中枢グルタミン酸受容体の分子構造と生理機能

• 研究課題/領域番号: 04267103
• 研究種目: 重点領域研究
• 配分区分: 補助金
• 研究機関: 東京大学 (1994); 新潟大学 (1992-1993)
• 研究代表者: 三品 昌美 東京大学, 医学部(医), 教授 (80144351)
• 研究分担者: 遠山 正彌 大阪大学, 医学部, 教授 (40028593) ; 杉山 博之 九州大学, 理学部, 教授 (20124224) ; 津本 忠治 大阪大学, 医学部, 教授 (50028619) ; 小澤 瀞司 群馬大学, 医学部, 教授 (40049044) ; 川合 述史 自治医科大学, 教授 (00073065) ; 渡辺 雅彦 北海道大学, 医学部, 助教授 (70210945) ; 相沢 慎一 新潟大学, 理化学研究所, 副主任研究員 (60073011) ; 勝木 元也 九州大学, 生体防御医学研究所, 教授 (20051732)
• 研究期間 (年度): 1994
• 研究課題ステータス: 完了 (1994年度)
• 配分額: 194,000千円 (直接経費: 194,000千円); 1994年度: 54,000千円 (直接経費: 54,000千円); 1993年度: 72,500千円 (直接経費: 72,500千円); 1992年度: 67,500千円 (直接経費: 67,500千円)
• キーワード: グルタミン酸受容体 / NMDA受容体チャネル / 脳 / 長期増強 / スライス / 標的遺伝子組換え / パッチクランプ / 海馬 / G蛋白共役型グルタミン酸受容体 / カルシウム / 脱感作 / 標的組換え / mRNA

研究概要

本研究班は、中枢における神経情報伝達シナプス可塑性の鍵を握るグルタミン酸受容体を実体として明らかにするとともにその生理機能を分子構造と対応させて明確にすることを目標とした。研究計画が順調に進行していることから、本年度は生理機能を分子レベルで理解することに重点をおいて、以下の成果を挙げた。NMDA受容体チャネルのε1サブユニット遺伝子を不活化されたマウスを作成し、海馬シナプスにおける長期増強と空間学習の低下が起こることを見い出した。この成果は、記憶・学習のシナプス可塑性仮説を支持するものである(三品)。短時間虚血負荷後のスナネズミ海馬錘体細胞においてAMPA型グルタミン酸受容体チャネル電流の持続性やカルシウム透過性が変化することを単一チャネル電流の解析により明らかにした(川合)。海馬切片を対象として、スライスパッチクランプ法とRT-PCR法を組み合わせることにより、グルタミン酸受容体チャネルの電気生理学的特性とサブユニット構成との関連を明らかにした(小澤)。ラット視覚野から調整した培養神経細胞標本に穿孔パッチクランプ法を適用することにより、視覚野におけるシナプス長期増強の誘発にはシナプス後細胞の脱分極と同期したシナプス前部の賦括が必要であることを見い出した(津本)。代謝型グルタミン酸受容体のサブタイプ5にはスプライシングの違いによる2種類の型が存在し、発生の時期により調節されていることを見い出した(杉山)。AMPA型グルタミン酸名受容体チャネルmRNAがラットの腺細胞に発現していることならびに虚血条件下ではグルタミン酸トランスポーターの遺伝子発現と蛋白の細胞内局在が変化することを見い出した(遠山)。ホメオ蛋白Otx2遺伝子のヘテロ欠損マウスを作製し、Otx2が頭蓋においても神経系においても下顎セグメントの形態形成を特異的に制御することを明らかにした(相沢)。5種類のNMDA受容体チャネルサブユニットの遺伝子発現パターンは生後2週間の間に、領域差の小さい胎児型から顕著な空間的異質性を特徴とする成熟型へと変換することを明らかにした(渡辺)。バキュロウイルス発現系により大量発現させたAMPA型およびNMDA型グルタミン酸受容体チャネルを用いて、リガンド結合活性にN-グリコシル化が必須であることを明らかにした(川本)。

研究成果

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