BDKRB1

BDKRB1 (bradykinin B1 receptor) is an inflammation-inducible G-protein-coupled receptor that couples extracellular stimuli to pro-inflammatory and proliferative signaling, encoded by a single-copy gene whose expression is tightly transcriptionally controlled (PMID:8660997, PMID:15705059). Its core promoter resides within a 300-bp fragment sufficient to drive reporter expression, with an additional enhancer-like element between -1842 and -812; the gene maps to chromosome 14q32.1-q32.2 near the B2 receptor gene (PMID:8808279). In cells that express the receptor, the core promoter is occupied by YY1 and the basal factors TBP/TFIIB, a pattern absent in non-expressing lymphocytes, and YY1 is implicated in NF-κB-linked regulation (PMID:15705059). BDKRB1 is further induced by the transcription factor TFAP2A, which binds the promoter directly and drives epithelial-mesenchymal transition in pulmonary fibrosis (PMID:41587695), and is stabilized post-transcriptionally by METTL1-mediated m7G modification of its mRNA in keratinocytes (PMID:42261843). Once expressed, BDKRB1 transduces signals through distinct effector arms: a Ca²⁺/CaMKII/MEK1/ERK axis that promotes calcium influx and cell proliferation in mechanically stressed alveolar epithelial cells (PMID:40296124), and a p38 MAPK pathway that drives CXCL chemokine secretion and neutrophil chemotaxis in psoriatic inflammation (PMID:42261843). In sepsis, BDKRB1 activation in neutrophils induces CXCR2 desensitization with upregulation of P110γ, impairing neutrophil migration and bacterial clearance, such that Bdkrb1 deletion or antagonism restores migration and reduces lethality (PMID:41355798).

1. 1996 Medium

   Established the genomic architecture and basal transcriptional landscape of BDKRB1, defining it as a single-copy gene whose coding region lies in a single exon under control of a TATA-box-containing promoter with multiple start sites.

   Evidence Genomic cloning, sequencing, and primer extension of the human gene

   PMID:8660997

   Open questions at the time

   • Did not identify the trans-acting factors controlling transcription
   • No functional dissection of the promoter elements
2. 1996 Medium

   Localized the cis-regulatory elements controlling BDKRB1, showing a 300-bp core promoter sufficient for expression plus a distal enhancer, and mapped the gene adjacent to the B2 receptor gene.

   Evidence CAT reporter deletion analysis and chromosomal localization

   PMID:8808279

   Open questions at the time

   • Did not identify which proteins bind these elements
   • Enhancer mechanism and tissue-specificity not resolved
3. 2005 Medium

   Connected cell-type-specific BDKRB1 expression to defined promoter occupancy, identifying YY1 and TBP/TFIIB as factors bound in expressing smooth muscle cells but not in non-expressing lymphocytes.

   Evidence In vivo DNase I/DMS/UV footprinting and EMSA in SMCs versus lymphocytes

   PMID:15705059

   Open questions at the time

   • YY1 link to NF-κB regulation not directly demonstrated
   • No functional knockdown of YY1 to confirm requirement for expression
4. 2025 High

   Defined a pathogenic role for BDKRB1 in sepsis by showing its activation desensitizes CXCR2 via P110γ to block neutrophil migration and bacterial clearance.

   Evidence Bdkrb1 knockout mice in CLP model, flow cytometry, pharmacological inhibition, and human neutrophil migration assays

   PMID:41355798

   Open questions at the time

   • Mechanism linking BDKRB1 to P110γ upregulation not resolved
   • Direct molecular coupling between BDKRB1 and CXCR2 desensitization unknown
5. 2025 Medium

   Identified mechanical stress as an inducer of BDKRB1 and traced a downstream Ca²⁺/CaMKII/MEK1/ERK axis driving epithelial proliferation.

   Evidence siRNA knockdown with western blot, calcium flow cytometry, and proliferation assays in alveolar epithelial cells

   PMID:40296124

   Open questions at the time

   • Mechanism by which mechanical stress upregulates BDKRB1 not defined
   • G-protein coupling linking receptor to calcium influx not characterized
6. 2026 Medium

   Established TFAP2A as a direct transcriptional activator of BDKRB1 driving EMT in pulmonary fibrosis, with BDKRB1 acting downstream of TFAP2A.

   Evidence Promoter binding assay, lentiviral/adenoviral knockdown, BLM mouse model with BDKRB1 overexpression rescue

   PMID:41587695

   Open questions at the time

   • Signaling pathway linking BDKRB1 to EMT not detailed
   • Whether TFAP2A acts at the core promoter or enhancer not specified
7. 2026 High

   Revealed post-transcriptional control of BDKRB1 by METTL1-mediated m7G mRNA modification and linked elevated BDKRB1 to p38-driven CXCL secretion and neutrophil recruitment in psoriasis.

   Evidence Keratinocyte-specific Mettl1 knockout mice with BDKRB1 overexpression and pharmacological rescue, m7G analysis, chemokine and chemotaxis assays

   PMID:42261843

   Open questions at the time

   • Direct demonstration of m7G sites on Bdkrb1 mRNA not detailed
   • Mechanism coupling BDKRB1 to p38 activation not resolved

• How BDKRB1 selects among its divergent downstream effector arms (Ca²⁺/CaMKII/MEK1/ERK versus p38/CXCL versus CXCR2 desensitization) in a tissue- and stimulus-specific manner remains unknown.
• No structural or G-protein-coupling data defining receptor signaling bias
• Ligand-dependence of the distinct downstream pathways not dissected
• No unified model of how transcriptional and post-transcriptional inputs converge on receptor output