* 113503

BRADYKININ RECEPTOR B2; BDKRB2


Alternative titles; symbols

BRADYKININ RECEPTOR 2; BKR2


HGNC Approved Gene Symbol: BDKRB2

Cytogenetic location: 14q32.2     Genomic coordinates (GRCh38): 14:96,204,839-96,244,164 (from NCBI)


TEXT

Description

Bradykinin (BK), a 9-amino acid peptide, is generated from high molecular weight precursors, the kininogens, by limited proteolysis in tissues and body fluids. It elicits numerous responses, including vasodilation, edema, smooth muscle spasm, and stimulation of pain fibers. When activated in pathophysiologic conditions, such as inflammation, trauma, burns, shock, and allergy, kininogens release bradykinin, kallidin (KD or lys-BK), and met-lys bradykinin. Kinin receptors are classified as B1 and B2 on the basis of relative potencies of agonists in isolated vascular smooth muscle preparations. BDKRB2 has high affinity for intact kinins.


Cloning and Expression

Hess et al. (1992) cloned a human BK-2 bradykinin receptor from a lung fibroblast cell line. The cDNA clone encoded a 364-amino acid protein that had the characteristics of a 7-transmembrane domain G protein-coupled receptor. The predicted amino acid sequence showed 81% identity to smooth muscle rat BK-2 receptor. Transfection of the cDNA into COS-7 cells resulted in the expression of high levels of specific BK binding sites.

Powell et al. (1993) used the published rat bradykinin B2 sequence to design PCR amplimers. The full-length cDNA that they obtained also coded for a 364-amino acid protein with a molecular mass of 41,442 Da that was 81% similar to rat bradykinin B2 receptor cDNA.

Genomic Southern blot analysis by Ma et al. (1994) showed that the B2 receptor is encoded by a single-copy gene and is expressed in most human tissues.

Kammerer et al. (1995) obtained both a full-length cDNA and a genomic clone.


Gene Function

The vasopressor angiotensin II regulates vascular contractility and blood pressure through binding to type 1 angiotensin II receptors (106165). Bradykinin, a vasodepressor, is a functional antagonist of angiotensin II. The 2 hormone systems are interconnected by the angiotensin-converting enzyme, which releases angiotensin II from its precursor and inactivates the vasodepressor bradykinin. AbdAlla et al. (2000) demonstrated that the type 1 angiotensin II receptor and the bradykinin B2 receptor also communicate directly with each other. They form stable heterodimers, causing increased activation of G-alpha-q (600998) and G-alpha-i proteins, the 2 major signaling proteins triggered by the type 1 angiotensin II receptor. Furthermore, the endocytotic pathway of both receptors changes with heterodimerization.


Gene Structure

Powell et al. (1993) stated that 'the genomic clone of the gene is intronless'; however, Ma et al. (1994) demonstrated that the BDKRB2 gene contains 3 exons separated by 2 introns. The first and second exons are noncoding, while the third exon contains the full-length coding region.


Mapping

Using PCR for specific amplification of DNA from somatic cell hybrids, Powell et al. (1993) mapped the BDKRB2 gene to chromosome 14. By fluorescence in situ hybridization, Ma et al. (1994) mapped the BDKRB2 gene to 14q32. Taketo et al. (1995) demonstrated that the mouse homolog maps to the distal portion of mouse chromosome 12.


Molecular Genetics

Braun et al. (1995) described 3 polymorphic sites in the BKR2 gene.

Erdmann et al. (1998) screened for mutations in the promoter and coding regions of the human BDKRB2 gene in a group of 92 unrelated subjects with a variety of forms of cardiovascular disease. They detected 8 previously unknown polymorphic sites in the promoter region with allele frequencies between 0.5 and 13%. One of them, (-412C-G), destroyed an Sp1 binding site and abolished protein binding to this SP1 site in human umbilical vein endothelial cells and human vascular smooth muscle cells. In the protein-coding region, a new coding variant, T21M, with the potential to create a truncated receptor isoform was detected. The -412C-G variant was found in 1 of 173 healthy blood donors; the T21M mutation was not found in the control population. The significance of these 2 mutations remained to be determined.


Animal Model

Souza et al. (2004) investigated the roles of B1r (600337) 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.

Humans with type I diabetes and mice with diabetes induced by streptozotocin have an increased risk of developing nephropathy when genetically determined levels of angiotensin-converting enzyme (ACE; 106180) are higher. Because experiments in mice and computer simulations indicated that modest increases in ACE have minimal effects on blood pressure and angiotensin II levels but cause a significant decrease in bradykinin levels, Kakoki et al. (2004) hypothesized that bradykinin is critical for protecting the kidney in diabetics. They confirmed this by demonstrating that Akita diabetic mice lacking the bradykinin B2 receptor developed overt albuminuria, excreting the equivalent of more than 550 mg/day of albumin in humans, which contrasted with the microalbuminuria (equivalent to less than 150 mg/day) seen in their simply diabetic littermates. The overt albuminuria was accompanied by a marked increase in glomerular mesangial sclerosis.

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.


REFERENCES

  1. AbdAlla, S., Lother, H., Quitterer, U. AT(1)-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 407: 94-98, 2000. [PubMed: 10993080, related citations] [Full Text]

  2. Braun, A., Kammerer, S., Bohme, E., Muller, B., Roscher, A. A. Identification of polymorphic sites of the human bradykinin B(2) receptor gene. Biochem. Biophys. Res. Commun. 211: 234-240, 1995. [PubMed: 7779090, related citations] [Full Text]

  3. Erdmann, J., Hegemann, N., Weidemann, A., Kallisch, H., Hummel, M., Hetzer, R., Fleck, E., Regitz-Zagrosek, V. Screening the human bradykinin B2 receptor gene in patients with cardiovascular diseases: identification of a functional mutation in the promoter and a new coding variant (T21M). Am. J. Med. Genet. 80: 521-525, 1998. [PubMed: 9880221, related citations]

  4. Hess, J. F., Borkowski, J. A., Young, G. S., Strader, C. D., Ransom, R. W. Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor. Biochem. Biophys. Res. Commun. 184: 260-268, 1992. [PubMed: 1314587, related citations] [Full Text]

  5. 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, images, related citations] [Full Text]

  6. Kakoki, M., Takahashi, N., Jennette, J. C., Smithies, O. Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor. Proc. Nat. Acad. Sci. 101: 13302-13305, 2004. [PubMed: 15326315, images, related citations] [Full Text]

  7. Kammerer, S., Braun, A., Arnold, N., Roscher, A. A. The human bradykinin B(2) receptor gene: full length cDNA, genomic organization and identification of the regulatory region. Biochem. Biophys. Res. Commun. 211: 226-233, 1995. [PubMed: 7779089, related citations] [Full Text]

  8. Ma, J., Wang, D., Ward, D. C., Chen, L., Dessai, T., Chao, J., Chao, L. Structure and chromosomal localization of the gene (BDKRB2) encoding human bradykinin B2 receptor. Genomics 23: 362-369, 1994. [PubMed: 7835885, related citations] [Full Text]

  9. Powell, S. J., Slynn, G., Thomas, C., Hopkins, B., Briggs, I., Graham, A. Human bradykinin B2 receptor: nucleotide sequence analysis and assignment to chromosome 14. Genomics 15: 435-438, 1993. [PubMed: 7916737, related citations] [Full Text]

  10. 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, related citations] [Full Text]

  11. Taketo, M., Yokoyama, S., Rochelle, J., Kimura, S., Higashida, H., Taketo, M., Seldin, M. F. Mouse B2 bradykinin receptor gene maps to distal chromosome 12. Genomics 27: 222-223, 1995. [PubMed: 7665180, related citations] [Full Text]


Paul J. Converse - updated : 06/19/2007
Victor A. McKusick - updated : 2/2/2005
Paul J. Converse - updated : 8/17/2004
Ada Hamosh - updated : 9/6/2000
Victor A. McKusick - updated : 1/15/1999
Creation Date:
Victor A. McKusick : 6/9/1992
mgross : 06/19/2007
wwang : 2/10/2005
wwang : 2/8/2005
wwang : 2/7/2005
terry : 2/2/2005
mgross : 8/18/2004
terry : 8/17/2004
alopez : 7/9/2001
alopez : 9/7/2000
alopez : 9/6/2000
kayiaros : 7/13/1999
carol : 1/20/1999
terry : 1/15/1999
dkim : 12/15/1998
dkim : 7/21/1998
mark : 2/7/1996
mark : 9/27/1995
carol : 11/30/1994
carol : 5/12/1993
carol : 3/18/1993
carol : 6/9/1992

* 113503

BRADYKININ RECEPTOR B2; BDKRB2


Alternative titles; symbols

BRADYKININ RECEPTOR 2; BKR2


HGNC Approved Gene Symbol: BDKRB2

Cytogenetic location: 14q32.2     Genomic coordinates (GRCh38): 14:96,204,839-96,244,164 (from NCBI)


TEXT

Description

Bradykinin (BK), a 9-amino acid peptide, is generated from high molecular weight precursors, the kininogens, by limited proteolysis in tissues and body fluids. It elicits numerous responses, including vasodilation, edema, smooth muscle spasm, and stimulation of pain fibers. When activated in pathophysiologic conditions, such as inflammation, trauma, burns, shock, and allergy, kininogens release bradykinin, kallidin (KD or lys-BK), and met-lys bradykinin. Kinin receptors are classified as B1 and B2 on the basis of relative potencies of agonists in isolated vascular smooth muscle preparations. BDKRB2 has high affinity for intact kinins.


Cloning and Expression

Hess et al. (1992) cloned a human BK-2 bradykinin receptor from a lung fibroblast cell line. The cDNA clone encoded a 364-amino acid protein that had the characteristics of a 7-transmembrane domain G protein-coupled receptor. The predicted amino acid sequence showed 81% identity to smooth muscle rat BK-2 receptor. Transfection of the cDNA into COS-7 cells resulted in the expression of high levels of specific BK binding sites.

Powell et al. (1993) used the published rat bradykinin B2 sequence to design PCR amplimers. The full-length cDNA that they obtained also coded for a 364-amino acid protein with a molecular mass of 41,442 Da that was 81% similar to rat bradykinin B2 receptor cDNA.

Genomic Southern blot analysis by Ma et al. (1994) showed that the B2 receptor is encoded by a single-copy gene and is expressed in most human tissues.

Kammerer et al. (1995) obtained both a full-length cDNA and a genomic clone.


Gene Function

The vasopressor angiotensin II regulates vascular contractility and blood pressure through binding to type 1 angiotensin II receptors (106165). Bradykinin, a vasodepressor, is a functional antagonist of angiotensin II. The 2 hormone systems are interconnected by the angiotensin-converting enzyme, which releases angiotensin II from its precursor and inactivates the vasodepressor bradykinin. AbdAlla et al. (2000) demonstrated that the type 1 angiotensin II receptor and the bradykinin B2 receptor also communicate directly with each other. They form stable heterodimers, causing increased activation of G-alpha-q (600998) and G-alpha-i proteins, the 2 major signaling proteins triggered by the type 1 angiotensin II receptor. Furthermore, the endocytotic pathway of both receptors changes with heterodimerization.


Gene Structure

Powell et al. (1993) stated that 'the genomic clone of the gene is intronless'; however, Ma et al. (1994) demonstrated that the BDKRB2 gene contains 3 exons separated by 2 introns. The first and second exons are noncoding, while the third exon contains the full-length coding region.


Mapping

Using PCR for specific amplification of DNA from somatic cell hybrids, Powell et al. (1993) mapped the BDKRB2 gene to chromosome 14. By fluorescence in situ hybridization, Ma et al. (1994) mapped the BDKRB2 gene to 14q32. Taketo et al. (1995) demonstrated that the mouse homolog maps to the distal portion of mouse chromosome 12.


Molecular Genetics

Braun et al. (1995) described 3 polymorphic sites in the BKR2 gene.

Erdmann et al. (1998) screened for mutations in the promoter and coding regions of the human BDKRB2 gene in a group of 92 unrelated subjects with a variety of forms of cardiovascular disease. They detected 8 previously unknown polymorphic sites in the promoter region with allele frequencies between 0.5 and 13%. One of them, (-412C-G), destroyed an Sp1 binding site and abolished protein binding to this SP1 site in human umbilical vein endothelial cells and human vascular smooth muscle cells. In the protein-coding region, a new coding variant, T21M, with the potential to create a truncated receptor isoform was detected. The -412C-G variant was found in 1 of 173 healthy blood donors; the T21M mutation was not found in the control population. The significance of these 2 mutations remained to be determined.


Animal Model

Souza et al. (2004) investigated the roles of B1r (600337) 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.

Humans with type I diabetes and mice with diabetes induced by streptozotocin have an increased risk of developing nephropathy when genetically determined levels of angiotensin-converting enzyme (ACE; 106180) are higher. Because experiments in mice and computer simulations indicated that modest increases in ACE have minimal effects on blood pressure and angiotensin II levels but cause a significant decrease in bradykinin levels, Kakoki et al. (2004) hypothesized that bradykinin is critical for protecting the kidney in diabetics. They confirmed this by demonstrating that Akita diabetic mice lacking the bradykinin B2 receptor developed overt albuminuria, excreting the equivalent of more than 550 mg/day of albumin in humans, which contrasted with the microalbuminuria (equivalent to less than 150 mg/day) seen in their simply diabetic littermates. The overt albuminuria was accompanied by a marked increase in glomerular mesangial sclerosis.

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.


REFERENCES

  1. AbdAlla, S., Lother, H., Quitterer, U. AT(1)-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 407: 94-98, 2000. [PubMed: 10993080] [Full Text: https://doi.org/10.1038/35024095]

  2. Braun, A., Kammerer, S., Bohme, E., Muller, B., Roscher, A. A. Identification of polymorphic sites of the human bradykinin B(2) receptor gene. Biochem. Biophys. Res. Commun. 211: 234-240, 1995. [PubMed: 7779090] [Full Text: https://doi.org/10.1006/bbrc.1995.1801]

  3. Erdmann, J., Hegemann, N., Weidemann, A., Kallisch, H., Hummel, M., Hetzer, R., Fleck, E., Regitz-Zagrosek, V. Screening the human bradykinin B2 receptor gene in patients with cardiovascular diseases: identification of a functional mutation in the promoter and a new coding variant (T21M). Am. J. Med. Genet. 80: 521-525, 1998. [PubMed: 9880221]

  4. Hess, J. F., Borkowski, J. A., Young, G. S., Strader, C. D., Ransom, R. W. Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor. Biochem. Biophys. Res. Commun. 184: 260-268, 1992. [PubMed: 1314587] [Full Text: https://doi.org/10.1016/0006-291x(92)91187-u]

  5. 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]

  6. Kakoki, M., Takahashi, N., Jennette, J. C., Smithies, O. Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor. Proc. Nat. Acad. Sci. 101: 13302-13305, 2004. [PubMed: 15326315] [Full Text: https://doi.org/10.1073/pnas.0405449101]

  7. Kammerer, S., Braun, A., Arnold, N., Roscher, A. A. The human bradykinin B(2) receptor gene: full length cDNA, genomic organization and identification of the regulatory region. Biochem. Biophys. Res. Commun. 211: 226-233, 1995. [PubMed: 7779089] [Full Text: https://doi.org/10.1006/bbrc.1995.1800]

  8. Ma, J., Wang, D., Ward, D. C., Chen, L., Dessai, T., Chao, J., Chao, L. Structure and chromosomal localization of the gene (BDKRB2) encoding human bradykinin B2 receptor. Genomics 23: 362-369, 1994. [PubMed: 7835885] [Full Text: https://doi.org/10.1006/geno.1994.1512]

  9. Powell, S. J., Slynn, G., Thomas, C., Hopkins, B., Briggs, I., Graham, A. Human bradykinin B2 receptor: nucleotide sequence analysis and assignment to chromosome 14. Genomics 15: 435-438, 1993. [PubMed: 7916737] [Full Text: https://doi.org/10.1006/geno.1993.1084]

  10. 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]

  11. Taketo, M., Yokoyama, S., Rochelle, J., Kimura, S., Higashida, H., Taketo, M., Seldin, M. F. Mouse B2 bradykinin receptor gene maps to distal chromosome 12. Genomics 27: 222-223, 1995. [PubMed: 7665180] [Full Text: https://doi.org/10.1006/geno.1995.1034]


Contributors:
Paul J. Converse - updated : 06/19/2007
Victor A. McKusick - updated : 2/2/2005
Paul J. Converse - updated : 8/17/2004
Ada Hamosh - updated : 9/6/2000
Victor A. McKusick - updated : 1/15/1999

Creation Date:
Victor A. McKusick : 6/9/1992

Edit History:
mgross : 06/19/2007
wwang : 2/10/2005
wwang : 2/8/2005
wwang : 2/7/2005
terry : 2/2/2005
mgross : 8/18/2004
terry : 8/17/2004
alopez : 7/9/2001
alopez : 9/7/2000
alopez : 9/6/2000
kayiaros : 7/13/1999
carol : 1/20/1999
terry : 1/15/1999
dkim : 12/15/1998
dkim : 7/21/1998
mark : 2/7/1996
mark : 9/27/1995
carol : 11/30/1994
carol : 5/12/1993
carol : 3/18/1993
carol : 6/9/1992