Journal
PEPTIDES
Volume 83, Issue -, Pages 16-20Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.peptides.2016.07.001
Keywords
Rubimetide; Rubisco; MMK1; Humanin; Anxiolytic-like activity; FPR2; Prostaglandin D-2; DP1 receptor; Adenosine A(2A) receptor; GABAA receptor
Funding
- Kagome Co. Ltd. (Tokyo Japan)
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Rubimetide (Met-Arg-Trp), which had been isolated as an antihypertensive peptide from an enzymatic digest of spinach ribulose-bisphosphate carboxylase/oxygenase (Rubisco), showed anxiolytic-like activity prostaglandin (PG) D-2-dependent manner in the elevated plus-maze test after administration at a dose of 0.1 mg/kg (ip.) or 1 mg/kg (p.o.) in male mice of ddY strain. In this study, we found that rubimetide has weak affinities for the FPR1 and FPR2, subtypes of formyl peptide receptor (FPR). The anxiolytic-like activity of rubimetide (0.1 mg/kg, ip.) was blocked by WRW4, an antagonist of FPR2, but not by Boc-FLFLF, an antagonist of FPR1, suggesting that the anxiolytic-like activity was mediated by the FPR2. Humanin, an endogenous agonist peptide of the FPR2, exerted an anxiolytic-like activity after intracerebroventricular (icy) administration, which was also blocked by WRW4. MMK1, a synthetic agonist peptide of the FPR2, also exerted anxiolytic-like activity. Thus, FPR2 proved to mediate anxiolytic-like effect as the first example of central effect exerted by FPR agonists. As well as the anxiolytic-like activity of rubimetide, that of MMK1 was blocked by BW A868C, an antagonist of the DPi-receptor. Furthermore, anxiolytic-like activity of rubimetide was blocked by SCH58251 and bicuculline, antagonists for adenosine A(2A) and GABA(A) receptors, respectively. From these results, it is concluded that the anxiolytic-like activities of rubimetide and typical agonist peptides of the FPR2 were mediated successively by the PGD2-DP1 receptor, adenosine-A(2A) receptor, and GABA-GABA(A) receptor systems downstream of the FPR2. (C) 2016 Elsevier Inc. All rights reserved.
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