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Gene Review

Brs3  -  bombesin-like receptor 3

Mus musculus

Synonyms: BRS-3, Bombesin receptor subtype-3
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Disease relevance of Brs3

  • In BRS-3-deficient mice, we found hyperphagia, subsequent hyperleptinemia, and brain leptin resistance that occurred after the onset of obesity [1].
  • Of the 22 ovarian cancer specimens analyzed, 17 tumors ( approximately 77%) expressed mRNA for GRPR, 19 ( approximately 86%) showed NMBR mRNA and six ( approximately 27%) revealed BRS-3 mRNA [2].
  • Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity [3].
  • To gain insight into the underlying structure and chromosomal localization of the BRS-3 genes, bacteriophage P1 genomic clones, harboring the genes for the human and mouse BRS-3, respectively, were isolated and their structure and chromosomal localizations determined [4].
  • Pharmacology and intracellular signaling mechanisms of the native human orphan receptor BRS-3 in lung cancer cells [5].
  • We conclude that hyperphagia is a major factor leading to increased body weight and hyperinsulinemia in BRS-3 KO mice [6].

High impact information on Brs3


Biological context of Brs3

  • GRPR gene expression was detected predominantly in utero, whereas NMBR and BRS-3 genes were expressed from embryonic days 13-16 and on multiple postnatal days [9].
  • The loci of the BRS-3 genes were mapped to a syntenic region of the human (Xq25) and mouse (XA7.1-7.2) X-chromosome, respectively [4].
  • Bombesin, gastrin-releasing peptide, NMB, and a bombesin receptor subtype 3-specific ligand induced mast cell proliferation and chemotaxis in vitro [10].
  • The open reading frame of the putative GRP-R gene encodes for a 384-amino-acid protein which demonstrates 48% identity with the mouse BRS-3 protein and 53% identity with the mouse NMB-R protein [11].
  • Using these mutant mouse, we have found unexpected phenotypes, such as hyperphagia and obesity in the BRS-3-deficient mouse, and abnormal social behaviour in the GRP-R-deficient mouse [12].

Anatomical context of Brs3

  • In contrast, BRS-3 has been shown to be expressed in rat testis and guinea-pig uterus, therefore it is possible that a different subtype of the bombesin receptor mediates the same response in different species [13].
  • In mouse testis, the NMB-R gene expression is prominent, and the expression of BRS-3 mRNA is barely detected [13].
  • To study the pharmacology of BRS-3 in the context of a mammalian cell, we used BR2 cells, which are Balb/3T3 fibroblasts transfected with BRS-3 cDNA [14].
  • Some bombesin-like peptides were shown to activate BRS-3 expressed in Xenopus laevis oocytes, but only at relatively high concentrations, which suggests that BRS-3 is an orphan receptor [14].
  • BN receptors on membranes of PC-3 tumors were detected by (125)I-[Tyr(4)]BN binding, and expression of mRNA for BRS-3 and GRP-R subtypes was also found [15].

Associations of Brs3 with chemical compounds

  • Dexamethasone and bombesin increased GRPR mRNA, bombesin downregulated NMBR, and neither agent affected BRS-3 [9].
  • One such analog, D-Phe6-BN(6-13) propyl amide, activated BRS-3-mediated calcium mobilization with an EC50 level of 84 nM [14].
  • Neuromedin B (NMB) receptor-null and bombesin receptor subtype 3-null mice had the same responses as their wild-type littermates [16].
  • Furthermore, a conditioned taste-aversion test measured the consumption of sodium saccharin (0.2%) and sodium chloride (0.9%) solutions after intraperitoneal injection of LiCl (0.3 M, 1 mg/kg), and BRS-3-deficient mice exhibited stronger aversion to both solutions than did control animals [17].
  • A radically modified heptapeptide agonist, maintaining only the Trp-Ala moiety of the parent [H-D-Phe6,betaAla11,Phe13,Nle14]-peptide amide, and with a very different carboxyl terminal region, has been produced which was potent at BRS3 and essentially had no NMB or GRP receptor activity [18].

Other interactions of Brs3

  • To explore the cause of this phenomenon, we examined changes in feeding responses to appetite-related neuropeptides in BRS-3-deficient, GRP-R-deficient, and wild-type littermate mice [1].
  • These results were confirmed by making the reverse mutations in BRS-3 to make GRP gain of affinity mutants [19].
  • The mRNA levels for BRS-3, but not for BRS-2, were lower in the AN-215-treated tumours as compared with controls [20].

Analytical, diagnostic and therapeutic context of Brs3


  1. Leptin resistance and enhancement of feeding facilitation by melanin-concentrating hormone in mice lacking bombesin receptor subtype-3. Maekawa, F., Quah, H.M., Tanaka, K., Ohki-Hamazaki, H. Diabetes (2004) [Pubmed]
  2. The presence of receptors for bombesin/GRP and mRNA for three receptor subtypes in human ovarian epithelial cancers. Sun, B., Schally, A.V., Halmos, G. Regul. Pept. (2000) [Pubmed]
  3. Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity. Ohki-Hamazaki, H., Watase, K., Yamamoto, K., Ogura, H., Yamano, M., Yamada, K., Maeno, H., Imaki, J., Kikuyama, S., Wada, E., Wada, K. Nature (1997) [Pubmed]
  4. Structure and chromosomal localization of the mouse bombesin receptor subtype 3 gene. Weber, H.C., Hampton, L.L., Jensen, R.T., Battey, J.F. Gene (1998) [Pubmed]
  5. Pharmacology and intracellular signaling mechanisms of the native human orphan receptor BRS-3 in lung cancer cells. Ryan, R.R., Weber, H.C., Mantey, S.A., Hou, W., Hilburger, M.E., Pradhan, T.K., Coy, D.H., Jensen, R.T. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  6. Factors contributing to obesity in bombesin receptor subtype-3-deficient mice. Ladenheim, E.E., Hamilton, N.L., Behles, R.R., Bi, S., Hampton, L.L., Battey, J.F., Moran, T.H. Endocrinology (2008) [Pubmed]
  7. Functional properties of two bombesin-like peptide receptors revealed by the analysis of mice lacking neuromedin B receptor. Ohki-Hamazaki, H., Sakai, Y., Kamata, K., Ogura, H., Okuyama, S., Watase, K., Yamada, K., Wada, K. J. Neurosci. (1999) [Pubmed]
  8. The bombesin receptor subtypes have distinct G protein specificities. Jian, X., Sainz, E., Clark, W.A., Jensen, R.T., Battey, J.F., Northup, J.K. J. Biol. Chem. (1999) [Pubmed]
  9. Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung. Shan, L., Emanuel, R.L., Dewald, D., Torday, J.S., Asokanathan, N., Wada, K., Wada, E., Sunday, M.E. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  10. Bombesin-like peptides and mast cell responses: relevance to bronchopulmonary dysplasia? Subramaniam, M., Sugiyama, K., Coy, D.H., Kong, Y., Miller, Y.E., Weller, P.F., Wada, K., Wada, E., Sunday, M.E. Am. J. Respir. Crit. Care Med. (2003) [Pubmed]
  11. Molecular organization of the mouse gastrin-releasing peptide receptor gene and its promoter. Weber, H.C., Jensen, R.T., Battey, J.F. Gene (2000) [Pubmed]
  12. Bombesin-like peptides: studies on food intake and social behaviour with receptor knock-out mice. Yamada, K., Wada, E., Wada, K. Ann. Med. (2000) [Pubmed]
  13. Cloning and expression of the neuromedin B receptor and the third subtype of bombesin receptor genes in the mouse. Ohki-Hamazaki, H., Wada, E., Matsui, K., Wada, K. Brain Res. (1997) [Pubmed]
  14. Discovery of high affinity bombesin receptor subtype 3 agonists. Wu, J.M., Nitecki, D.E., Biancalana, S., Feldman, R.I. Mol. Pharmacol. (1996) [Pubmed]
  15. In vivo inhibition of PC-3 human androgen-independent prostate cancer by a targeted cytotoxic bombesin analogue, AN-215. Plonowski, A., Nagy, A., Schally, A.V., Sun, B., Groot, K., Halmos, G. Int. J. Cancer (2000) [Pubmed]
  16. Bombesin inhibits alveolarization and promotes pulmonary fibrosis in newborn mice. Ashour, K., Shan, L., Lee, J.H., Schlicher, W., Wada, K., Wada, E., Sunday, M.E. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  17. Hyperresponsiveness to palatable and aversive taste stimuli in genetically obese (bombesin receptor subtype-3-deficient) mice. Yamada, K., Wada, E., Imaki, J., Ohki-Hamazaki, H., Wada, K. Physiol. Behav. (1999) [Pubmed]
  18. The design of a new potent and selective ligand for the orphan bombesin receptor subtype 3 (BRS3). Boyle, R.G., Humphries, J., Mitchell, T., Showell, G.A., Apaya, R., Iijima, H., Shimada, H., Arai, T., Ueno, H., Usui, Y., Sakaki, T., Wada, E., Wada, K. J. Pept. Sci. (2005) [Pubmed]
  19. Identification of key amino acids in the gastrin-releasing peptide receptor (GRPR) responsible for high affinity binding of gastrin-releasing peptide (GRP). Nakagawa, T., Hocart, S.J., Schumann, M., Tapia, J.A., Mantey, S.A., Coy, D.H., Tokita, K., Katsuno, T., Jensen, R.T. Biochem. Pharmacol. (2005) [Pubmed]
  20. Targeted cytotoxic analogue of bombesin/gastrin-releasing peptide inhibits the growth of H-69 human small-cell lung carcinoma in nude mice. Kiaris, H., Schally, A.V., Nagy, A., Sun, B., Armatis, P., Szepeshazi, K. Br. J. Cancer (1999) [Pubmed]
  21. Differential effects of social isolation upon body weight, food consumption, and responsiveness to novel and social environment in bombesin receptor subtype-3 (BRS-3) deficient mice. Yamada, K., Ohki-Hamazaki, H., Wada, K. Physiol. Behav. (2000) [Pubmed]
  22. Molecular cloning, genomic organization and selective expression of bombesin receptor subtype 3 in the sheep hypothalamus and pituitary. Whitley, J.C., Moore, C., Giraud, A.S., Shulkes, A. J. Mol. Endocrinol. (1999) [Pubmed]
  23. Mutation in bombesin receptor subtype-3 gene is not a major cause of obesity in the Japanese. Hotta, K., Matsukawa, Y., Nishida, M., Kotani, K., Takahashi, M., Kuriyama, H., Nakamura, T., Wada, K., Yamashita, S., Funahashi, T., Matsuzawa, Y. Horm. Metab. Res. (2000) [Pubmed]
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