Contractile Activity of Porcine Neuromedin U-25 and Various Neuromedin U-Related Peptide Fragments on Isolated Chicken Crop Smooth Muscle.

Okimura, Keiko; Sakura, Naoki; Ohta, Satoru; Kurosawa, Katsuro; Hashimoto, Tadashi

doi:10.1248/cpb.40.1500

Cited by 16 publications

(14 citation statements)

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“…The longer COOH-terminally amidated porcine peptide (NmU-25) contains 25 amino acids, while the shorter peptide (NmU-8) is a result of proteolytic processing of NmU-25 at the Arg 16 -Arg 17 site and represents the amidated COOH-terminal 8 amino acids of the longer form. NmU was subsequently identified in many mammals, including humans (24), and the human gene encoding the NmU precursor peptide has been cloned (25).…”

Section: Discussionmentioning

confidence: 99%

“…NmU-like immunoreactivity has since been detected in neurones in the mammalian brain and gastrointestinal tracts of various species (8 -10) and in the thyroid and endocrine cells of the pituitary gland (8,11). The smooth muscle-contracting effects of NmU are now well documented: NmU causes hypertension (7), can regulate local blood flow in the intestine (12)(13)(14), and exhibits contractile activity in various smooth muscle preparations in vitro, such as human ileum and urinary bladder (15), chicken crop (16), and rat stomach (17). In addition, complex effects on steroid secretion from the adrenal cortex have also been reported (18,19).…”

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confidence: 99%

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Neuromedin U Is a Potent Agonist at the Orphan G Protein-coupled Receptor FM3

Szekeres¹,

Muir²,

Spinage³

et al. 2000

Journal of Biological Chemistry

162

151

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Neuromedins are a family of peptides best known for their contractile activity on smooth muscle preparations. The biological mechanism of action of neuromedin U remains unknown, despite the fact that the peptide was first isolated in 1985. Here we show that neuromedin U potently activates the orphan G proteincoupled receptor FM3, with subnanomolar potency, when FM3 is transiently expressed in human HEK-293 cells. Neuromedins B, C, K, and N are all inactive at this receptor. Quantitative reverse transcriptase-polymerase chain reaction analysis of neuromedin U expression in a range of human tissues showed that the peptide is highly expressed in the intestine, pituitary, and bone marrow, with lower levels of expression seen in stomach, adipose tissue, lymphocytes, spleen, and the cortex. Similar analysis of FM3 expression showed that the receptor is widely expressed in human tissue with highest levels seen in adipose tissue, intestine, spleen, and lymphocytes, suggesting that neuromedin U may have a wide range of presently undetermined physiological effects. The discovery that neuromedin U is an endogenous agonist for FM3 will significantly aid the study of the full physiological role of this peptide. G protein-coupled receptors (GPCRs)1 represent one of the largest gene superfamilies identified to date, with more than 1000 members cloned from a wide range of species. The current explosion in the availability of human genomic sequence data is allowing many more members of this family to be identified in man. Most if not all of these newly identified GPCRs fall into the category of orphan receptors, for which the endogenous ligand(s) remain to be identified. Typically these orphan receptors show only low levels of similarity (less than 35% identity) with known GPCRs, too low to classify them with any confidence into a specific receptor subfamily, although one can often predict the likely class of ligand for these receptors, e.g. peptide, nucleotide, lipid, etc., by using phylogenetic analysis.Recently, naturally occurring ligands have been identified for a number of these orphan GPCRs using a "reverse-pharmacological" approach (1), that is using the recombinant orphan receptor as a specific sensor component of a bioassay. Tissue extracts have often been the source of these natural ligands (2, 3), although more recently the ligands for several orphans have been identified as a result of screening large libraries of known or putative GPCR ligands (4 -6). Here, we describe how this latter approach has been used to identify neuromedin U (NmU) as a naturally occurring ligand for the orphan receptor FM3.Neuromedin U was first isolated over 15 years ago from extracts of porcine spinal cord, using a uterine smooth muscle contraction bioassay to monitor purification (7). Two molecular forms were isolated; neuromedin U-8 (NmU-8) and neuromedin U-25 (NmU-25). NmU-like immunoreactivity has since been detected in neurones in the mammalian brain and gastrointestinal tracts of various species (8 -10) and in the thyroid and endocri...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Neuromedin U Is a Potent Agonist at the Orphan G Protein-coupled Receptor FM3

Szekeres¹,

Muir²,

Spinage³

et al. 2000

Journal of Biological Chemistry

162

151

View full text Add to dashboard Cite

show abstract

“…These sequences may act to fold the peptide, holding it in a conformation that is more favorable for activity. Similarly, fragmentation of the NH 2 -terminal regions of NmU-25 from rabbit, pig, and frog demonstrates that the C-terminal 11-peptide amides retain contractile activity on chicken crop smooth-muscle that is at least three times more potent than their C-terminal 8-peptide amide equivalents (Okimura et al, 1992). This suggests a functional role for the three amino acids directly extending from the C-terminal octapeptide, despite considerable heterogeneity between species.…”

Section: Structure-activity Relationships Of Neuromedin Umentioning

confidence: 95%

“…Indeed, porcine NmU-25 is approximately three to five times more potent than porcine NmU-8 in mediating hypertensive effects in the rat and causing contraction of either rat uterine smooth-muscle or chicken crop smooth-muscle in vitro (Minamino et al, 1985a;Okimura et al, 1992). Similarly in the rat, intravenous porcine NmU-25 is a more potent mediator of mesenteric vasoconstriction (see Section V.B.)…”

Section: Structure-activity Relationships Of Neuromedin Umentioning

confidence: 99%

Neuromedin U and Its Receptors: Structure, Function, and Physiological Roles

Brighton

Szekeres²,

Willars³

2004

Pharmacol Rev

248

219

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“…It was found that the neuromedin U-8 RIA system employing the antiserum ASH-15 was C-terminal specific, because the synthetic N-terminal analogs such as porcine neuromedin U-25 1,13) (Fig. 8) displaced the tracer,…”

Section: Smooth Muscle Contractile Activity and Immunochemical Cross-mentioning

confidence: 99%