Alternative titles; symbols
HGNC Approved Gene Symbol: BDKRB1
Cytogenetic location: 14q32.2 Genomic coordinates (GRCh38): 14:96,256,210-96,264,763 (from NCBI)
BDKRB1 is one of 2 physiologically distinct G protein-couple receptors that mediate the biologic activities of kinins, a family of bioactive octo- to decapeptides generated from kininogen (KNG1; 612358) in a stepwise cleavage process. Under physiologic condition, BDKRB1 is not found on immune cells, whereas the other kinin receptor, BDKRB2, is ubiquitously expressed (Schulze-Topphoff et al., 2009).
Menke et al. (1994) isolated a cDNA clone encoding BDKRB1, or B1R, from a human embryonic lung fibroblast cDNA library by expression cloning. The open reading frame encodes a 353-amino acid protein with the characteristics of a G protein-coupled receptor. It shares 36% amino acid identity with the B2 bradykinin receptor (B2R; 113503).
Yang and Polgar (1996) isolated the human B1 bradykinin receptor gene from a human lung fibroblast genomic DNA library. They found 2 differences between their coding sequence and that which was obtained by Menke et al. (1994): an A-to-C exchange at nucleotide 2897, leading to replacement of arginine-246 with serine, and a C-to-T exchange at position 3025, which converts serine-259 to phenylalanine.
Using RT-PCR-Southern blot analysis, Chai et al. (1996) found that the B1 receptor gene had widespread tissue expression. Northern blot analysis identified a 1.7- to 1.8-kb mature mRNA transcript in kidney and pancreas.
Chai et al. (1996) cloned and sequenced the BDKRB1 gene, which contains an uninterrupted coding exon. A putative promoter was identified by linking various lengths of the 5-prime flanking region of the coding sequence to a CAT reporter and assaying for CAT activity. Deletion analysis showed that a 300-bp fragment of the promoter region is sufficient to direct the synthesis of the reporter and that an enhancer-like element is present between nucleotides -1842 and -812. A genomic Southern blot using B1 cDNA revealed that the receptor is encoded by a single-copy gene.
Bachvarov et al. (1996) showed that the BDKRB1 gene contains 3 exons, the first 2 of which contain noncoding sequences. A TATA box occurs 5-prime of exon 1.
Using luciferase activity assays, Yang and Polgar (1996) found 2 promoters for the human BDKRB1 gene. The first is a 451-bp fragment located in the 5-prime flanking region, and the second is an 812-bp fragment found in the intron II region. The intron II region promoter showed a 10-fold decrease in luciferase activity relative to the 5-prime flanking region promoter. Yang and Polgar (1996) mapped the transcriptional initiation site of the BDKRB1 gene at 21 bp downstream of the TATA box. This site is 12 bp longer than that of the 5-prime untranslated region sequence published by MacNeil et al. (1995). In addition, 2 inverted orientation Alu repeats were found in the BDKRB1 gene.
By fluorescence in situ hybridization, Chai et al. (1996) mapped the BDKRB1 gene to chromosome 14q32.1-q32.2, in close proximity to the B2 receptor gene.
Two mammalian bradykinin receptor subtypes, B1 and B2, had been defined based on their pharmacologic properties. The B1 receptor is synthesized de novo following tissue injury and mediates hyperalgesia in animal models of chronic inflammation. The B2 bradykinin receptor is normally present in smooth muscle and certain neurons where activation of B2 receptors causes pronounced hypotension, bronchoconstriction, pain, and inflammation. Menke et al. (1994) confirmed that the B1 receptor that they cloned had the pharmacologic characteristics of the B1 receptor subtype when expressed.
Souza et al. (2004) investigated the roles of B1r and B2r in a model of intestinal ischemia/reperfusion (I/R) injury in mice. They found that a B2r antagonist inhibited injury and delayed lethality. After I/R, there was an increase in B1r mRNA expression in the absence of the B2r antagonist. In mice lacking B1r, inflammatory injury was also abrogated and death was delayed or prevented, except in mice treated with the B2r antagonist. Souza et al. (2004) concluded that there is significant interaction between B1 and B2 receptors and proposed that blockade of B1R could be a more effective strategy than B2 or B1/B2 receptor blockade for the treatment of inflammatory injuries following I/R.
Kakoki et al. (2007) generated mice lacking both Bdkrb1 and Bdkrb2. The mutant mice were extremely vulnerable to renal ischemia/reperfusion injury, and the vulnerability was greater in mice lacking both receptors than in those lacking only Bdkrb2.
Schulze-Topphoff et al. (2009) found that a Bdkrb1 agonist decreased the clinical symptoms of experimental autoimmune encephalomyelitis in mice, whereas a Bkdrb1 antagonist caused earlier onset and greater severity of disease. Bdkrb1 -/- mice showed more severe disease and enhanced central nervous system (CNS)-immune cell infiltration, and mice reconstituted with mutant T cells showed enhanced Th17 (see 603149) invasion of the CNS. Schulze-Topphoff et al. (2009) concluded that the kallikrein-kinin system is involved in the regulation of CNS inflammation and limits encephalitogenic T-cell infiltration into the CNS.
Bachvarov, D. R., Hess, J. F., Menke, J. G., Larrivee, J.-F., Marceau, F. Structure and genomic organization of the human B(1) receptor gene for kinins (BDKRB1). Genomics 33: 374-381, 1996. [PubMed: 8660997] [Full Text: https://doi.org/10.1006/geno.1996.0213]
Chai, K. X., Ni, A., Wang, D., Ward, D. C., Chao, J., Chao, L. Genomic DNA sequence, expression, and chromosomal localization of the human B1 bradykinin receptor gene BDKRB1. Genomics 31: 51-57, 1996. [PubMed: 8808279] [Full Text: https://doi.org/10.1006/geno.1996.0008]
Kakoki, M., McGarrah, R. W., Kim, H.-S., Smithies, O. Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury. Proc. Nat. Acad. Sci. 104: 7576-7581, 2007. [PubMed: 17452647] [Full Text: https://doi.org/10.1073/pnas.0701617104]
MacNeil, T., Bierilo, K. K., Menke, J. G., Hess, J. F. Cloning and pharmacological characterization of a rabbit bradykinin B-1 receptor. Biochim. Biophys. Acta 1264: 223-228, 1995. [PubMed: 7495867] [Full Text: https://doi.org/10.1016/0167-4781(95)00152-7]
Menke, J. G., Borkowski, J. A., Bierilo, K. K., MacNeil, T., Derrick, A. W., Schneck, K. A., Ransom, R. W., Strader, C. D., Linemeyer, D. L., Hess, J. F. Expression cloning of a human B1 bradykinin receptor. J. Biol. Chem. 269: 21583-21586, 1994. [PubMed: 8063797]
Schulze-Topphoff, U., Prat, A., Prozorovski, T., Siffrin, V., Paterka, M., Herz, J., Bendix, I., Ifergan, I., Schadock, I., Mori, M. A., Van Horssen, J., Schroter, F., Smorodchenko, A., Han, M. H., Bader, M., Steinman, L., Aktas, O., Zipp, F. Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system. Nature Med. 15: 788-793, 2009. [PubMed: 19561616] [Full Text: https://doi.org/10.1038/nm.1980]
Souza, D. G., Lomez, E. S. L., Pinho, V., Pesquero, J. B., Bader, M., Pesquero, J. L., Teixeira, M. M. Role of bradykinin B(2) and B(1) receptors in the local, remote, and systemic inflammatory responses that follow intestinal ischemia and reperfusion injury. J. Immun. 172: 2542-2548, 2004. [PubMed: 14764727] [Full Text: https://doi.org/10.4049/jimmunol.172.4.2542]
Yang, X., Polgar, P. Genomic structure of the human bradykinin B1 receptor gene and preliminary characterization of its regulatory regions. Biochem. Biophys. Res. Commun. 222: 718-725, 1996. [PubMed: 8651911] [Full Text: https://doi.org/10.1006/bbrc.1996.0810]