Neuropeptide S Receptor Induces Neuropeptide Expression and Associates With Intermediate Phenotypes of Functional Gastrointestinal Disorders

Camilleri, Michael; Carlson, Paula; Zinsmeister, Alan R.; McKinzie, Sanna; Busciglio, Irene; Burton, Duane; Zucchelli, Marco; D’Amato, Mauro

doi:10.1053/j.gastro.2009.08.051

Cited by 51 publications

(61 citation statements)

References 53 publications

(62 reference statements)

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“…NPSR1 induces the production of several neuropeptides, including cholecystokinin, vasoactive intestinal peptide, peptide YY, and somatostatin. NPSR1 variants are associated with gastrointestinal motor and sensory functions that are relevant to IBS [107] .…”

Section: Neurotransmitters and Cytokinesmentioning

confidence: 99%

Irritable bowel syndrome: Emerging paradigm in pathophysiology

Lee

Park

2014

WJG

132

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Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, characterized by abdominal pain, bloating, and changes in bowel habits. These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS. Therefore, IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination. Although a great deal of research has been carried out in this area, the pathophysiology of IBS is complex and not completely understood. Multiple factors are thought to contribute to the symptoms in IBS patients; altered gastrointestinal motility, visceral hypersensitivity, and the brain-gut interaction are important classical concepts in IBS pathophysiology. New areas of research in this arena include inflammation, postinfectious low-grade inflammation, genetic and immunologic factors, an altered microbiota, dietary factors, and enteroendocrine cells. These emerging studies have not shown consistent results, provoking controversy in the IBS field. However, certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients, confirming that IBS symptoms cannot be explained by a single etiological mechanism. Therefore, it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.

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Section: Neurotransmitters and Cytokinesmentioning

confidence: 99%

Irritable bowel syndrome: Emerging paradigm in pathophysiology

Lee

Park

2014

WJG

132

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“…The neuropeptide S (NPS) receptor 1 (NPSR1) gene on chromosome 7 is associated with asthma and inflammatory bowel disease (30). NPSR1 is expressed on the intestinal epithelium and is upregulated in inflammation; NPS-NPSR1 signaling induced increased expression of cholecystokinin, vasoactive intestinal peptide, peptide YY, and somatostatin in HEK-293 cells (23). In a study with 699 participants (approximately two-thirds patients and one-third healthy controls) of 18 NPSR1 polymorphisms (23) that span the gene, rs1419793 was significantly associated with colonic transit (P Ͻ 0.003, with false discovery rate correction).…”

Section: Inflammatory Mechanismsmentioning

confidence: 99%

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Camilleri

Katzka

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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103

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The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, ␣ 2-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNF␣, GN␤3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region (5-HTTLPR) and 5-HT3 genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klotho␤ (KLB) and fibroblast growth factor receptor 4 (FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published. adrenergic; serotonergic; solute carrier 6A4; 5-hydroxytryptamine transporter-linked polymorphic region; inflammation; susceptibility; klotho␤; bile acid malabsorption EPIDEMIOLOGICAL STUDIES of familial aggregation (57, 99) and twins (7,70,72,82,83) suggest a genetic contribution to irritable bowel syndrome (IBS). While the data are conflicting, they are generally consistent with the hypothesis that IBS may be a complex genetic disorder. Understanding of genetic variation and its influence on gut motility, secretion, sensation, and inflammation, as it is applied to IBS, has the potential to help elucidate mechanisms of control of a poorly understood syndrome. Similarly, the impact of genetic variation on the targets of therapy in IBS may enhance the efficacy of pharmacological therapies. These targets include receptors and regulators of gut function and variations in drug metabolism.This review addresses the available literature on the role of genetics in IBS. There are no published genome-wide association studies in functional gastrointestinal (GI) or motility disorders specifically focusing on genetic epidemiology and pharmacogenetics. Genetic Epidemiology of IBS: Candidate Gene ApproachAs the general approach followed in genotype association studies (Fig. 1), investigators have sought the relationship between genotype and clinical phenotype, while appreciating that intermediaries, such as th...

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“…These publications have driven efforts focused on NPSR1 signaling in the context of inflammation. However, NPS also increases mRNA expression of gastrointestinal peptides that act on motility (e.g., CCK, VIP, PYY, and somatostatin) (2), suggesting that in addition to a role in inflammation, NPSR1 signaling can influence gastrointestinal motor and sensory disturbances such as hastening of colonic transit, pain, gas, and urgency sensations (2).…”

mentioning

confidence: 99%

Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide

Saudi

Halim

Rudholm-Feldreich

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Wan Saudi WS, Halim MA, Rudholm-Feldreich T, Gillberg L, Rosenqvist E, Tengholm A, Sundbom M, Karlbom U, Näslund E, Webb DL, Sjöblom M, Hellström PM. Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide. Am J Physiol Gastrointest Liver Physiol 309: G625-G634, 2015. First published July 23, 2015; doi:10.1152/ajpgi.00104.2015.-Neuropeptide S (NPS) receptor (NPSR1) polymorphisms are associated with enteral dysmotility and inflammatory bowel disease (IBD). This study investigated the role of NPS in conjunction with nitrergic mechanisms in the regulation of intestinal motility and mucosal permeability. In rats, small intestinal myoelectric activity and luminal pressure changes in small intestine and colon, along with duodenal permeability, were studied. In human intestine, NPS and NPSR1 were localized by immunostaining. Pre-and postprandial plasma NPS was measured by ELISA in healthy and active IBD humans. Effects and mechanisms of NPS were studied in human intestinal muscle strips. In rats, NPS 100-4,000 pmol·kg Ϫ1 ·min Ϫ1 had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (P Ͻ 0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (P Ͻ 0.05-0.01), and increased permeability (P Ͻ 0.01) through NO-dependent mechanisms. In human intestine, NPS localized at myenteric nerve cell bodies and fibers. NPSR1 was confined to nerve cell bodies. Circulating NPS in humans was tenfold below the ϳ0.3 nmol/l dissociation constant (K d) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips precontracted by bethanechol, NPS 1-1,000 nmol/l induced NO-dependent muscle relaxation (P Ͻ 0.05) that was sensitive also to tetrodotoxin (P Ͻ 0.01). In conclusion, NPS inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans. Aberrant signaling and upregulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.inflammation; inflammatory bowel disease; migrating motor complex; NO; peristalsis NEUROPEPTIDE S (NPS) is localized to the brain stem and gastrointestinal tract. NPS activates the G protein-coupled receptor NPSR1 (also named GPR154) and activates adenylate cyclase to increase cAMP (17). NPS is regarded as an excitatory neurotransmitter and is involved in stress responses with regulation of arousal, wakefulness, and anxiety in mammals (4,5,22). The presence of an Asn-Gly (NG) sequence is a defining feature of a phylogenetically ancient family of neuropeptides called "NG peptides" (4). Rodent and human NPS possesses this NG sequence (18).NPS and NPSR1 exist in gastrointestinal mucosal epithelial cells (3,9,21). An NPSR1 polymorphism was reported along with higher mucosal epithelial immunoreactivity of NPSR1 in inflammatory bowel disease (IBD) with expression...

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Neuropeptide S Receptor Induces Neuropeptide Expression and Associates With Intermediate Phenotypes of Functional Gastrointestinal Disorders

Cited by 51 publications

References 53 publications

Irritable bowel syndrome: Emerging paradigm in pathophysiology

Irritable bowel syndrome: Emerging paradigm in pathophysiology

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide

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