Neuromedin U stimulates contraction of human long saphenous vein and gastrointestinal smooth muscle in vitro

Jones, Nick D.; Morton, Magda F.; Prendergast, Clodagh; Powell, Garth L.; Shankley, Nigel P.; Hollingsworth, Simon J.

doi:10.1016/j.regpep.2006.05.003

Cited by 11 publications

(4 citation statements)

References 41 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: 67%

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: 67%

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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“…Firstly, it is necessary to determine whether the role of NMU in the animal model reflects that observed in humans. NMU has been shown to cause direct contraction of human ascending colon (Jones et al. , 2006), though it is not reported whether NMU could also potentiate electrically induced contractions.…”

Section: Functions Of Nmumentioning

confidence: 99%

Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin S

Mitchell

Maguire

Davenport

2009

British J Pharmacology

103

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Neuromedin U (NMU) has been paired with the G-protein-coupled receptors (GPRs) NMU1 (formely designated as the orphan GPR66 or FM-3) and NMU2 (FM-4 or hTGR-1). Recently, a structurally related peptide, neuromedin S (NMS), which shares an amidated C-terminal heptapeptide motif, has been identified in both rat and human, and has been proposed as a second ligand for these receptors. Messenger RNA encoding NMU receptor subtypes shows differential expression: NMU1 is predominantly expressed in peripheral tissues, particularly the gastrointestinal tract, whereas NMU2 is abundant within the brain and spinal cord. NMU peptide parallels receptor distribution with highest expression in the gastrointestinal tract and specific structures within the brain, reflecting its major role in the regulation of energy balance. The NMU knockout mouse has an obese phenotype and, in agreement, the Arg165Trp amino acid variant of NMU-25 in humans, which is functionally inactive, co-segregated with childhood-onset obesity. Emerging physiological roles for NMU include vasoconstriction mediated predominantly via NMU1 with nociception and bone remodelling via NMU2. The NMU system has also been implicated in the pathogenesis of septic shock and cancers including bladder carcinoma and acute myeloid leukaemia. Intriguingly, NMS is more potent at NMU2 receptors in vivo where it has similar central actions in suppression of feeding and regulation of circadian rhythms to NMU. Taken together with its vascular actions, NMU may be a functional link between energy balance and the cardiovascular system and may provide a future target for therapies directed against the disorders that comprise metabolic syndrome.

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“…NmU contracted strips of rat uterus in vitro hence the suffix U was added. NmU mediates smooth muscle contraction in a variety of tissues especially in intestine, urinary bladder, and uterus in a concentration-dependent manner that is direct, involving neither cholinergic activation nor nervous stimulation [1, [56][57][58]. Prendergast et al [59] studied the smooth muscle contractile effect of NmU on different tissues in different animals and suggested the effect may be related to NmU-R2.…”

Section: S M O O T H M U S C L E C O N T R a C T I O N ( O T H E R T mentioning

confidence: 99%

Neuromedin U: physiology, pharmacology and therapeutic potential

Budhiraja

Chugh

2009

Fundamemntal Clinical Pharma

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Neuromedin U (NmU), a multifunctional neuropeptide, belongs to a family of neuropeptides, the neuromedins. It is ubiquitously distributed with highest levels found in the gastrointestinal tract and pituitary. The conservation of structural elements of NmU across species, the widespread distribution of NmU and its receptors throughout the body point to a fundamental role in key physiological processes. Two G protein coupled receptors for NmU have been cloned NmU R1 and NmU R2. NmU R1 is expressed pre-dominantly in the periphery especially the gastrointestinal tract whereas NmU R2 is expressed pre-dominantly in the central nervous system. Current evidence suggests a role of NmU in pain, in regulation of feeding and energy homeostasis, stress, cancer, immune mediated inflammatory diseases like asthma, inflammatory diseases, maintaining the biological clock, in the regulation of smooth muscle contraction in the gastrointestinal and genitourinary tract, and in the control of blood flow and blood pressure. With the development of drugs selectively acting on receptors and knockout animal models, exact pathophysiological roles of NmU will become clearer.

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Neuromedin U stimulates contraction of human long saphenous vein and gastrointestinal smooth muscle in vitro

Cited by 11 publications

References 41 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

Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin S

Neuromedin U: physiology, pharmacology and therapeutic potential

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