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Research ArticleArticle

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

L. M. Fredrik Leeb-Lundberg, Francois Marceau, Werner Müller-Esterl, Douglas J. Pettibone and Bruce L. Zuraw
Pharmacological Reviews March 2005, 57 (1) 27-77; DOI: https://doi.org/10.1124/pr.57.1.2
L. M. Fredrik Leeb-Lundberg
Division of Cellular and Molecular Pharmacology, Department of Experimental Medical Science, Lund University, Lund, Sweden (L.M.F.L.-L.); Centre de Recherche, Centre Hospitalier Universitaire de Quebec, Quebec, Canada (F.M.); Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine, Frankfurt, Germany (W.M.-E.); Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, Pennsylvania (D.J.P.); and Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, California (B.L.Z.)
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Francois Marceau
Division of Cellular and Molecular Pharmacology, Department of Experimental Medical Science, Lund University, Lund, Sweden (L.M.F.L.-L.); Centre de Recherche, Centre Hospitalier Universitaire de Quebec, Quebec, Canada (F.M.); Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine, Frankfurt, Germany (W.M.-E.); Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, Pennsylvania (D.J.P.); and Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, California (B.L.Z.)
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Werner Müller-Esterl
Division of Cellular and Molecular Pharmacology, Department of Experimental Medical Science, Lund University, Lund, Sweden (L.M.F.L.-L.); Centre de Recherche, Centre Hospitalier Universitaire de Quebec, Quebec, Canada (F.M.); Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine, Frankfurt, Germany (W.M.-E.); Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, Pennsylvania (D.J.P.); and Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, California (B.L.Z.)
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Douglas J. Pettibone
Division of Cellular and Molecular Pharmacology, Department of Experimental Medical Science, Lund University, Lund, Sweden (L.M.F.L.-L.); Centre de Recherche, Centre Hospitalier Universitaire de Quebec, Quebec, Canada (F.M.); Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine, Frankfurt, Germany (W.M.-E.); Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, Pennsylvania (D.J.P.); and Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, California (B.L.Z.)
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Bruce L. Zuraw
Division of Cellular and Molecular Pharmacology, Department of Experimental Medical Science, Lund University, Lund, Sweden (L.M.F.L.-L.); Centre de Recherche, Centre Hospitalier Universitaire de Quebec, Quebec, Canada (F.M.); Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine, Frankfurt, Germany (W.M.-E.); Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, Pennsylvania (D.J.P.); and Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, California (B.L.Z.)
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  • Fig. 1.
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    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).

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    Fig. 2.

    Structures of peptidic and nonpeptidic B1 and B2 receptor modulators.

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    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.

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    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.

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    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).

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    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

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    TABLE 1

    Human B1 and B2 receptor nomenclature

    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

    • ↵ b Hess et al., 1994

    • ↵ c Hess et al., 1996

    • ↵ d MacNeil et al., 1995

    • ↵ e Bachvarov et al., 1995

    • ↵ f Doctrow et al., 1994

    • ↵ g G. Morissette and F. Marceau, unpublished data

    • ↵ h Sabourin et al., 2002a (binding to rabbit B1 conjugated to yellow fluorescent protein)

    • ↵ i MacNeil et al., 1997

    • ↵ j Stewart et al., 1996

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    TABLE 3

    GenBank accession numbers for kinin receptor genes of various species

    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
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    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

    • ↵ b NPC, NPC17731; Icatib., Icatibant; LDBK, Lys-des-Arg9-BK; LDLBK, Lys-[Leu8]des-Arg9-BK

    • ↵ c Inferred as an important residue by extrapolating data for NPC18565

    • ↵ d Domain is important but no specific residues have been identified

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    TABLE 5

    Kinin receptor polymorphisms associated with clinical phenotype a

    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.

    • ↵ 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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    TABLE 6

    Potential clinical applications of kinin receptor ligands

    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
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Pharmacological Reviews: 57 (1)
Pharmacological Reviews
Vol. 57, Issue 1
1 Mar 2005
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Research ArticleArticle

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

L. M. Fredrik Leeb-Lundberg, Francois Marceau, Werner Müller-Esterl, Douglas J. Pettibone and Bruce L. Zuraw
Pharmacological Reviews March 1, 2005, 57 (1) 27-77; DOI: https://doi.org/10.1124/pr.57.1.2

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Research ArticleArticle

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

L. M. Fredrik Leeb-Lundberg, Francois Marceau, Werner Müller-Esterl, Douglas J. Pettibone and Bruce L. Zuraw
Pharmacological Reviews March 1, 2005, 57 (1) 27-77; DOI: https://doi.org/10.1124/pr.57.1.2
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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
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