Neuromedin U receptors (provisional nomenclature as recommended by NC-IUPHAR [2]) are activated by the endogenous 25 amino acid peptide neuromedin U (neuromedin U-25 (NMU, P48645), NmU-25), a peptide originally isolated from pig spinal cord [10]. In humans, NmU-25 appears to be the sole product of a precursor gene (NMU, P48645) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (neuromedin S-33 (NMS, Q5H8A3)) has also been identified as an endogenous agonist [11]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25.

NMU1 and NMU2 couple predominantly to G_q/11 although there is evidence of good coupling to G_i/o [1,4,6]. NMU1 and NMU2 can be labelled with [¹²⁵I]-NmU and [¹²⁵I]-NmS (of various species, e.g. [9]), BODIPY^® TMR-NMU or Cy3B-NMU-8 [1]. A range of radiolabelled (¹²⁵I-), fluorescently labelled (e.g. Cy3, Cy5, rhodamine and FAM) and biotin labelled versions of neuromedin U-25 (NMU, P48645) and neuromedin S-33 (NMS, Q5H8A3) are now commercially available.

* Key recommended reading is highlighted with an asterisk

* Brighton PJ, Szekeres PG, Willars GB. (2004) Neuromedin U and its receptors: structure, function, and physiological roles. Pharmacol Rev, 56 (2): 231-48. [PMID:15169928]

* Budhiraja S, Chugh A. (2009) Neuromedin U: physiology, pharmacology and therapeutic potential. Fundam Clin Pharmacol, 23 (2): 149-57. [PMID:19645813]

* Mitchell JD, Maguire JJ, Davenport AP. (2009) Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin S. Br J Pharmacol, 158 (1): 87-103. [PMID:19519756]

* Novak CM. (2009) Neuromedin S and U. Endocrinology, 150 (7): 2985-7. [PMID:19549882]

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2. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

3. Hedrick JA, Morse K, Shan L, Qiao X, Pang L, Wang S, Laz T, Gustafson EL, Bayne M, Monsma FJ Jr. (2000) Identification of a human gastrointestinal tract and immune system receptor for the peptide neuromedin U. Mol Pharmacol, 58: 870-875. [PMID:10999960]

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5. Howard AD, Wang R, Pong SS, Mellin TN, Strack A, Guan XM, Zeng Z, Williams Jr DL, Feighner SD, Nunes CN et al.. (2000) Identification of receptors for neuromedin U and its role in feeding. Nature, 406 (6791): 70-4. [PMID:10894543]

6. Hsu SH, Luo CW. (2007) Molecular dissection of G protein preference using Gsalpha chimeras reveals novel ligand signaling of GPCRs. Am J Physiol Endocrinol Metab, 293 (4): E1021-9. [PMID:17652154]

7. Kojima M, Haruno R, Nakazato M, Date Y, Murakami N, Hanada R, Matsuo H, Kangawa K. (2000) Purification and identification of neuromedin U as an endogenous ligand for an orphan receptor GPR66 (FM3). Biochem Biophys Res Commun, 276 (2): 435-8. [PMID:11027493]

8. Liu JJ, Payza K, Huang J, Liu R, Chen T, Coupal M, Laird JM, Cao CQ, Butterworth J, Lapointe S et al.. (2009) Discovery and pharmacological characterization of a small-molecule antagonist at neuromedin U receptor NMUR2. J Pharmacol Exp Ther, 330 (1): 268-75. [PMID:19369576]

9. Meng T, Su HR, Binkert C, Fischli W, Zhou L, Shen JK, Wang MW. (2008) Identification of non-peptidic neuromedin U receptor modulators by a robust homogeneous screening assay. Acta Pharmacol Sin, 29 (4): 517-27. [PMID:18358099]

10. Minamino N, Kangawa K, Matsuo H. (1985) Neuromedin U-8 and U-25: novel uterus stimulating and hypertensive peptides identified in porcine spinal cord. Biochem Biophys Res Commun, 130 (3): 1078-85. [PMID:3839674]

11. Mori K, Miyazato M, Ida T, Murakami N, Serino R, Ueta Y, Kojima M, Kangawa K. (2005) Identification of neuromedin S and its possible role in the mammalian circadian oscillator system. EMBO J, 24 (2): 325-35. [PMID:15635449]

12. Raddatz R, Wilson AE, Artymyshyn R, Bonini JA, Borowsky B, Boteju LW, Zhou S, Kouranova EV, Nagorny R, Guevarra MS et al.. (2000) Identification and characterization of two neuromedin U receptors differentially expressed in peripheral tissues and the central nervous system. J Biol Chem, 275 (42): 32452-9. [PMID:10899166]

13. Shan L, Qiao X, Crona JH, Behan J, Wang S, Laz T, Bayne M, Gustafson EL, Monsma Jr FJ, Hedrick JA. (2000) Identification of a novel neuromedin U receptor subtype expressed in the central nervous system. J Biol Chem, 275 (50): 39482-6. [PMID:11010960]

14. Szekeres PG, Muir AI, Spinage LD, Miller JE, Butler SI, Smith A, Rennie GI, Murdock PR, Fitzgerald LR, Wu Hl et al.. (2000) Neuromedin U is a potent agonist at the orphan G protein-coupled receptor FM3. J Biol Chem, 275 (27): 20247-50. [PMID:10811630]

15. Takayama K, Mori K, Asari T, Sohma Y, Nomura E, Sasaki Y, Taguchi A, Taniguchi A, Miyazato M, Minamino N et al.. (2020) Design and synthesis of peptidic partial agonists of human neuromedin U receptor 1 with enhanced serum stability. Bioorg Med Chem Lett, 30 (18): 127436. [PMID:32721452]

16. Takayama K, Mori K, Taketa K, Taguchi A, Yakushiji F, Minamino N, Miyazato M, Kangawa K, Hayashi Y. (2014) Discovery of selective hexapeptide agonists to human neuromedin u receptors types 1 and 2. J Med Chem, 57 (15): 6583-93. [PMID:24999562]

17. Takayama K, Mori K, Tanaka A, Sasaki Y, Sohma Y, Taguchi A, Taniguchi A, Sakane T, Yamamoto A, Miyazato M et al.. (2020) A chemically stable peptide agonist to neuromedin U receptor type 2. Bioorg Med Chem, 28 (10): 115454. [PMID:32247748]

18. Tan CP, McKee KK, Liu Q, Palyha OC, Feighner SD, Hreniuk DL, Smith RG, Howard AD. (1998) Cloning and characterization of a human and murine T-cell orphan G-protein-coupled receptor similar to the growth hormone secretagogue and neurotensin receptors. Genomics, 52 (2): 223-9. [PMID:9782091]

19. Vigo E, Roa J, López M, Castellano JM, Fernandez-Fernandez R, Navarro VM, Pineda R, Aguilar E, Diéguez C, Pinilla L et al.. (2007) Neuromedin s as novel putative regulator of luteinizing hormone secretion. Endocrinology, 148 (2): 813-23. [PMID:17110433]

Subcommittee members: Khaled Al-hosaini Assistant Professor of Molecular Pharmacology Dept. of Pharmacology & Toxicology College of Pharmacy King Saud University PO Box 2457 Riyadh 11451 Kingdom of Saudi Arabia Gary B. Willars (Chairperson) Department of Cell Physiology and Pharmacology University of Leicester University Road Leicester, LE1 9HN UK

Other contributors: Stephen R. Bloom (Past chairperson) Department of Metabolic Medicine Imperial College London 6th Floor Commonwealth Building Hammersmith Campus Du Cane Road London, W12 0NN UK Joseph Hedrick Functional Genomics Research Discovery Technologies Department Schering-Plough Research Institute 2015 Galloping Hill Rd. Kenilworth NJ 07033 USA Andrew Howard Department of Metabolic Disorders Merck Research Laboratories P.O. Box 2000 RY80T-150 Rahway NJ 07065 USA Preeti Jethwa Department of Metabolic Medicine Imperial College London 6th Floor Commonwealth Building Hammersmith Campus Du Cane Road London, W12 0NN UK Simon Luckman School of Biological Sciences University of Manchester Manchester, M13 9PT UK Rita Raddatz AstraZeneca Lead Discovery Department Wilmington DE 19850 USA Nina Semjonous Department of Metabolic Medicine Imperial College London 6th Floor Commonwealth Building Hammersmith Campus Du Cane Road London, W12 0NN UK