非定型中枢神経伝達物質D-セリンの病態生理

• Project/Area Number: 17659073
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: General pharmacology
• Research Institution: Kyoto University
• Principal Investigator: 赤池 昭紀 京都大学, 薬学研究科, 教授 (80135558)
• Co-Investigator(Kenkyū-buntansha): 香月 博志 京都大学, 薬学研究科, 助教授 (40240733) ; 久米 利明 京都大学, 薬学研究科, 助手 (10303843)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥2,800,000 (Direct Cost: ¥2,800,000); Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: 脳神経疾患 / 生体分子 / 薬理学 / 網膜 / 神経節細胞 / 興奮毒性 / NMDA受容体 / グリシン / アポトーシス / D-セリン

Research Abstract

大脳皮質においてD-セリンが主要な内在性リガンドであることの確証を得るため、以下の検討を行った。大脳皮質培養切片を用いてNMDA誘発神経毒性に対するグリシンおよびD-セリンの作用を検討した。単独では神経毒性を発現しない濃度のNMDAに、グリシンおるいはD-セリンを併用したところニューロン死が観察された。単独で神経毒性を惹起するNMDA処置に対してグリシンは作用を示さなかったが、D-セリンはNMDA神経毒性を増悪した。次に内在性グリシン結合部位アゴニストがNMDA誘発神経毒性にどの程度寄与しているのか解析するために、グリシン結合部位の競合的遮断薬である5,7-ジクロロキヌレン酸(DCKA)の作用を検討した。NMDA処置に対してDCKAは有意な保護作用が観察された。グリシントランスポータI(GLYTI)による細胞外グリシン濃度の調節がNMDA誘発神経毒性に影響を及ぼすかどうかを検討するためGLYTIの阻害薬の作用を検討した。GLYTI阻害薬であるALX5407はNMDA毒性のDCKA感受性を有意に減弱させた。また、ALX5407はbuffer中のグリシン遊離量を顕著に増加させた。L-セリン処置を行ったところ、NMDA毒性のDCKA感受性が有意に減弱した。L-セリン処置により切片内D-セリン含量は有意に増加し、それに伴いbuffer中へのD-セリン遊離量は増加した。これらの結果よりGLYTIによる細胞外グリシン濃度の調節およびセリンラセマーゼによるD-セリン合成のNMDA受容体機能の制御において重要な役割を果たしていることが示唆された。

Research Products

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