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

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 protein-coupled 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.

[1]  N. Minamino,et al.  Neuromedin U-8 and U-25: novel uterus stimulating and hypertensive peptides identified in porcine spinal cord. , 1985, Biochemical and biophysical research communications.

[2]  M. Ghatei,et al.  Characterization of neuromedin U like immunoreactivity in rat, porcine, guinea-pig and human tissue extracts using a specific radioimmunoassay. , 1986, Biochemical and biophysical research communications.

[3]  S. Sumi,et al.  Effect of synthetic neuromedin U-8 and U-25, novel peptides identified in porcine spinal cord, on splanchnic circulation in dogs. , 1987, Life sciences.

[4]  M. Ghatei,et al.  Neuromedin U—A study of its distribution in the rat , 1987, Peptides.

[5]  M. Tohyama,et al.  Topographic localization of neuromedin u-like structures in the rat brain: An immunohistochemical study , 1987, Neuroscience.

[6]  S. Augood,et al.  Distribution and characterisation of neuromedin U-like immunoreactivity in rat brain and intestine and in guinea pig intestine , 1988, Regulatory Peptides.

[7]  C. Maggi,et al.  Motor response of the human isolated small intestine and urinary bladder to porcine neuromedin U‐8 , 1990, British journal of pharmacology.

[8]  S. Gardiner,et al.  Differential effects of neuropeptides on coeliac and superior mesenteric blood flows in conscious rats , 1990, Regulatory Peptides.

[9]  J. Domin,et al.  The motor effect of neuromedin U on rat stomach in vitro. , 1991, European journal of pharmacology.

[10]  H. Wu,et al.  Endothelin receptor binding and cellular signal transduction in neurohybrid NG108-15 cells , 1991, Neuroscience.

[11]  Contractile activity of porcine neuromedin U-25 and various neuromedin U-related peptide fragments on isolated chicken crop smooth muscle. , 1992, Chemical & pharmaceutical bulletin.

[12]  S. Legon,et al.  Distribution and developmental pattern of neuromedin U expression in the rat gastrointestinal tract. , 1994, Journal of molecular endocrinology.

[13]  J. Warchoł,et al.  Effects of neuromedin U-8 on the secretory activity of the rat adrenal cortex: evidence for an indirect action requiring the presence of the zona medullaris , 1994, Research in experimental medicine. Zeitschrift fur die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie.

[14]  J. Warchoł,et al.  Effects of neuromedin U (NMU)-8 on the rat hypothalamo-pituitary-adrenal axis. Evidence of a direct effect of NMU-8 on the adrenal gland , 1994, Neuropeptides.

[15]  Marc Parmentier,et al.  Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor , 1995, Nature.

[16]  S. Bloom,et al.  Cloning and characterization of the cDNA encoding the human neuromedin U (NmU) precursor: NmU expression in the human gastrointestinal tract. , 1995, Journal of molecular endocrinology.

[17]  D. Bergsma,et al.  Orphan G protein-coupled receptors: a neglected opportunity for pioneer drug discovery. , 1997, Trends in pharmacological sciences.

[18]  Hirokazu Matsumoto,et al.  A prolactin-releasing peptide in the brain , 1998, Nature.

[19]  A. Howard,et al.  Cloning and characterization of a human and murine T-cell orphan G-protein-coupled receptor similar to the growth hormone secretagogue and neurotensin receptors. , 1998, Genomics.

[20]  M. Nakazato,et al.  Ghrelin is a growth-hormone-releasing acylated peptide from stomach , 1999, Nature.

[21]  J. Chambers,et al.  Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1 , 1999, Nature.

[22]  J. Chambers,et al.  Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. , 1999, Molecular pharmacology.

[23]  S. Bloom,et al.  Isolation, Structural Characterization, and Bioactivity of a Novel Neuromedin U Analog from the Defensive Skin Secretion of the Australasian Tree Frog, Litoria caerulea * 210 , 2000, The Journal of Biological Chemistry.

[24]  J. Chambers,et al.  A G Protein-coupled Receptor for UDP-glucose* , 2000, The Journal of Biological Chemistry.

[25]  J. Trill,et al.  Human AT1 receptor is a single copy gene: Characterization in a stable cell line , 1994, Molecular and Cellular Biochemistry.