Linked Life Data

17699739

Source:http://linkedlifedata.com/resource/pubmed/id/17699739

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2007-10-23
pubmed:abstractText
The bradykinin B(2) receptor is a heptahelical receptor regulated by a cycle of phosphorylation, endocytosis, and extensive recycling at the cell surface following agonist stimulation. B-9430 (d-Arg-[Hyp(3),Igl(5),D-Igl(7),Oic(8)]-bradykinin) is a second generation peptide antagonist found to be competitive at the human B(2) receptor and insurmountable at the rabbit B(2) receptor (contractility assays, isolated human umbilical and rabbit jugular veins). Two isomers of this peptide were prepared: B-10344 (D-Arg-[Hyp(3),Igl(5),Oic(7),D-Igl(8)]-bradykinin; inverted sequence Oic(7), D-Igl(8)) and B-9972 (D-Arg-[Hyp(3),Igl(5),Oic(7),Igl(8)]-bradykinin); they are low- and high-potency agonists, respectively, in vascular preparations. The potency gap between bradykinin and B-9972 is narrow in contractility assays, despite the fact that B-9972 affinity is 7-fold inferior at the rabbit B(2) receptor (radioligand binding competition assay). The effects of agonists on receptors were compared using two chimerical constructions based on rabbit B(2) receptors: conjugate of the B(2) receptor with green fluorescent protein (B(2)R-GFP) and the N-terminally tagged conjugate of the myc epitope with the B(2) receptor. Imaging and immunoblotting showed that B-9972 induced a persistent endocytosis of cell surface B(2) receptors in human embryonic kidney 293 cells with slow receptor degradation (weak after 3 h of treatment, important at 12 h) and B(2)R-GFP desensitization ([(3)H]bradykinin endocytosis and extracellular signal-regulated kinase 1/2 phosphorylation assays). Bradykinin was not active in this respect but when combined with captopril, induced some degradation. B-9430 reduced the endocytosis and degradation of B(2) receptors by the agonists. The results illustrate the agonist-antagonist transition in B(2) receptor peptide ligands with a constrained C-terminal structure, the importance of species in their pharmacological profile, and the possibility of selectively degrading receptors using a peptidase-resistant agonist.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
323
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
534-46
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
B-9972 (D-Arg-[Hyp3,Igl5,Oic7,Igl8]-bradykinin) is an inactivation-resistant agonist of the bradykinin B2 receptor derived from the peptide antagonist B-9430 (D-Arg-[Hyp3,Igl5,D-Igl7,Oic8]-bradykinin): pharmacologic profile and effective induction of receptor degradation.
pubmed:affiliation
Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Quebec, Canada.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't