Neuromedin U octapeptide alters ion transport in porcine jejunum

doi:10.1016/0014-2999(88)90415-3

European Journal of Pharmacology

Volume 155, Issues 1–2, 11 October 1988, Pages 159-162

https://doi.org/10.1016/0014-2999(88)90415-3 Get rights and content

Abstract

The gut neuropeptide, neuromedin U octapeptide (NMU-8) produced transient elevations in short-circuit current (EC₅₀ = 0.7 nmol/1) after its contraluminal administration to sheets of porcine distal jejunal mucosa in vitro. Mucosal responses to NMU-8 were unaffected by 1 μmol/1 atropine or hexamethonium, but were abolished by tetrodotoxin (0.1 μmol/l), dependent upon extracellular Cl, and underwent tachyphylaxis upon repeated peptide application. NMU-8 did not affect contractility of isolated jejunal longitudinal muscle. Thus, NMU-8 appears to selectively modify intestinal ion transport through interactions with non-cholinergic enteric neurons.

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Cited by (68)

Distribution of neuromedin U (NMU)-like immunoreactivity in the goldfish brain, and effect of intracerebroventricular administration of NMU on emotional behavior in goldfish
2022, Peptides
Neuromedin U (NMU) is a multifunctional neuropeptide implicated in regulation of smooth muscle contraction in the circulatory and digestive systems, energy homeostasis and the stress response, but especially food intake in vertebrates. Recent studies have indicated the possible involvement of NMU in the regulation of psychomotor activity in rodents. We have identified four cDNAs encoding three putative NMU variants (NMU-21, −25 and −38) from the goldfish brain and intestine. Recently, we have also purified these NMUs and the truncated C-terminal form NMU-9 from these tissues, and demonstrated their anorexigenic action in goldfish. However, there is no information on the brain localization of NMU-like immunoreactivity and the psychophysiological roles of NMU in fish. Here, we investigated the brain distribution of NMU-like immunoreactivity and found that it was localized throughout the fore- and mid-brains. We subsequently examined the effect of intracerebroventricular (ICV) administration of NMU-21, which is abundant only in the brain on psychomotor activity in goldfish. As goldfish prefer the lower to the upper area of a tank, we developed an upper/lower area preference test in a tank for evaluating the psychomotor activity of goldfish using a personal tablet device without an automatic behavior-tracking device. ICV administration of NMU-21 at 10 pmol g^-1 body weight (BW) prolonged the time spent in the upper area of the tank, and this action mimicked that of ICV administration of the central-type benzodiazepine receptor (CBR) agonist tofisopam at 100 pmol g^-1 BW. These results suggest that NMU-21 potently induces anxiolytic-like action in the goldfish brain.
Circulating neuromedin U levels are similar in subjects with NGT and newly diagnosed T2DM and do not correlate with insulin secretion
2019, Diabetes Research and Clinical Practice
Neuromedin U (NMU), a highly conserved peptide, is implicated in energy homeostasis and is involved in regulating insulin secretion as a decretin hormone in animals. However, there have been no reports on the relationship between NMU and type 2 diabetes mellitus (T2DM). The aim of this study was to investigate circulating NMU concentrations in healthy subjects and T2DM patients and to evaluate the association between serum NMU levels and glucose-stimulated insulin secretion.
We used ELISA to analyze NMU concentrations in blood samples from newly diagnosed T2DM patients (n = 57) and age-, sex- and BMI-matched healthy control subjects (n = 50). Anthropometric parameters, oral glucose tolerance, glycosylated hemoglobin, blood lipids, insulin sensitivity, and insulin secretion were measured.
No difference was observed in serum NMU levels between control subjects and newly diagnosed T2DM patients (p = 0.788). The oral glucose tolerance test (OGTT) results indicated that serum NMU concentrations did not change and did not correlate with insulin levels at fasting and 1 h, 2 h and 3 h after glucose load in both healthy controls and newly diagnosed T2DM patients.
Circulating NMU concentrations were similar in control subjects and newly diagnosed T2DM patients and were not associated with glucose-stimulated insulin secretion. Serum NMU is not a human decretin hormone and may not play a role in the pathogenesis of T2DM.
Identification and immunoregulatory function of neuromedin U (Nmu) in the Japanese pufferfish Takifugu rubripes
2017, Developmental and Comparative Immunology
Citation Excerpt :
The primarily identified biological functions of NMU included control of contraction of uterus smooth muscle and regulation of arterial blood pressure (Minamino et al., 1985). Thereafter, its involvement in other biological activities, including the regulation of stress response (Malendowicz et al., 1993), alteration of ion transport in the jejunum (Brown and Quito, 1988), reduction of food intake and body weight (Howard et al., 2000), involvement in the circadian oscillator system (Nakahara et al., 2004), insulin secretion (Kaczmarek et al., 2006), and bone remodeling (Sato et al., 2007), were revealed in mammals. Moreover, it has been reported that NMU plays a role in immune regulation (especially inflammation), such as activation of macrophages indicated by in vivo analysis using NMU-deficient mice (Moriyama et al., 2006b) and cytokine release in a mouse Th2-type cell line (D10.G4.1) (Johnson et al., 2004), activation of eosinophils (Moriyama et al., 2006a), direct activation of mast cells (Moriyama et al., 2005) exhibited by in vivo analysis using NMU-deficient mice and the involvement of NMU receptor subtype1 (NMU1R) in inflammatory regulation demonstrated by in vivo analysis using NNU1R-deficient mice (Abbondanzo et al., 2009).
In this study, immunoregulatory function of neuromedin U (Nmu) in the teleost fish Fugu (Takifugu rubripes) was characterized. Three splicing variants of nmu mRNA encoding preproNMUs consisting of 164 (Nmu1), 139 (Nmu2), and 129 (Nmu3) amino acid residues were found in Fugu.The biologically active C-terminal region of Fugu Nmu showed high homology among fish and other vertebrate NMUs. The genomic organization of Fugu nmu differed from those of zebrafish and mammals. However, in phylogenetic analysis, Fugu Nmu formed a cluster with NMUs of other vertebrates, in addition to neuromedin S. The splicing variants of mRNA were identified in various tissues. Nmu-21 and Nmu-9 were purified as endogenous peptides from Fugu intestine. The synthetic Nmu-21 peptide activated phagocytic cells, and elevated the expression of cytokine mRNA in peripheral blood leukocytes.
Neuromedin: An insight into its types, receptors and therapeutic opportunities
2017, Pharmacological Reports
Citation Excerpt :
Electrogenic ions consist of Ca2+, Na2+, K+ for this electrogenic pumps play a very important role. The whole process is mediated by external Cl− and is controlled by noncholinergic enteric neurons [83]. NMU-R1 receptors are present in immune cells which suggest of NMU playing an important role in immunomodulation.
Neuropeptides are small protein used by neurons in signal communications. Neuromedin U was the first neuropeptide discovered from the porcine spinal and showed its potent constricting activities on uterus hence was entitled with neuromedin U. Following neuromedin U another of its isoform was discovered neuromedin S which was observed in suprachiasmatic nucleus hence was entitled neuromedin S. Neuromedin K and neuromedin L are of kanassin class which belong to tachykinin family. Bombesin family consists of neuromedin B and neuromedin C. All these different neuromedins have various physiological roles like constrictive effects on the smooth muscles, control of blood pressure, pain sensations, hunger, bone metastasis and release and regulation of hormones. Over the years various newer physiological roles have been observed thus opening ways for various novel therapeutic treatments. This review aims to provide an overview of important different types of neuromedin, their receptors, signal transduction mechanism and implications for various diseases.
Neuromedin U inhibits food intake partly by inhibiting gastric emptying
2015, Peptides
Citation Excerpt :
Similar short-lived effects on food intake and body weight have also been described for other gut-brain peptides such as neurotensin, xenin and cholecystokinin (CCK) [34,35]. Repeated in vitro administration of NMU8 to isolated porcine jejunum has been shown to lead to tachyphylaxis [36]. Similarly, the contractile response of human isolated ileum was also characterized by the development of tachyphylaxis following repeated application of NMU8 [37].
Neuromedin U (NMU) is a gut-brain peptide, implicated in energy and glucose homeostasis via the peripherally expressed NMU receptor 1 (NMUR1) and the central NMUR2. We investigated the effects of a lipidated NMU analog on gastric emptying (GE), glucose homeostasis and food intake to evaluate the use of a NMU analog as drug candidate for treatment of obesity and diabetes. Finally mRNA expression of NMU and NMUR1 in the gut and NMUR2 in the hypothalamus was investigated using a novel chromogen-based in situ hybridization (ISH) assay. Effects on food intake (6 and 18 h post dosing) were addressed in both mice and rats. The effects on GE and glycaemic control were assessed in mice, immediately after the first dose and after seven days of bidaily (BID) dosing. The lipidated NMU analog exerted robust reductions in GE and food intake in mice and improved glycaemic control when measured immediately after the first dose. No effects were observed after seven days BID. In rats, the analog induced only a minor effect on food intake. NMU mRNA was detected in the enteric nervous system throughout the gut, whereas NMUR1 was confined to the lamina propria. NMUR2 was detected in the paraventricular (PVN) and arcuate nuclei (ARC) in mice, with a reduced expression in ARC in rats. In summary, the anorectic effect of the lipidated NMU is partly mediated by a decrease in gastric emptying which is subject to tachyphylaxis after continuous dosing. Susceptibility to NMU appears to be species specific.
Design, synthesis and biological activity of flavonoid derivatives as selective agonists for neuromedin U 2 receptor
2014, Bioorganic and Medicinal Chemistry
Citation Excerpt :
Neuromedin U (NMU) regulates a variety of physiological activities in mammals, including stimulation of smooth-muscle contraction,1 blood pressure regulation,2 ion transport,3,4 local blood flow control,5 gastric acid secretion and gastric emptying.6
Central neuromedin U 2 receptor (NMU2R) plays important roles in the regulation of food intake and body weight. Identification of NMU2R agonists may lead to the development of pharmaceutical agents to treat obesity. Based on the structure of rutin, a typical flavonoid and one of the NMU2R agonists we previously identified from an in-house made natural product library, 30 flavonoid derivatives have been synthesized and screened on a cell-based reporter gene assay. A number of compounds were found to be selective and highly potent to NMU2R. For example, the EC₅₀ value of compound NRA 4 is very close to that of NMU, the endogenous peptide ligand of NMU2R. Structure–activity relationship analysis revealed that a 3-hydroxyl group in ring C and a 2′-fluoride group in ring B were essential for this class of compounds to be active against NMU2R.

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Short communicationNeuromedin U octapeptide alters ion transport in porcine jejunum

Abstract

Reg. Pept.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Short communication
Neuromedin U octapeptide alters ion transport in porcine jejunum