Neuropeptide S (human)

Neuropeptides play important modulatory roles throughout the nervous system, functioning as direct effectors or as interacting partners with other neuropeptide and neurotransmitter systems. Limbic brain areas involved in learning, memory and emotions are particularly rich in neuropeptides. This review will focus on the amygdala, a limbic region that plays a key role in emotional-affective behaviors and pain modulation. The amygdala is comprised of different nuclei; the basolateral (BLA) and central (CeA) nuclei and in between, the intercalated cells (ITC), have been linked to pain-related functions. A wide range of neuropeptides are found in the amygdala, particularly in the CeA, but this review will discuss those neuropeptides that have been explored for their role in pain modulation. Calcitonin gene-related peptide (CGRP) is a key peptide in the afferent nociceptive pathway from the parabrachial area and mediates excitatory drive of CeA neurons. CeA neurons containing corticotropin releasing factor (CRF) and/or somatostatin (SOM) are a source of long-range projections and serve major output functions, but CRF also acts locally to excite neurons in the CeA and BLA. Neuropeptide S (NPS) is associated with inhibitory ITC neurons that gate amygdala output. Oxytocin and vasopressin exert opposite (inhibitory and excitatory, respectively) effects on amygdala output. The opioid system of mu, delta and kappa receptors (MOR, DOR, KOR) and their peptide ligands (β-endorphin, enkephalin, dynorphin) have complex and partially opposing effects on amygdala function. Neuropeptides therefore serve as valuable targets to regulate amygdala function in pain conditions. This article is part of the special issue on Neuropeptides.

The neuropeptide S receptor (NPSR) belongs to the G protein-coupled receptor (GPCR) superfamily and is activated by the neuropeptide S (NPS). Although recently discovered, the vertebrate NPSR-NPS system has been established as an important signaling system in the central nervous system and is involved in physiological processes such as locomotor activity, wakefulness, asthma pathogenesis, anxiety and food intake. The availability of a large number of genome sequences from multiple bilaterian lineages has provided an opportunity to establish the evolutionary history of the system. This review describes the origin and the molecular evolution of the NPSR-NPS system using data derived primarily from comparative genomic analyses. These analyses indicate that the NPSR-NPS system and the vasopressin-like receptor-vasopressin/oxytocin peptide (VPR-VP/OT) system originated from a single system in an ancestral bilaterian. Multiple duplications of this ancestral system gave rise to the bilaterian VPR-VP/OT system and to the protostomian cardioacceleratory peptide receptor-cardioacceleratory peptide (CCAPR-CCAP) system and to the NPSR-NPS system in the deuterostomes. Gene structure features of the receptors were consistent with the orthology annotations derived from phylogenetic analyses. The orthology of the peptide precursors closely paralleled that of the receptors suggesting an ancient coevolution of the receptor-peptide pair. An important challenge for the coevolution hypothesis will be to establish the molecular and structural basis of the divergence between orthologous receptor-ligand pairs in this system.

Neuropeptide S and its receptor represent a novel neurotransmitter system mainly expressed in the brain. A single nucleotide polymorphism in the first extracellular loop (I107) increases the potency of neuropeptide S and has been identified for both the human neuropeptide S receptor short (A) and long (B) C-terminal forms. Preliminary human genetic studies link this polymorphism to asthma, panic disorders and altered sleep behavior. No polymorphism or splice variants have been reported for the rat neuropeptide S receptor, however it carries an isoleucine at position 107. To identify a suitable tracer for neuropeptide S receptor binding and investigate the role of specific amino acids within neuropeptide S we carried out mutagenesis of the peptide and assessed the ability of the mutations to stimulate calcium release in HEK293 cells expressing human neuropeptide S receptor variants (A, B, AI(107), BI(107)) and rat neuropeptide S receptor. Replacement of threonine at position 8 by arginine and methionine at position 10 by tyrosine resulted in a mutant peptide slightly more potent on all neuropeptide S receptor variants compared to neuropeptide S and more importantly the iodinated mutant peptide was found to be a suitable tracer for binding studies with improved signal to noise ratio and stability compared to [(125)I-Y(10)] neuropeptide S. Replacement of serine at position 1 of neuropeptide S peptide by arginine resulted in a complete loss of potency for the neuropeptide S receptor (long and short form) but not for the I(107) receptor variants (long and short) or rat neuropeptide S receptor.