Disease relevance of BDKRB1

• 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].
• Characterization of two polymorphic sites in the human kinin B1 receptor gene: altered frequency of an allele in patients with a history of end-stage renal failure [2].
• The B1 receptor expression is up-regulated following tissue injury and inflammation (hyperemia, exudation, hyperalgesia, etc.). In the present study, we have cloned and sequenced the gene encoding human B1 receptor from a human genomic library [3].
• Kinin B1 receptor expression on multiple sclerosis mononuclear cells: correlation with magnetic resonance imaging T2-weighted lesion volume and clinical disability [4].
• Immunolocalization and expression of kinin B1R and B2R receptors in human inflammatory bowel disease [5].

High impact information on BDKRB1

• Because a better understanding of the mechanism of the upregulation will help in understanding its potential importance in inflammation, we have studied the molecular mechanism of B1-receptor upregulation in cultured human lung fibroblasts (IMR 90) in response to IL-1beta and the B1-agonist [des-Arg10]-kallidin [6].
• BK-induced IL-1beta synthesis was inhibited by a B2-type BK receptor antagonist and by treatment of the cells with pertussis toxin, indicating the involvement of a BK receptor that couples to the G(i)/G(o) class of heterotrimeric G proteins [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].
• Altered frequency of a promoter polymorphic allele of the kinin B1 receptor gene in inflammatory bowel disease [8].
• RESULTS: Only the B1 receptor promoter polymorphism (G-699-->C) exhibited a significantly different allele frequency between the two groups (prevalence of the C allele of 5.7% in patients with IBD compared with 33.6% in controls; P = 0.0002) or between the controls and either etiologic subgroup (ulcerative colitis and Crohn's disease) [8].

Chemical compound and disease context of BDKRB1

• 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].
• Using androgen-insensitive prostate cancer PC3 cells, we show that specific stimulation of endogenous B1R promotes cell growth, migration, and invasion [9].
• The present results support that compound 11 is a potent and highly selective antagonist suitable for further investigations of the role of the kinin B1R in models of inflammation, pain, and sepsis based on the rabbit [10].
• We investigated the expression and localization of B1 receptor in tissues of rats submitted to a renin-dependent model of hypertension (2K-1C), and analyzed the influence of endogenous Ang II in modulating the in vivo expression of these receptors [11].
• Diabetic hyperalgesia is absent in streptozotocin-induced type 1 diabetic BKB1-R knockout mice [12].

Biological context of BDKRB1

• Genomic DNA sequence, expression, and chromosomal localization of the human B1 bradykinin receptor gene BDKRB1 [13].
• An obvious difference was found in the DNase I-footprinting patterns between cellular systems that express a functional BDKRB1 (SMCs) in comparison with human lymphocytes, where randomly distributed nucleosome-like footprinting patterns were found in the bulk of the core promoter region studied [14].
• The amino acid sequence of the B1 bradykinin receptor is 36% identical to the amino acid sequence of the B2 bradykinin receptor [15].
• A cDNA clone encoding a human B1 bradykinin receptor was isolated from a human embryonic lung fibroblast cDNA library by expression cloning [15].
• On the basis of the genomic structure of the human B1 receptor (B1R) for kinins, the presence of possible allelic polymorphisms of this gene was investigated using restriction fragment-length polymorphism and single-strand conformation polymorphism [2].

Anatomical context of BDKRB1

• In the present study we used the highly sensitive DNase I in vivo footprinting approach to delineate more precisely the functional domains of the BDKRB1 gene promoter in human SMCs (smooth muscle cells) [14].
• The photoprotein aequorin was utilized as an indicator of the ability of the B1 receptor agonist [des-Arg10]kallidin to mediate Ca2+ mobilization in Xenopus laevis oocytes injected with RNA [15].
• Here, we show that B1R spontaneously forms a proteolytic plasma membrane complex with B2R along with increased receptor signaling capacity [16].
• Northern blot analysis identified a 1.7- to 1.8-kb mature mRNA transcript of the B1 receptor gene in the kidney and pancreas [13].
• Bradykinin (BK)-related peptides are suspected to negatively influence diverse functions in vascular smooth muscle cells (SMCs), notably via stimulation of the inducible B1 receptor (B1R), and have been shown to inhibit the migration of rat SMCs [17].

Associations of BDKRB1 with chemical compounds

• Human lymphocytes that do not express a functional BDKRB1 were also studied as a reference using dimethyl sulphate, UV light type C and DNase I treatments [14].
• The cloned B1 bradykinin receptor expressed in mammalian cells exhibits high affinity binding for 3H-labeled [des-Arg10]kallidin and low affinity for bradykinin [15].
• Constitutive B1R activity was further increased by alanine mutation of Asn(121) in the third transmembrane domain of the receptor (B1A(121)) [18].
• Studies with BK receptor antagonists and agonists indicate that inositol lipid signalling and arachidonic acid mobilization in response to BK are B2 receptor-mediated pathways, whereas the inhibition of DNA synthesis appears to be via B1 receptors [19].
• High-affinity binding of peptide agonists to the human B1 bradykinin receptor depends on interaction between the peptide N-terminal L-lysine and the fourth extracellular domain of the receptor [20].

Physical interactions of BDKRB1

• These findings indicate, for the first time, that the BK receptor is coupled to the important protooncogene c-src and that the src pathway may mediate some of the events downstream from BK binding [21].

Regulatory relationships of BDKRB1

• The B2 receptor antagonist HOE140 and the B1 receptor agonist des-Arg9-bradykinin failed to induce significant phosphorylation of the B2 receptor [22].
• The increase in CTGF mRNA was blocked by the B1 receptor antagonist des-Arg(10),Leu(9)-kallidin [23].
• BK-induced IL-6 and IL-8 synthesis was inhibited by a B2-type BK receptor antagonist [24].
• We sought to determine whether kinin B1 receptor can be expressed on human brain endothelial cells (HBECs) in vitro and whether signaling via this receptor can regulate permeability and chemokine production properties of these cells [25].
• Transcription factor nuclear factor kappaB regulates the inducible expression of the human B1 receptor gene in inflammation [26].

Other interactions of BDKRB1

• 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 [16].
• We investigated whether cyclooxygenase (COX)-2 induction was involved in prostaglandin (PG) E2 release by BK in cultured human airway smooth muscle (ASM) cells and analyzed the BK receptor subtypes responsible [27].
• Although these data support a role for prostaglandins and EGF receptor down-modulation in the inhibitory action of BK on DNA synthesis in breast fibroblasts, a B1 receptor-mediated pathway is also implicated [19].
• We investigated the contribution of the B1 receptor to the maintenance of vascular tone and t-PA release in patients with heart failure [28].
• We examined B1 receptor mRNA expression in nasal tissue samples from allergic rhinitis and normal subjects [29].

Analytical, diagnostic and therapeutic context of BDKRB1

• No significant changes in the promoter foot-printing pattern were found after treatment with interleukin-1beta or serum (known BDKRB1 gene inducers), indicating that definite regulatory motifs could exist outside the BDKRB1 gene core promoter region studied [14].
• Genomic Southern blot analysis indicated that the human B1 receptor is encoded by a single-copy gene [3].
• 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 [30].
• 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 [31].
• The new compounds were tested against the contractile effect induced by desArg9BK on 2 B1 receptor bioassays, the human umbilical vein, and the rabbit aorta [32].

References