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Role of extracellular and transmembrane domains for binding and activation of kinin B1 receptor and of angiotensin II AT1 receptor: structure-activity correlation

Grant number: 10/05255-9
Support Opportunities:Regular Research Grants
Duration: August 01, 2010 - July 31, 2012
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Suma Imura Shimuta
Grantee:Suma Imura Shimuta
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated researchers:Clovis Ryuichi Nakaie


Recent study on the structure-activity of the kinin B1 receptor (B1R) revealed that important residues for its binding to des-Arg9-bradykinin (DBK) are homologous to those in the interaction between angiotensin II and the angiotensin II (AngII) type I receptor (AT1R). In addition, as the B1R and AT1R have the same two residues at the C-terminal side (Pro7-Phe8) we hypothesized that both receptors, B1R and AT1R present crucial binding sites at the top of helix V and VI for interaction. Based on these data is our aim: (1) identify important residues to the interaction between DBK and B1R, by binding assays using DBK analogues and B1R mutants; (2) determine the functional expression of wild-type receptor and its mutants, by testing the IP3 production and the determination of [Ca2+]i; (3) verify whether the N-terminal region of DBK (Arg1) interacts with Asp301 (712) of B1R; (4) investigate whether the Asn130 (325) of the B1R, the homologue residue for Asn111 (325) of AT1R, interacts with the DBK Phe5 by the replacement of Asn130 (325) to Gly; (5) evaluate the role of the B1R second disulfide bond (Cys25 (100) -Cys294 (650) by replacing the Cys25 (100) for Ser. If the hypothesis that Arg1 of the peptide interacts with Asp301 (712) of the receptor EC-3 loop, [Lys1] DBK will be tested, to verify the importance of guanidine group in this position. These receptors will be labeled with GFP and fluorescence technique will be used to find out their preferential distribution, to verify whether the mutants were expressed on the cell membrane or retained in the endoplasmic reticulum. If the receptors were not transported from the endoplasmic reticulum because of the deficient maturation of the mutants, it will be assessed using calnexin, a reticulum marker. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RODRIGUES, ELIETE S.; SILVA, RAFAEL F.; MARTIN, RENAN P.; OLIVEIRA, SUZANA M.; NAKAIE, CLOVIS R.; SABATINI, REGIANE A.; MERINO, VANESSA F.; PESQUERO, JOAO B.; BADER, MICHAEL; SHIMUTA, SUMA I.. Evidence that kinin B-2 receptor expression is upregulated by endothelial overexpression of B-1 receptors. Peptides, v. 42, p. 1-7, . (09/08336-2, 10/05255-9)

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