In this article, we found that rubimetide (Met-Arg-Trp) derived from spinach Rubisco has affinities for the formyl peptide receptor (FPR) 1 and 2. The anxiolytic-like activity of rubimetide evaluated by the elevated-plus maze test in mice was mediated by the FPR2 since it was blocked by a selective antagonist of the receptor. Based on this results, we found that typical agonist peptides of the FPR2 such as humanin and MMK1 also exert anxiolytic-like activities as the first example of central effect mediated by the FPR2.

We demonstrated that anxiolytic-like activities of rubimetide and typical agonist peptides of the FPR2 are mediated by successive activation of the PGD₂-DP₁ receptor, adenosine-A_2A receptor, and GABA-GABA_A receptor systems downstream of the FPR2.