Disease relevance of BDKRB2

• One SNP in the promoter region of BDKRB2 (rs1799722) was associated with hypertension (P = 0.044) in African-Americans [1].
• Relationship of bradykinin B2 receptor gene polymorphism with essential hypertension and left ventricular hypertrophy [2].
• Immunolocalization and expression of kinin B1R and B2R receptors in human inflammatory bowel disease [3].
• Association of the human bradykinin B2 receptor gene with chronic renal failure [4].
• These new genetic markers provide valuable tools to elucidate a potential role of a hereditary dysfunction of the B2 bradykinin receptor gene in disorders such as hypertension or ischemic heart disease [5].

High impact information on BDKRB2

• BK-induced NF-kappaB activation correlated with IL-1beta message upregulation with respect to agonist concentration, time course, sensitivity to bacterial toxins, and blockade by the B2 receptor antagonist [6].
• In additional 4 and 16-wk-old animals, bradykinin B1 and B2 receptor antagonists (BKA) were also injected with EB [7].
• Allelic polymorphisms affecting exon 3 of the B1 receptor gene (A1098-->G) or exon 2 (C181-->T) or 1 (a 9-base pair deletion) of the B2 receptor gene were found to be neutral [8].
• Incubation with norepinephrine or the alpha2-adrenergic agonist BHT 920 also caused dose-dependent increases in nitrite production, which were blocked by the B2-receptor antagonist HOE 140 [9].
• We have made mutations in the predicted sixth transmembrane segment of a rat B2 bradykinin receptor and analyzed the variant proteins by expressing them in COS-1 cells [10].

Chemical compound and disease context of BDKRB2

• OBJECTIVE: To identify variants in the complete genomic sequence of the two subtypes of bradykinin receptors: B1 (BDKRB1) and B2 (BDKRB2) and to examine the association of these variants with essential hypertension [1].
• Identification of a B2-bradykinin receptor linked to phospholipase C and inhibition of dopamine stimulated cyclic AMP accumulation in the human astrocytoma cell line D384 [11].
• After 4 weeks, the B2 receptor antagonist icatibant (0.5 mg/kg body weight) was administered on top of active treatment for 4 weeks to 50% of the TGRen2 rats [12].
• In addition, the inducible NO synthase (iNOS) mRNA level increased markedly, and this was reduced by LF 16-0687 Ms. Taken together, these data support a detrimental role of B2R in the development of the neurological deficit and of the inflammatory secondary damage resulting from diffuse traumatic brain injury [13].
• To determine whether kinins contribute to allergic reactions, the effect of a potent, nonpeptide BK B2-receptor-specific antagonist, FR173657, on VPE induced in the reaction sites was investigated [14].

Biological context of BDKRB2

• One SNP in BDKRB2 and three SNPs in BDKRB1 were associated with hypertension (P-values between 0.026 and 0.0004) in American-Caucasians [1].
• Furthermore, the frequency of LVH in hypertensives was significantly higher in the subjects with both the BDKRB2 CC and ACE D allele than those with other genotypes (p =0.002, chi2 =9.4) [2].
• The amino acid sequence of the B1 bradykinin receptor is 36% identical to the amino acid sequence of the B2 bradykinin receptor [15].
• A previously described B2R polymorphism (exon 2, C181-->T) had an allele frequency of 9.7% in the control sample and appears to be clinically neutral [16].
• Other investigators have mapped the bradykinin B2 receptor (B2R) gene to a close site on human chromosome 14 [16].

Anatomical context of BDKRB2

• Here, we show that B1R spontaneously forms a proteolytic plasma membrane complex with B2R along with increased receptor signaling capacity [17].
• Kinin B2 receptor-coupled signal transduction in human cultured keratinocytes [18].
• A human BK-2 bradykinin receptor was cloned from the lung fibroblast cell line CCD-16Lu [19].
• Saturation binding analysis indicates that the human BK-2 receptor expressed in COS-7 cells binds BK with a KD of 0.13 nM [19].
• The predicted amino acid sequence of the human BK-2 receptor is 81% identical to the smooth muscle rat BK-2 receptor (1) [19].

Associations of BDKRB2 with chemical compounds

• Structure and chromosomal localization of the gene (BDKRB2) encoding human bradykinin B2 receptor [20].
• Activity was partially recovered by subsequent alanine mutation of a cluster of two serines and two threonines in IC-IV of either B1(B2ICIV) or B1(B2ICIV)A(121), a cluster that is important for B2R desensitization [21].
• Steady-state absorbance spectra of nNOS recorded during uncoupled NADPH oxidation showed that the heme remained oxidized in the presence of the synthetic peptide consisting of amino acids 310-329 of the B2R, whereas the reduced oxyferrous heme complex was accumulated in its absence [22].
• These data suggest that binding of the B2R 310-329 peptide blocks flavin to heme electron transfer [22].
• Endothelial nitric-oxide synthase (type III) (eNOS) was reported to form an inhibitory complex with the bradykinin receptor B2 (B2R) from which the enzyme is released in an active form upon receptor activation (Ju, H., Venema, V. J., Marrero, M. B., and Venema, R. C. (1998) J. Biol. Chem. 273, 24025-24029) [22].

Physical interactions of BDKRB2

• Interaction of endothelial and neuronal nitric-oxide synthases with the bradykinin B2 receptor. Binding of an inhibitory peptide to the oxygenase domain blocks uncoupled NADPH oxidation [22].
• A prototypic study of the molecular mechanisms of activation or inactivation of peptide hormone G protein-coupled receptors was carried out on the human B2 bradykinin receptor [23].

Co-localisations of BDKRB2

• B2 receptor mRNA was colocalized with kininogen mRNA in the kidney except the podocytes [24].

Regulatory relationships of BDKRB2

• In conclusion, this study shows that BK upregulates IL-1beta- and TNFalpha-stimulated IL-8 production via BK B2 receptor and that PKC signal pathway seems to be involved in the upregulation of the cytokine-induced IL-8 production in gingival fibroblasts [25].
• The B2 receptor antagonist HOE140 and the B1 receptor agonist des-Arg9-bradykinin failed to induce significant phosphorylation of the B2 receptor [26].
• Furthermore, the treatment of primary cultures of trigeminal ganglia with inhibitors of EP24.15/16 led to the potentiation of several bradykinin-induced events that occur downstream of B2R activation [27].
• TNF-alpha and IL-1beta both induced a rapid and transient increase in B1 and B2 receptor mRNA expression that was maximal by 2 h, accompanied by an increase in B1 and B2 receptor protein, as measured by radioligand binding assay with [(3)H]des-Arg(10)-kallidin, and [(3)H]bradykinin, respectively [28].
• Furthermore, increasing doses of this inhibitor partially affected the bradykinin-mediated ERK/MAP kinase activation and fully blocked the protein kinase C-independent component of the signaling pathway from the B2 receptor to the ERK/MAP kinase cascade [29].

Other interactions of BDKRB2

• Selective immunoprecipitation with epitope-specific antibodies revealed a spontaneously formed heterologous receptor complex, which was composed of the intact 35-kDa B1R and the B2R degradation products [17].
• Using a synthetic peptide derived from the known inhibitory sequence of the B2R (residues 310-329) we studied the interaction of the receptor with purified eNOS and neuronal nitric-oxide synthase (type I) (nNOS) [22].
• The stimulatory effect of BK on the IL-1beta- or TNFalpha-stimulated IL-8 production was reduced in the presence of BK B2 receptor antagonist HOE 140, whereas the B1 receptor antagonist Lys-(des-arg9, Leu8)-BK had no effect [25].
• Negative and positive regulatory epitopes in the C-terminal domains of the human B1 and B2 bradykinin receptor subtypes determine receptor coupling efficacy to G(q/11)-mediated [correction of G(9/11)-mediated] phospholipase Cbeta activity [30].
• Low-molecular-weight kininogen and B2 receptor mRNAs were colocalized in the zona glomerulosa and zona fasciculata and also in the zona reticularis and chromaffin cells but to a lesser degree [31].

Analytical, diagnostic and therapeutic context of BDKRB2

• The polymorphism (-58 T/C) in the promoter region of the BDKRB2 was determined using the TaqMan-polymerase chain reaction (PCR) method, the exon 1 +9/-9 polymorphism of the BDKRB2 and I/D polymorphism of the ACE were monitored by PCR and gel electrophoresis [2].
• Co-immunoprecipitation of B2R and nNOS from human embryonic kidney cells stably transfected with human nNOS suggests that the B2R may functionally interact with nNOS in vivo [22].
• Using surface plasmon resonance analysis, we observed that an immunoreceptor tyrosine-based inhibitory motif (ITIM) located in the C-terminal part of the B2 receptor interacted specifically with the protein-tyrosine phosphatase SHP-2 [32].
• Previous works have shown a neuroprotector effect for kinin B2 receptor and a deleterious, pro-epileptogenic action for kinin B1 receptor in animal models of TLE [33].
• CLR contained B2R and B1R as determined by both receptor immunoblotting and the increase in specific activity of receptor agonist binding to cells at both 4 and 37 degrees C when binding was followed by CLR enrichment [34].

References