title: Rubimetide, humanin, and MMK1 exert anxiolytic-like activities via the formyl peptide receptor 2 in mice followed by the successive activation of DP1, A2A, and GABAA receptors.
abstract: 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) D2-dependent manner in the elevated plus-maze test after administration at a dose of 0.1mg/kg (ip.) or 1mg/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 (0.1mg/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 (icv) 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 DP1-receptor. Furthermore, anxiolytic-like activity of rubimetide was blocked by SCH58251 and bicuculline, antagonists for adenosine A2A and GABAA 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-A2A receptor, and GABA-GABAA receptor systems downstream of the FPR2.
authors.affiliation: Department of Functional Food Science, Research Institute for Production Development, Sakyo-ku, Kyoto 606-0805, Japan.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Functional Food Science, Research Institute for Production Development, Sakyo-ku, Kyoto 606-0805, Japan.
authors.forename: Soushi
authors.initials: S
authors.lastname: Sonada
authors.affiliation: Department of Functional Food Science, Research Institute for Production Development, Sakyo-ku, Kyoto 606-0805, Japan; Functional Research Laboratory, 8-1 Kitagaito, Ichinobe, Joyo, Kyoto 610-0114, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yoshikawa
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohinata
authors.affiliation: Department of Functional Food Science, Research Institute for Production Development, Sakyo-ku, Kyoto 606-0805, Japan; Functional Research Laboratory, 8-1 Kitagaito, Ichinobe, Joyo, Kyoto 610-0114, Japan. Electronic address: yosikawa@kais-kyoto-u.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yoshikawa
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism; D001640:Bicuculline / Q000008:administration & dosage; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D051379:Mice; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012273:Ribulose-Bisphosphate Carboxylase / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D018724:Spinacia oleracea / Q000737:chemistry; D050680:Transcription Factor DP1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D014151:Anti-Anxiety Agents; C469988:Fpr1 protein, mouse; D058787:GABA-A Receptor Antagonists; D047908:Intracellular Signaling Peptides and Proteins; C408903:MMK-1 peptide; D010446:Peptide Fragments; D010455:Peptides; D043705:Receptor, Adenosine A2A; D044042:Receptors, Formyl Peptide; D011963:Receptors, GABA-A; C493736:Tfdp1 protein, mouse; D050680:Transcription Factor DP1; C481578:formyl peptide receptor 2, mouse; C427211:humanin; C530457:rubimetide; D012273:Ribulose-Bisphosphate Carboxylase; D001640:Bicuculline
keywords: Adenosine A(2A) receptor; Anxiolytic-like activity; DP(1) receptor; FPR2; GABA(A) receptor; Humanin; MMK1; Prostaglandin D(2); Rubimetide; Rubisco