The motor effect of neuromedin U on rat stomach in vitro

Benito-Orfila, M.A.; Domin, Jan; Nandha, Kiran A.; Bloom, Stephen R.

doi:10.1016/0014-2999(91)90147-i

Cited by 27 publications

(29 citation statements)

References 12 publications

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“…Of relevance to the present study are the observations that NmU mediates contraction of canine (Westfall et al, 2001) and human colon (Jones et al, 2006) but not colon from rat, guinea pig, or mouse (Benito-Orfila et al, 1991;Prendergast et al, 2006). The lack of a direct effect of NmU on contraction of mouse colon has been supported by a recent study, although it did potently enhance electrically stimulated, nerve-evoked contractions, possibly through prejunctional effects within the enteric ganglia (Dass et al, 2007).…”

Section: Neuromedin U Signaling In Smooth Musclesupporting

confidence: 68%

Paradoxical Behavior of Neuromedin U in Isolated Smooth Muscle Cells and Intact Tissue

Brighton

Wise²,

Dass³

et al. 2008

J Pharmacol Exp Ther

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Neuromedin U (NmU) is a neuropeptide showing high levels of structural conservation across different species. Since its discovery in 1985, NmU has been implicated in numerous physiological roles, including smooth muscle contraction, energy homeostasis, stress, intestinal ion transport, pronociception, and circadian rhythm. Two G-protein-coupled receptors have been identified for NmU and cloned from humans, rats, and mice. Recombinantly expressed NmU receptors couple to both G␣ q/11 and G␣ i G-proteins, and NmU binds essentially irreversibly, preventing signaling to repetitive applications of NmU. However, it is unclear whether these properties reflect those of endogenously expressed NmU receptors or how these properties influence the functional consequences of NmU receptor signaling. Here, we have explored the signaling by rat NmU receptors expressed endogenously in cultured rat colonic smooth muscle cells and explore the functional consequence of this signaling by investigating the NmU-mediated contraction of ex vivo rat colonic smooth muscle preparations. We demonstrate that endogenous rat NmU receptors couple to both G␣ q/11 and G␣ i G-proteins. Furthermore, we show complex patterns of Ca 2ϩ signaling, including oscillations, and provide evidence of essentially irreversible binding of NmU to smooth muscle cells. Challenge of either circular or longitudinal rat isolated colonic smooth muscle preparations with NmU resulted in robust contractions. Stimulation was direct, and paradoxically, repetitive applications of NmU mediated repetitive contractions with no evidence of desensitization, highlighting a major discrepancy in the behavior of NmU in single cells and in intact tissues. The reason for this discrepancy is presently unknown.

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Section: Neuromedin U Signaling In Smooth Musclesupporting

confidence: 68%

Paradoxical Behavior of Neuromedin U in Isolated Smooth Muscle Cells and Intact Tissue

Brighton

Wise²,

Dass³

et al. 2008

J Pharmacol Exp Ther

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“…We observed no difference in the intestinal transit of a charcoal-based marker between wild-type and NmU Tg mice. Although NmU stimulates ileal smooth muscle contraction in dogs and humans in vitro (Maggi et al 1990, Westfall et al 2002, it failed to stimulate porcine jejunum, guinea pig ileal smooth muscle, and rat small and large intestinal longitudinal smooth muscle in vitro (Minamino et al 1985a, Brown & Quito 1988, Benito-Orfila et al 1991. The absence of a difference between wild-type and NmU Tg mice in this regard is therefore not entirely surprising, and indicates that changes in intestinal motility are probably not involved in the phenotype observed.…”

Section: Discussionmentioning

confidence: 87%

“…Recent work, however, has shown that central administration of NmU decreases gastric acid secretion and slows gastric emptying in rats (Mondal et al 2003), potentially affecting meal size and frequency. This contrasts with studies showing that NmU directly stimulates contraction of rat fundic circular smooth muscle in vitro (Benito-Orfila et al 1991). Given that there are species differences in smooth muscle contractility in response to NmU in vitro, studies examining gastric emptying and nutrient absorption are required to fully assess whether changes in GI smooth muscle physiology play a role in the phenotype of these Tg mice.…”

Section: Discussionmentioning

confidence: 90%

Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice

Kowalski¹,

Spar²,

Markowitz³

et al. 2005

Journal of Endocrinology

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Recent work has shown that neuromedin U (NmU), a peptide initially identified as a smooth muscle contractor, may play a role in regulating food intake and energy homeostasis. To further evaluate this putative function, we measured food intake, body weight, energy expenditure and glucose homeostasis in transgenic mice that ubiquitously overexpress murine proNmU. NmU transgenic mice were lighter and had less somatic and liver fat, were hypophagic, and had improved insulin sensitivity as judged by an intraperitoneal insulin tolerance test. Transgenic mice had higher levels of hypothalamic NPY, POMC and MCH mRNA. There was no difference in O 2 consumption between genotypes; however, NmU transgenic mice displayed a modest increase in respiratory quotient during food deprivation and refeeding. There were no behavioral disturbances in the NmU transgenic mice that could account for the results (e.g. changes in locomotor activity). When placed on a high-fat diet, transgenic mice remained lighter than wild-type mice and ate less, but gained weight at a rate similar to wild-type mice. Despite the increased weight gain with high-fat feeding, glucose tolerance was significantly improved in the transgenic mice. These findings support the hypothesized role of NmU as an endogenous anorexigenic peptide.

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“…Since then, neuromedin U has been found to show various biological activities including the elevation of blood pressure and the induction of adrenocorticotropin and corticosterone release in vivo in rats (1,(3)(4)(5)(6)). Applying our previously described strategy to identify endogenous ligands for orphan G protein-coupled receptors (GPCRs) 1 (7-9), we recently succeeded in demonstrating that the orphan GPCR, FM-3, a homologue of the neurotensin (NT) and growth hormone secretagogue receptors, is a specific and functional receptor for neuromedin U (10).…”

mentioning

confidence: 99%

Identification and Functional Characterization of a Novel Subtype of Neuromedin U Receptor

Hashimoto

Moriya

Kawamata

et al. 2000

Journal of Biological Chemistry

113

110

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Neuromedin U is a bioactive peptide isolated originally from the porcine spinal cord. We recently identified neuromedin U as the cognate ligand for the orphan G protein-coupled receptor FM-3. In this study, we isolated cDNA coding for a novel G protein-coupled receptor, TGR-1, which was highly homologous with FM-3. We found that neuromedin U specifically and clearly elevated the extracellular acidification rates, arachidonic acid metabolite release, and intracellular Ca 2؉ mobilization in Chinese hamster ovary cells expressing TGR-1. Radiolabeled neuromedin U specifically bound with high affinity to membrane fractions prepared from these cells. These results show that TGR-1, like FM-3, is a specific and functional receptor for neuromedin U. We analyzed TGR-1 mRNA tissue distribution in rats using quantitative reverse transcription-polymerase chain reaction and found it to considerably differ from that of FM-3 mRNA. TGR-1 mRNA was primarily expressed in the uterus, suggesting that TGR-1 mediates the contractile activity of neuromedin U in this tissue. The identification of specific and functional receptor subtypes for neuromedin U will facilitate the study of their physiological roles and the search for their specific agonists and antagonists.The bioactive peptides neuromedin U-8 and U-25 were originally isolated from the porcine spinal cord based on their powerful contractile activity in the uterine smooth muscle of rats (1, 2). Since then, neuromedin U has been found to show various biological activities including the elevation of blood pressure and the induction of adrenocorticotropin and corticosterone release in vivo in rats (1, 3-6). Applying our previously described strategy to identify endogenous ligands for orphan G protein-coupled receptors (GPCRs) 1 (7-9), we recently succeeded in demonstrating that the orphan GPCR, FM-3, a homologue of the neurotensin (NT) and growth hormone secretagogue receptors, is a specific and functional receptor for neuromedin U (10). When FM-3 was expressed in Chinese hamster ovary (CHO) cells, neuromedin U induced specific and clear elevation of extracellular acidification rates, arachidonic acid metabolite (AA) release, and intracellular Ca 2ϩ mobilization. Radiolabeled neuromedin U specifically bound with high affinity to membrane fractions prepared from these cells. Our analyses for FM-3 mRNA expression levels using quantitative reverse transcription-polymerase chain reaction (RT-PCR) indicated that FM-3 mRNA was expressed highly in the small intestine and lung of rats, but only very low levels were detected in the uterus. Nonetheless neuromedin U has reportedly shown very strong contractile activity (1, 2), and numerous binding sites have been detected in rat uterine tissue (11, 12). We considered that this discrepancy might be due to the existence of an unknown receptor subtype for neuromedin U in the rat uterus. We therefore searched for another neuromedin U receptor subtype in addition to FM-3.In this paper, we report on the isolation of human and rat cDNA encoding a n...

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The motor effect of neuromedin U on rat stomach in vitro

Cited by 27 publications

References 12 publications

Paradoxical Behavior of Neuromedin U in Isolated Smooth Muscle Cells and Intact Tissue

Paradoxical Behavior of Neuromedin U in Isolated Smooth Muscle Cells and Intact Tissue

Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice

Identification and Functional Characterization of a Novel Subtype of Neuromedin U Receptor

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