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Uneven Evolutionary Rates of Bradykinin B1 and B2 Receptors in Vertebrate Lineages
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
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2006 (English)In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 373, 100-108 p.Article in journal (Refereed) Published
Abstract [en]

Bradykinin acts through two receptor subtypes in mammals and generates a variety of responses including pain, inflammation and hypotension. The evolutionary history of the bradykinin system has been unclear due to shortage of information outside mammals. We describe here two receptor subtypes and the bradykinin precursor in three species of bony fish (the zebrafish Danio rerio, the Japanese pufferfish Takifugu rubripes, and the green spotted pufferfish Tetraodon nigroviridis) and chicken and analyze the relationships to mammals by a combination of phylogeny, conserved synteny and exon–intron organization. All of these species have two receptor genes located close to each other in a tandem formation, with the B2 gene 5′ to the B1 gene, in chromosomal regions displaying conserved synteny between the species (albeit conservation of synteny in zebrafish is still unclear due to poor genome assembly). The evolutionary rate differs between the two genes as well as between lineages leading to differing pharmacological properties for both B1 and B2 across vertebrate classes. Also the bradykinin precursor gene was identified in all of these species in a chromosome region with conserved synteny. The tissue distribution of mRNA in T. rubripes is similar for B1 and B2, suggesting more similar regulation for the two genes than in mammals. In conclusion, the receptor tandem duplication predates the divergence of ray-finned fish and tetrapods and no additional duplicates of the receptors or bradykinin seem to have survived the ray-finned fish tetraploidization.

Place, publisher, year, edition, pages
Elsevier , 2006. Vol. 373, 100-108 p.
Keyword [en]
Animals, Chickens, Chromosome Mapping, Evolution; Molecular, Fishes, Mammals, Phylogeny, Receptor; Bradykinin B1/chemistry/*genetics, Receptor; Bradykinin B2/chemistry/*genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Alignment, Synteny, Vertebrates
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-93707DOI: 10.1016/j.gene.2006.01.017PubMedID: 16530355OAI: oai:DiVA.org:uu-93707DiVA: diva2:167267
Available from: 2005-11-11 Created: 2005-11-11 Last updated: 2010-07-21Bibliographically approved
In thesis
1. Evolution and Pharmacology of Receptors for Bradykinin and Neuropeptide Y in Vertebrates
Open this publication in new window or tab >>Evolution and Pharmacology of Receptors for Bradykinin and Neuropeptide Y in Vertebrates
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The bradykinin and neuropeptide Y (NPY) receptors belong to the superfamily of G-protein coupled receptors (GPCRs). The GPCRs form the largest class of therapeutic targets and it is therefore of great interest to investigate the pharmacological properties, functions and evolution of these receptors.

Bradykinin (BK) is a nonapeptide that contributes to inflammatory responses, mediates pain signals and influences blood pressure. The two bradykinin receptor subtypes B1 and B2 are well characterized in mammals, but have received little attention in non-mammals. This thesis describes the cloning and characterization of the first piscine bradykinin receptor, from the Danio rerio (zebrafish). Ligand-receptor interactions were measured as production of intracellular inositol phosphate. Zebrafish BK activated the receptor with highest potency (pEC50=6.97±0.1) while mammalian BK was almost inactive. A complete alanine and D-amino acid scan of the BK peptide revealed important roles for receptor interaction for residues Gly4, Ser6, Pro7, Leu8 and Arg9. The receptor gene was mapped to chromosome 17 in the zebrafish genome in a region that shows conserved synteny to the human B1-B2 gene region on chromosome 14. The release of the zebrafish and pufferfish genomes enabled us to identify both B1 and B2 genes in Danio rerio and pufferfishes (Takifugu rubripes and Tetraodon nigroviridis) as well as the B1 gene in chicken. All of these species display conserved synteny of the gene region. Interestingly, the evolutionary rate is clearly greater for B1 than for B2. Kininogen, the precursor for bradykinin, is also located in a chromosome region with extensive conserved synteny.

Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) comprise a family of related peptides and are involved in a variety of neuronal and endocrine functions. Receptor subtypes Y6 and Y7 were cloned and pharmacologically characterized in chicken. The genes are located one megabase apart on chromosome 13 in a region with conserved synteny to human chromosome 5. Porcine PYY bound to chicken Y6 with a Kd of 0.80±0.36 nM and chicken Y7 with a Kd of 0.14±0.01 nM. The Y6 mRNA is expressed in hypothalamus, gastrointestinal tract and adipose tissue and may be involved in appetite regulation like other NPY receptors. Chicken Y7 mRNA was only detected in adrenal gland. These results may help explain why these receptors have lost function in humans.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 52 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 83
Neurosciences, Pharmacology, Evolution, Neurovetenskap
National Category
urn:nbn:se:uu:diva-6085 (URN)91-554-6390-8 (ISBN)
Public defence
2005-12-06, Room B42, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2005-11-11 Created: 2005-11-11Bibliographically approved

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