Neuropeptide S

Abstract

Arousal and anxiety are behavioral responses that involve complex neurocircuitries and multiple neurochemical components. Here, we report that a neuropeptide, neuropeptide S (NPS), potently modulates wakefulness and could also regulate anxiety. NPS acts by activating its cognate receptor (NPSR) and inducing mobilization of intracellular Ca2+. The NPSR mRNA is widely distributed in the brain, including the amygdala and the midline thalamic nuclei. Central administration of NPS increases locomotor activity in mice and decreases paradoxical (REM) sleep and slow wave sleep in rats. NPS was further shown to produce anxiolytic-like effects in mice exposed to four different stressful paradigms. Interestingly, NPS is expressed in a previously undefined cluster of cells located between the locus coeruleus (LC) and Barrington's nucleus. These results indicate that NPS could be a new modulator of arousal and anxiety. They also show that the LC region encompasses distinct nuclei expressing different arousal-promoting neurotransmitters.

Structure-Function Relationships in the Neuropeptide S Receptor

“…The results demonstrate that residues in the NH 2 -terminal third of the peptide are necessary and sufficient for receptor activation. Indeed, removal of the C-terminal 14 residues (peptide 1-6) has limited effect on the potency of the peptide, whereas removing Ser-1 (peptide 2-20) is detrimental to function and removing the first two (peptide [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] or three (peptide 4-20) NH 2 -terminal residues results in largely inactive peptides. Interestingly, peptides 1-7, 1-8, and 1-10 are significantly less potent compared with both full-length NPS and peptide 1-6, indicating that residues in this region, although not critical for function, can affect receptor activation.…”

“…One approach, involving whole genome scanning followed by refined genetic mapping, has led to the recent identification of four specific candidate genes (3)(4)(5)(6). One of these, GPR154, encoding neuropeptide S receptor (NPSR) 4 (4,7), also known as G protein receptor for asthma susceptibility (GPRA) (4), GPR154 (8), and vasopressin receptor-related receptor 1 (VRR1) (9), has been confirmed as an asthma-linked gene in five distinct Caucasian populations (4,10,11). The gene for NPSR encodes at least two splice variants that differ only in their C termini (4,12) and are referred to herein as NPSR-A and NPSR-B, corresponding to GPRA-A and GPRA-B (4), respectively.…”

“…Its ligand is a 20-amino acid peptide known as neuropeptide S (NPS) because of its expression in the brain and its putative role in centrally mediated responses (as outlined below) (7). Activation of NPSR by NPS results in increased intracellular cAMP levels and Ca 2ϩ mobilization, leading to the conclusion that it is coupled to G s and G q proteins (7,9).…”

“…Its ligand is a 20-amino acid peptide known as neuropeptide S (NPS) because of its expression in the brain and its putative role in centrally mediated responses (as outlined below) (7). Activation of NPSR by NPS results in increased intracellular cAMP levels and Ca 2ϩ mobilization, leading to the conclusion that it is coupled to G s and G q proteins (7,9). Reinforcing the genetic evidence that NPSR is involved in asthma, it has been reported that expression of the NPSR-B isoform, but not the NPSR-A isoform, is increased in bronchiolar smooth muscle and epithelial cells of asthmatics compared with healthy controls (4,12).…”

“…It has also been shown that lung NPSR is up-regulated in a murine model of allergic asthma (4). Recently, it was reported that the B isoform of NPSR is expressed in a wide variety of tissues and cells in addition to * The costs of publication of this article were defrayed in part by the payment the lung (12), although other studies have shown that expression of the receptor is restricted to the brain, in particular the hypothalamus, and the retina (7,9). Consistent with this latter pattern of expression, NPSR has been shown to be involved in sleep, anxiety (7), and feeding (13) in rodents.…”