Article Figures & Data
Figures
- Fig. 1.
Phylogenetic tree for the kinin receptor family. The dendogram was constructed using PAUP and Clustalw1.7 software. Branch lengths are proportional to distances between sequences. Human AT2 receptor (not shown) was used as an outgroup to root the tree (modified after Schroeder et al., 1997 and Dunér et al., 2002).
- Fig. 2.
Structures of peptidic and nonpeptidic B1 and B2 receptor modulators.
- Fig. 3.
Schematic representations of the human B1 and B2 amino acid sequences. In B2, amino acids residues (single letter code) are numbered from the most 3′ putative translational start site with negative numbers for the 27 residues N-terminal to that methionine. EL, extracellular loops; IL, intracellular loops. Single amino acid residues or sequence segments discussed in the text are highlighted with potential residues facing specifically the binding pockets filled with red or red line (agonist), blue (antagonist), and orange (agonist and antagonist). In the B2 receptor, the boxed area indicates the putative helix 8, and the stars indicate the cluster of serines and threonines phosphorylated by GRK or PKC and important for desensitization.
- Fig. 4.
Schematic diagram of the human kinin receptor gene locus and polymorphisms associated with a clinical phenotype. The area shown (chromosome 14q32, positions 94.66 to 94.73 Mb, total of 70 kb) contains the two kinin receptor genes organized in tandem. The three major exons (E) of each gene are shown. The open box in B2 receptor exon 3 represents the large 3′-untranslated sequence. Single nucleotide polymorphisms are indicated below the gene structure. The alternatively spliced exon 2b of the B2 receptor is indicated (Cayla et al., 2002a). *, CKS1BP pseudogene.
- Fig. 5.
In vivo phosphorylation sites present in the human B2 receptor tail region. A schematic representation of the amino acid sequence (single letter code) is shown starting from the distal palmitoylation site (Cys329) and ending at the receptor C terminus. Identified phosphoacceptor sites are numbered and highlighted, and candidate kinases are indicated (GRK, PKC). The thickness of the arrows reflects the relative quantity of phosphate incorporation (modified after Blaukat et al., 2001).
- Fig. 6.
The vascular responses to kinins involve secondarily released mediators from the endothelial cells and their subsequent action on vascular smooth muscle cells. The preformed B2 receptor is illustrated, but the B1 receptor has been documented to recruit the same pathways if expressed by endothelial cells.
Tables
International Union of Pharmacology (IUPHAR) name B1 B2 IUPHAR code 2.1:BK:1:B1:HUMAN:00 2.1:BK:2:B2:HUMAN:00 Alternate names Bradykinin B1 Bradykinin B2 Amino acid composition 353 391a Gene/chromosome BDKRB1/14q32.2 BDKRB2/14q32.2 Gene accession no. U12512 M88714 SwissProt accession no. P46663 P30411 Selective agonist Lys-des-Arg9-BK BK Selective antagonist Lys-[Leu8]des-Arg9-BK Icatibant Primary G protein coupling Gαq/Gαi Gαq/Gαi Primary regulation Expression Induction Constitutive Signaling Limited desensitization Extensive desensitization -
↵ a Includes N-terminal sequence coded in exon 2 (27 residues; AbdAlla et al., 1996a)
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- TABLE 2
Affinities of selected peptide ligands obtained using radioligand binding assays for recombinant kinin receptors The reference sequence is that of BK: H-Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9-OH.
Affinity Estimates Peptide Human Receptors Mouse Receptors Rabbit Receptors Notes B1 B2 B1 B2 B1 B2 nM B2 agonists BK >10,000 (Ki)a 0.54 (Ki)b 200 (Ki)c 0.48 (IC50)b >5000 (Ki)d 4.5 (IC50)e Labradimil (RMP-7, [Hyp3, Thi5, 4-Me-Tyr8 ψ(CH2-NH)Arg9]-BK) IC50 10 nM for wild-type rat B2.f Resistant to carboxypeptidases. Promiscuous agonist Kallidin (Lys-BK) 2.54 (Ki)a 0.63 (Ki)b 510 (Ki)c 0.52 (IC50)b 19 (Ki)d 2 (IC50)e B1 agonists Des-Arg9-BK 1930 (Ki)a 8100 (Ki)b 0.7 (Ki)c 6400 (IC50)b 32 (Ki)d >1000 (IC50)e Des-Arg10-kallidin (Lys-des-Arg9-BK) 0.12 (Ki)a >30,000 (Ki)b 1.7 (Ki)c 25,000 (IC50)b 0.23 (Ki)d >1000 (IC50)e Sar[d-Phe8]des-Arg9-BK 60 (IC50)g 100 (IC50)h Resistant to multiple kininases. B2 antagonists Icatibant (Hoe 140; d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]BK) 437 (Ki)a 0.41 (IC50)b >10,000 (Ki)c 0.23 (IC50)b >5000 (IC50)d 2 (IC50)e B1 antagonists [Leu8]des-Arg9-BK 276 (Ki)a >30,000 (IC50)b 4.1 (Ki)c >30,000 (IC50)b 80 (Ki)d 374 (IC50)h [Leu8]des-Arg10-kallidin (Lys-[Leu8]des-Arg9-BK) 0.58 (Ki)a >30,000 (IC50)b 7.5c >30,000 (IC50)b 0.43 (Ki)d >1000 (IC50)e B-9858 (Lys-Lys-[Hyp3, Igl5, d-Igl7, Oic8]des-Arg9-BK) 0.04 (Ki)i 146 (Ki)i 5.4 (Ki)i 44 (Ki)i 15 (IC50)h Promiscuous antagonists B-9430 (d-Arg-[Hyp3, Igl5, d-Igl7, Oic8]BK) 12.6 0.25 248 (Ki)i 0.33 (Ki)i Combined blockade of B1 and B2 in vivo.j des-Arg10-Hoe 140 (d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]-des-Arg9-BK) 174 (Ki)a 24 (Ki)c 27 (Ki)d -
↵ a Bastian et al., 1997
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↵ b Hess et al., 1994
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↵ c Hess et al., 1996
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↵ d MacNeil et al., 1995
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↵ e Bachvarov et al., 1995
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↵ f Doctrow et al., 1994
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↵ g G. Morissette and F. Marceau, unpublished data
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↵ h Sabourin et al., 2002a (binding to rabbit B1 conjugated to yellow fluorescent protein)
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↵ i MacNeil et al., 1997
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↵ j Stewart et al., 1996
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Zoological Group Species B1 B2 Primates Human U12512 M88714 Macaca mulatta AY045568; AF540785 Two species of Cercopithecus AY045569, AF540784 Prosimians Tupaia AF540786 Lagomorphs Rabbit U20507 U33334 Rodents Mouse U47281 L26047 Rat U66107 M59967 Guinea pig AJ003243 Other mammals Pig AF540788 AB051422 Dog AF0334947 AF33498 - TABLE 4
Summary of potential residues facing the B2 and B1 agonist and antagonist binding pockets as determined by mutagenesis, cross-linking, and competition with domain-specific antibodies a
B2 B1 Domain Agonists Antagonists Agonist Antagonist BK FR190997 NPC/Icatib.b LF16–0335 FR173657 LDBKb LDLBKb NPC18565 Compound 11 N Cys20 TM-I TM-II Trp86 EL-II TM-III Ser111 Ile110 Ser111 Ile110 Ile110 Lys118 (Lys118)c Lys118 Asn114 TM-IV Lys172 EL-III Yesd Yesd TM-V TM-VI Phe259,Thr263 Phe259 Trp256 EC-IV Cys277,Asp266,Asp284 Yesd TMVII Gln288 Gln288,Tyr295 Tyr295 Leu294,Phe302 Phe302 Gln295 -
↵ a Discussion of individual residues and references are in the main text
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↵ b NPC, NPC17731; Icatib., Icatibant; LDBK, Lys-des-Arg9-BK; LDLBK, Lys-[Leu8]des-Arg9-BK
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↵ c Inferred as an important residue by extrapolating data for NPC18565
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↵ d Domain is important but no specific residues have been identified
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Gene Location Position Polymorphism Comment Reference B2 Promoter -58 -58C/T Braun et al., 1996 Exon 1 21 9 nt insertion/deletion -9 allele linked to higher transcript levels Lung et al., 1997; Braun et al., 1995 Exon 2 181 181C/T R14C; T allele associated with increased potency of B2 agonist Braun et al., 1995 B1 Promoter -699 G/C ActI RFLP; C allele linked to higher transcription Bachvarov et al., 1998 Exon 3 1098 A/G TaqI RFLP Bachvarov et al., 1998 -
RFLP, restriction fragment length polymorphism.
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↵ a Eight additional polymorphisms in the BDKRB2 promoter region as well as one missense mutation (T21M) were found by Erdmann et al. (1998); however, these polymorphisms appear to be present at too low a frequency to be of value for association studies. Eight additional polymorphisms in the BDKBR1 coding region, including two coding for substitution and one coding for premature truncation, were described by Hess et al. (2002). Three of these were found at a frequency >2%; however, none of these polymorphisms have been reported yet to be associated with a clinical phenotype
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Type of Agent Application Investigational Status References B2 receptor agonists Labradimil Transient opening of the blood-brain barrier (adjuvant to chemotherapy of brain tumors) Extensive animal studies performed Emerich et al., 2001 Lys-BK Additive to vaccines to skew the immune response from humoral (TH2) to cellular responses (TH1) Hypothesis supported by animal data Aliberti et al., 2003 FR190997, others Renal, cardiac protection, and hypertension, via endothelial mediator release Speculative; unfavorable risk to benefit ratio probable Heitsch, 2002 B1 receptor agonists Sar-[d-Phe8]-des-Arg9-BK Angiogenesis, vasculogenesis in severe ischemic disease Speculative; supported by animal data Emanueli et al., 2002 B2 receptor antagonists Icatibant, several others Inflammatory pain (hyperalgesia) Abundantly supported by animal studies Steranka et al., 1988; Perkins et al., 1993; Burgess et al., 2000 Icatibant, others Inflammatory edema Supported by many animal studies Uknis et al., 2002; Samadfam et al., 2000 LF16-0687, deltibant Brain edema (post-traumatic or secondary to stoke) Mixed results of a limited clinical trial of deltibant for head trauma; extensive animal data supporting LF16-0687; the later drug is being clinically evaluated for head trauma Narotam et al., 1998; Kaplanski et al., 2002; Zausigner et al., 2002 Icatibant Hereditary angioedema Active in a mouse model (C1 inhibitor gene knockout); Icatibant being clinically evaluated for this indication, as well as for ascites secondary to liver cirrhosis (Jerini AG) Han et al., 2002 Icatibant Allergic asthma, rhinitis Objective and protracted anti-inflammatory effects shown in humans following local application to mucosa Akbary et al., 1996; Turner et al., 2001 Deltibant Sepsis Disappointing results of a clinical trial Fein et al., 1997 B1 receptor antagonists [Leu8]-des-Arg9-BK, others Inflammatory pain (hyperalgesia); effect may extend to neuropathic pain, wind-up, and viscero-visceral hyper-reflexia Abundantly supported by animal studies; may be effective during a retarded time window, relative to B2 receptor antagonists Perkins et al., 1993; Bélichard et al., 2000; Levy and Zochodne, 2000; Pesquero et al., 2000; Jaggar et al., 1998 Lys-[Leu8]-des-Arg9-BK, others Inflammation Effects in animal models Blais et al., 2000; deBlois and Horlick, 2001 Unspecified Epilepsy Speculative; based on the epileptogenic effect of the agonist in animal models Bregola et al., 1999 Des-Arg10-Hoe 140 Airway allergy Benefits in a rat model; speculative in humans Huang et al., 1999; Christiansen et al., 2002 Unspecified Sepsis Speculative; based on the counterproductive hemodynamic effect of agonist in LPS-pretreated rabbits Audet et al., 1997 Promiscuous ligands CU201 = B9870 Cancer Whereas both antagonists of the B1 and B2 receptors have been proposed or used in a limited manner as experimental antineoplasic agents, CU201 may be more effective in specific tumorigenic cell lines than conventional antagonists Chan et al., 2002a,b; Stewart et al., 2003
In this issue
International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences
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- Article
- Abstract
- I. A Short History of Kinins and Their Receptors
- II. Pharmacological Classification of Kinin Receptor Subtypes
- III. Structural Aspects of Kinin Receptors and Their Genes
- IV. Molecular and Cellular Aspects of Kinin Receptor Signaling and Regulation
- V. Long-Term Regulation of Kinin Receptors by Proinflammatory Factors
- VI. Distribution and Pathophysiological Function of Kinin Receptors
- VII. Kinin Receptors and Human Disease
- VIII. Kinin Receptors and Drug Development
- IX. Epilogue
- Footnotes
- References
- Figures & Data
- Info & Metrics
- eLetters