
Activity of Bradykinin B2 Receptor Is Regulated by Long-Chain Polyunsaturated Fatty Acids
Author(s) -
José Candelario,
Mirianas Chachisvilis
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0068151
Subject(s) - bradykinin , polyunsaturated fatty acid , phosphorylation , mapk/erk pathway , docosahexaenoic acid , chemistry , biochemistry , receptor , biology , fatty acid
The molecular and cellular mechanisms by which long-chain polyunsaturated fatty acids (LCPUFA) exert their beneficial effects on cardiovascular health remain obscure. While both LCPUFA and bradykinin (BK) signaling pathway play a role in the cardiovascular system, any direct link between the two is yet to be established. Using picosecond time-resolved fluorescence microscopy and a genetically engineered bradykinin B 2 receptor (B 2 R) sensor (B2K-CC), we detected LCPUFA-induced conformational responses in the B 2 R similar to those caused by its cognate ligand, BK. The selective B 2 R antagonist (HOE-140) blocked the eicosapentaenoic acid (EPA, C20∶5, n-3) induced conformational response of the B2K-CC. Further analysis suggests that LCPUFA are capable of direct, B 2 R-dependent activation of extracellular ligand-regulated kinases (ERK). From a wide range of fatty acids studied, varying in chain length, saturation, and position of double bonds, EPA, docosahexaenoic (DHA, C22∶6, n-3), docosadienoic (DDA, C22∶2, n-6), and dihomo-gamma linoleic (DGLA, C20∶3, n-6) fatty acids caused the highest ERK phosphorylation. EPA or DHA dependent ERK phosphorylation was inhibited by the selective B 2 R antagonist. We show that LCPUFA stimulates downstream signaling by B 2 R such as B 2 R-dependent phosphorylation and expression regulation of endothelial nitric-oxide synthase (eNOS). Further analysis indicated that LCPUFA also alters levels of the eNOS transcription factor, kruppel-like factor 2 (KLF2). Moreover we show that EPA increases membrane fluidity on the same time scale as B 2 R conformational response, suggesting that partitioning of LCPUFA into bilayer is a primary step required for receptor activation. In summary our data show that LCPUFA activate B 2 R receptor at nanomolar concentrations suggesting a novel molecular mechanism by which fatty acids may affect the cardiovascular system.