GENERAL

Neuropeptide S (NPS) was named for its amino-terminal serine residue that is conserved across all species where NPS sequences have been found at the genomic level. NPS was isolated as a ligand of an orphan GPCR and first disclosed in a patent in 2002 [6]. Similar to other neuropeptides, NPS is encoded by a precursor protein that contains a pair of basic amino acid residues immediately preceding the immature peptide which will likely serve as processing sites for proteolytic cleavage. The NPS precursor is divided into at least three exons and is located on human Chr. 10. The NPS peptide is located at the carboxy-terminal end of the protein. Thus far, DNA sequences encoding NPS have been found in a number of vertebrate species with the exception of fish [7]. A comparison of the amino acid sequences of NPS has revealed that the peptide has been well conserved throughout evolution. This degree of conservation is indicative of the importance of the amino-terminal sequence for biological activity (Fig. 1).

NPS precursor is expressed mainly in the brain [2]. A cluster of cells located in between the locus coeruleus and Barrington's nucleus in the pontine brain stem shows high expression levels of NPS precursor mRNA. This previously unidentified group of cells could define a novel brainstem nucleus. NPS precursor expression was also found in the lateral parabrachial nucleus, the principle 5 nucleus of the brainstem and in a few scattered neurons in the amygdala and hypothalamus. NPS appears to be colocalized with other excitatory neurotransmitters. In the pericoerulear region, NPS-synthesizing cells were found to coexpress vesicular glutamate transporters and are thus glutamatergic neurons [8]. A few cells in this region might be cholinergic neurons. NPS-expressing cells in the lateral parabrachial nucleus also express corticotropine-releasing factor while all NPS-expressing cells in the principle 5 nucleus are glutamatergic. Overall, the expression of NPS precursor is rather restricted in the brain. Peripheral sites expressing NPS precursor include mostly endocrine tissues such as thyroid, mammary gland, salivary gland and testis.

NPS was found to promote arousal in mice and is able to suppress all stages of sleep in rats [2]. Nanomolar doses of NPS administered centrally induce hyperlocomotion. In addition, NPS appears to produce anxiolytic-like behavior in rodents. This pharmacological spectrum is quite unique since classical psychostimulants either increase anxiety-like behavior or do not affect emotionality. On the other hand, typical anxiolytics normally reduce locomotion and cause sedation. Central administration of NPS was also found to suppress feeding [9-10] and modulate HPA axis activity [10].

NPS RECEPTOR

The NPS receptor is a typical GPCR, also known as GPR154, vasopressin-receptor related receptor 1 (VRR1) [4], or GPRA [3]. The receptor gene contains at least 9 exons and is located on human Chr 7p14. NPSR was found mainly expressed in the central nervous system of rats by using in-situ hybridization [2,8]. NPS receptor mRNA is widely distributed in many brain areas with high expression levels in cortex, hypothalamus, amygdala and multiple midline thalamic nuclei. Many of these areas have been functionally associated with arousal and processing of emotional behavior.

In 2004, the NPS receptor was identified as an asthma susceptibility gene in a genome wide screen in Finnish and Canadian patients [3]. This study termed the gene "G protein-coupled receptor for asthma susceptibility, (GPRA)" but did not provide functional data which might explain the physiological role of the NPS receptor in asthma. The study showed that a number of polymorphic variants of the NPS receptor exist in human and that particular sets of these variants (haplotypes) are associated with an increased risk of asthma and possibly allergic diseases characterized by high IgE serum levels. A carboxy-terminal splice variant of human NPS receptor was found to be over-expressed in asthmatic airway tissue. Expression of NPS receptor mRNA was also found upregulated in a mouse model of airway inflammation. One of the polymorphisms codes for an amino acid change in position 107 (Asn/Ile) of the human NPS receptor. NPS receptor Ile¹⁰⁷ was found to display increased agonist sensitivity in second messenger coupling without changing binding affinity [11].