system and various organ tissues, especially NPSR is widely distributed in the central nervous system. Current research shows that NPS has a variety of neurophysiological functions. Moreover, research on the physiological and pharmacological effects of NPS has been extensively carried out, and the spectrum of NPS effects is gradually expanding. With the elucidation of the physiological and pathological effects of the NPS system, NPS has become a promising new drug target in regulating wakefulness and sleep, anti-anxiety, and regulating food intake.

The role of NPS in promoting arousal may be mediated in part by NPSR expressed in the midline nucleus of the thalamus, because this part of the brain area is a relay station between the brainstem arousal center and the cerebral cortex. NPSR mRNA is significantly expressed in several pathways that activate wakefulness, such as expression in multiple mid thalamic nucleus, junctional nucleus, diamond nucleus, and scattered in the plate core group. These regions relay the projection of the brainstem reticular structure into the cortex, which is very important for regulating arousal. In view of this distribution of NPSR, it is speculated that NPS may promote the arousal state of experimental animals and inhibit the sleep behavior of experimental animals by promoting the wake-related brain regions and the GABA-inhibiting neurons in the sleeping brain regions.

References:

Thomas, G. , & Neumann, I. D. . (2018). Brain neuropeptide s: via gpcr activation to a powerful neuromodulator of socio-emotional behaviors. Cell and Tissue Research.
Lefevre, A., Hurlemann, R., & Grinevich, V. (2019). Imaging neuropeptide effects on human brain function. Cell and tissue research, 375(1), 279-286.
Semmens, D. C., & Elphick, M. R. (2017). The evolution of neuropeptide signalling: insights from echinoderms. Briefings in functional genomics, 16(5), 288-298.

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