| Co-Investigator(Kenkyū-buntansha) |
TANI Fumito Kyoto University, Graduate School of Agriculture, Associate Professor, 農学研究科, 助教授 (70212040)
OHINATA Kousaku Kyoto University, Graduate School of Agriculture, Lecturer, 農学研究科, 講師 (00361147)
大森 謙司 田辺製薬(株), 探索研究所, 主席部員
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| Budget Amount *help |
¥15,700,000 (Direct Cost: ¥15,700,000)
Fiscal Year 2005: ¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 2004: ¥8,900,000 (Direct Cost: ¥8,900,000)
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| Research Abstract |
Most bioactive peptides derived from food proteins bind to receptors for endogenous bioactive ones. However, their selectivities for receptor subtypes are different from those of endogenous peptides ; sometimes they are selective for minor subtypes. In this study, function of minor receptor subtypes for bioactive peptides are investigated by use of food-derived peptides.
β-Lactotensin (HIRL) derived from β-lactoglobulin induces an ileum-contracting via neurotensin NT_1 receptor, and induces analgesia, and reduction of serum cholesterol via NT_2 receptor. We newly found that β-lactotensin stimulated bile acid secretion and improved learning performance via NT_2 receptor. It was also suggested that dopamine was released at the downstream of NT_2 receptor. In fact, β-lactotensin stimulated dopamine release from striatum and nucleus accumbens in mice.
Novokinin (RPLKPW) which has been obtained by replacing four amino acid residues in ovokinin(2-7) (RADHPF), a vasorelaxing-hypotensive peptide
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derived from ovalbumin, showed potent hypotensive activity after oral administration at a dose of 0.1 mg/kg in spontaneously hypertensive rats (SHR). Novokinin showed affinity (Ki = 7.35 μm) for AT_2 receptor, a minor subtype of angiotensin receptor. Vasorelaxing and hypotensive activities of novokinin were blocked by PD123319, an antagonist for AT_2 receptor. This means novokinin is the first AT_2 agonist peptide showing hypotensive activity. Vasorelaxing and hypotensive activities of novokinin were blocked by indomethacin, a COX inhibitor, and CAY-10441, an antagonist for IP receptor. This suggests that PGI2 is involved in vasorelaxating and hypotensive activities at the downstream of AT_2 receptor in mesenteric artery. Novokinin stimulated hair growth in shaven mice and prevented etoposite-induced alopecia in neonatal rats. The antialopecia effect of novokinin was also blocked by antagonists for AT_1 and AT_2 receptors suggesting the involvement of both receptors. The antialopecia effect was also blocked by indomethacin and an antagonist for EP_4 receptor, AH23848 suggesting the involvement of EP_4 receptor. Novokinin suppressed food intake after icv. or oral administration in mice. The anorectic activity was also blocked by PD123319, indomethacin, and an antagonist for EP_4 receptor, ONO-AE3-203. This suggests that the anorectic activity of novokinin is mediated by PGE2 bound to EP_4 receptor at the downstream of AT_2 receptor. Furthermore, both angiotensin II and III showed anorectic activity.
Thus, AT_2 receptor mediates various physiological effects of AT_2 agonist by releasing PGs ; PGI2-IP mediates vasorelaxation and hypotension. in mesenteric artery, and PGE2-EP_4 in hair follicle and brain. Less
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