Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1)

Abstract

Backgroundneuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02).Principal Findingswe identified one promoter SNP (rs2530547 [−103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk.Significancethese findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.

Neuropeptide S (NPS) variants modify the signaling and risk effects of NPS Receptor 1 (NPSR1) variants in asthma

“…Our cell assays confirmed that stimulation of cells transfected with either NPSR1-Asn(107) or NPSR-Ile(107) with the wildtype NPS-Val(6), induced CRE activity as described previously [26, 27]. Reinscheid et al .…”

Neuroleptics Affect Neuropeptide S and NPSR mRNA Levels in the Rat Brain

“…Some data have associated NPSR polymorphisms with the neuropsychiatric disorders including schizophrenia (Anedda et al 2011;Lennertz et al 2012). However, so far, limited data exists regarding the influence of neuroleptics on brain peptidergic signaling pathways.…”

Persistent nociception induces anxiety-like behavior in rodents: Role of endogenous neuropeptide S

“…NPS binds to its cognate receptor NPS receptor (NPSR) [46] to modulate anxiety, arousal, memory and immune response. Abnormal NPS-NPSR signaling caused by NPSR gene mutation or polymorphism has been associated with pathological conditions including panic disorder [14; 41], catastrophizing [45], asthma [6], and rheumatoid arthritis[1] in human subjects. Another study in mice revealed the antinociceptive effect of NPS on inflammatory pain [44].…”