Neurobiology, pharmacology, and medicinal chemistry of neuropeptide S and its receptor

Abstract

Neuropeptide S (NPS) is the last neuropeptide identified via reverse pharmacology techniques. NPS selectively binds and activates a previous orphan GPCR, now named NPSR, producing intracellular calcium mobilization and increases in cAMP levels. Biological functions modulated by the NPS/NPSR system include anxiety, arousal, locomotion, food intake, memory, and drug addiction. The primary sequence of NPS (in humans SFRNGVGTGMKKTSFQRAKS) is highly conserved among vertebrates especially at the N-terminus. Ala-and D-scan studies demonstrated that this part of the molecule is crucial for biological activity. ]NPS whose antagonist properties were confirmed in vivo. Finally, the pharmacological features of substituted bicyclic piperazine molecules (e.g. SHA 68 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide) were recently published making available the first generation of nonpeptide NPSR antagonists. The use in future studies of NPSR antagonists will be of paramount importance for understanding which biological functions are controlled by the NPS/NPSR system and for defining the therapeutic potential of selective NPSR ligands.

Human Neuropeptide S Receptor Is Activated via a Gαq Protein-biased Signaling Cascade by a Human Neuropeptide S Analog Lacking the C-terminal 10 Residues

“…NPS and its receptor have been suggested to be involved in the regulation of a variety of aspects of central nervous system physiology and pathology, including those related to stress and anxiety, locomotor activity, wakefulness, food intake, and drug and alcohol abuse, all through G␣ q -and G␣ sdependent pathways and the ERK1/2 signaling cascade (52). However, the contribution of individual G protein and ERK1/2 pathways to the diverse physiological responses mediated by NPS/NPSR remains unknown.…”

Neuropeptide S: a novel regulator of pain-related amygdala plasticity and behaviors

“…Selectivity and target concentrations were established in our previous studies Li et al 2011) and the literature (Camarda et al 2009;Guerrini et al 2009Guerrini et al , 2010Jungling et al 2008;Ruzza et al 2012). ACSF served as vehicle control in all experiments.…”

“…NPS binds with high affinity to a G q /G s -coupled receptor (NPSR) to increase intracellular calcium and cAMP-PKA signaling (Guerrini et al 2010;Reinscheid 2008). NPSR is expressed in discrete brain areas including the rat amygdala (Leonard and Ring 2011), where the highest level of NPSR mRNA is found in and around ITC cells, while NPSR is absent in other nuclei (LA, BLA, and CeA) relevant for pain processing (Xu et al 2007).…”

“…However, a mechanistic analysis of pain-related NPS effects has been lacking. Using a selective NPSR agonist (NPS; Guerrini et al 2010;Reinscheid 2008) and antagonist ([D-Cys(tBu) 5 ]NPS; Camarda et al 2009), we tested the hypothesis that the amygdala is an important site for pain-inhibiting effects of NPS and that NPS increases feedforward inhibition of CeA neurons through a PKA-dependent postsynaptic action on inhibitory ITC cells. To do so, we used the well-established kaolin/carrageenan-induced monoarthritis model, which generates nocifensive and emotional-affective pain behaviors and synaptic plasticity in the amygdala network within a few hours, reaching a plateau effect at 5-6 h (Neugebauer et al 20045-6 h (Neugebauer et al , 20075-6 h (Neugebauer et al , 2009).…”

High prevalence of serum antibodies reacting with simian virus 40 capsid protein mimotopes in patients affected by malignant pleural mesothelioma

“…The amino acid residues of the two specific SV40 VP peptides show low homology to the VPs of BKV and JCV (33). The human peptide hNPS, amino acid sequence SFRNGVGTGMKKTSFQRAKS, was used as a negative control peptide (53). The synthetic peptides were synthesized by standard procedures and purchased from UFPeptides.…”