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Characterization of dual agonists for kinin B1 and B2 receptors and their biased activation of B2 receptors

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Title: Characterization of dual agonists for kinin B1 and B2 receptors and their biased activation of B2 receptors
Author(s): Brovkoyvch, Viktor; Lowry, Jessica L.; Skidgel, Randal A.; Zhang, Xianming
Subject(s): Kinin B1 receptor kinin B2 receptor biased agonist kinin peptides endocytosis
Abstract: Kinin B1 and B2 receptors (kB1R and kB2R) play important roles in many physiological and pathological processes. In some cases, kB1R or kB2R activation can have overlapping or complementary beneficial effects, thus an activator of both receptors might be advantageous. We found that replacement of the C-terminal Arg in the natural kB2R activators bradykinin (BK) or kallidin (KD) with Lys (K9-BK or K10-KD) resulted in agonists that effectively stimulate the downstream signaling of both the kB1R and kB2R as measured by increased inositol turnover, intracellular calcium, ERK1/2 phosphorylation, arachidonic acid release and NO production. However, K9-BK and K10-KD displayed some characteristics of biased agonism for kB2Rs as indicated by the rapid kinetics of ERK1/2 phosphorylation induced by K9-BK or K10-KD compared with the prolonged response mediated by BK or KD. In contrast, kinetics of ERK phosphorylation stimulated by K10-KD activation of the kB1R was as same as that induced by known kB1R agonist des-Arg10-KD. Furthermore, the endocytosis of kB2Rs mediated by K9- BK and K10-KD was remarkably less than that induced by BK and KD respectively. K10-KD stimulated kB1R and kB2R-dependent calcium responses and ERK1/2 phosphorylation in bovine endothelial cells. In cytokine-treated human endothelial cells, K10-KD stimulated ERK1/2 phosphorylation and a transient peak of NO production that was primarily kB2R-dependent. K10-KD also stimulated prolonged NO production that was both kB1R and kB2R-dependent. These data provide the first examples of dual agonists of kB1R and kB2R, and a biased agonist of kB2R and may provide useful clues for developing dual modulators of kB1Rs and kB2Rs for potential therapeutic use.
Issue Date: 2012-08
Publisher: Elsevier
Citation Info: Zhang X, Lowry JL, Brovkovych V, Skidgel RA. Characterization of dual agonists for kinin B1 and B2 receptors and their biased activation of B2 receptors. Cellular Signalling. 2012 Aug;24(8):1619-31 DOI: 10.1016/j.cellsig.2012.04.002
Type: Article
Description: NOTICE: this is the author’s version of a work that was accepted for publication in Cellular Signalling. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in PUBLICATION, [Vol 24, Issue 8, 2012 Aug] DOI: 10.1016/j.cellsig.2012.04.002
ISSN: 1873-3913
Sponsor: National Institutes of Health Grants DK41431, HL 36473 and HL60678
Date Available in INDIGO: 2012-10-02

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