JPWO2019131936A1 - 塩味受容体を用いた塩味増強剤のスクリーニング方法 - Google Patents
塩味受容体を用いた塩味増強剤のスクリーニング方法 Download PDFInfo
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- JPWO2019131936A1 JPWO2019131936A1 JP2019562199A JP2019562199A JPWO2019131936A1 JP WO2019131936 A1 JPWO2019131936 A1 JP WO2019131936A1 JP 2019562199 A JP2019562199 A JP 2019562199A JP 2019562199 A JP2019562199 A JP 2019562199A JP WO2019131936 A1 JPWO2019131936 A1 JP WO2019131936A1
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Abstract
Description
(i)被験物質が、TMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物であるか否かを判定する工程、および
(ii)前記工程(i)においてTMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物であると判定された被験物質を、塩味増強剤の有効成分として選択する工程。
項5、マウスである、項4に記載のモデル動物。
TMC(transmembrane channel like)4遺伝子は、公知の遺伝子であり、TMC4タンパク質は公知のタンパク質である。TMC4タンパク質は、TMCタンパク質の1種である。TMC タンパク質は、8回膜貫通領域を有し、細胞内にN末端及びC末端が存在する膜タンパク質である。TMCタンパク質は、TM5とTM6間にTMCモチーフという共通領域を有する。哺乳類において、TMCタンパク質は配列上、アノクタミンファミリーに属する。
ヒトTMC4遺伝子:NM_001145303(NM_001145303.2)、NM_144686(NM_144686.3)、BC025323(BC025323.1)
ヒトTMC4タンパク質:NP_001138775(NP_001138775.2)、NP_653287(NP_653287.2)
マウスTMC4遺伝子:.NM_181820(NM_181820.2)
マウスTMC4タンパク質:NP_861541(NP_861541.2)。
本発明の塩味増強剤は、TMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物を含む。
TMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物の、塩味増強剤としての使用。
塩味増強剤としての使用するための、TMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物。
塩味増強剤を製造するための、TMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物の使用。
本発明のスクリーニング方法は、下記の工程を含む、:
(i)被験物質が、TMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物であるか否かを判定する工程、および
(ii)前記工程(i)においてTMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物であると判定された被験物質を、塩味増強剤の有効成分として選択する工程。
(2)前記のTMC4タンパク質と類似の性質を有しその立体構造が明らかにされているタンパク質を活性化する化合物(リガンド)が知られている場合、当該リガンドの立体構造に基づいてドッキングシミュレーションを行い、当該リガンドにおけるTMC4タンパク質の構造領域に作用する領域を類推し、ドッキング部位の立体構造に基づいてよりTMC4タンパク質を活性化させるリガンド構造をスクリーニングする方法が挙げられる。
本発明において高塩濃度に対する嗜好性を有するモデル動物として使用される非ヒト動物は、TMC4遺伝子がノックアウトされた非ヒト動物である。
TMC4遺伝子がノックアウトされた非ヒト動物の、高塩濃度に対する嗜好性を有するモデル動物としての使用。
高塩濃度に対する嗜好性を有するモデル動物としての使用するための、TMC4遺伝子がノックアウトされた非ヒト動物。
口腔内の味蕾を持つ組織(有郭乳頭、葉状乳頭、茸状乳頭)でのTMC4の局在確認をIn situ hybridizationを用いて行った。
In situ hybridization
野生型C57BL/6J(B6)マウス(日本クレアから購入)7週齢以上のオスを用いた。マウスは頸椎脱臼により安楽死させた後、舌から乳頭周辺上皮を摘出し、クリオモルド1号(サクラファインテック)の中にO.C.T.コンパウンド(サクラファインテック)で包埋し、液体窒素を用いて凍結した。凍結ブロックは、7μmに薄切りし、MASコートスライドグラス(松浪硝子)に張り付けた。
結果を図1に示す。TMC4は有郭乳頭(Circumvallatepapillae、CvP)、葉状乳頭(Foliatepapillae、FoP)の味蕾特異的に強く局在していることが明らかとなった。
TMC4の電気生理学的性質を調べるために、TMC4を発現するHEK293T細胞を用いてWhole cell patch clamp assay(全細胞記録)を行った。
プラスミド及び発現タンパク質
マウスTMC4(mTMC4)をHEK293T細胞に発現させるために、CMVプロモーターを持つプラスミドベクター pIRES2 -AcGFP1(Clontech社)を用いた。pIRES2-AcGFP1 の制限酵素EcoR1サイトとNot1サイト間にmTMC4(accession NM_181820.2の配列をマウスの有郭乳頭上皮由来のcDNAからクローニング)を挿入した発現コンストラクトを、1 μg/35mm dishの割合で遺伝子導入を行った。遺伝子導入試薬にはLipofectamine(商標)LTX Reagent with PLUS& Reagent(商標)(Thermo Fisher社)を用いた。また蛍光指示を目的としてpEGFP-N1(Clontech社)を0.1 μg/35mm を同時に遺伝子導入した。
HEK293T細胞を用いたwhole cell patch-clamp recordingにおいて、増幅器としてAxopatch 200B(Molecular Devices)を用いて、Digidata 1550(Axon Instruments、Union City、CA、USA)からデジタルデータを取得した。取得したデータは、ソフトウェアpCLAMP 10.2(Axon Instruments)を使用し解析を行った。
結果を図2に示す。
TMC4の塩味受容行動への影響を観察するために、TMC4遺伝子のノックアウトマウス(KO)を作成しリック解析実験(Brief access test)行った。
TMC4 KOマウス
動物実験は、承認を受け、動物実験実施マニュアルを順守し行った。
リック解析実験は、実験動物に味溶液を短時間提示し、飲み口を舐める回数(リック数)をカウントする方法であり、摂食後効果(post-ingestive effects)を除いた味の認知のみ(脳を介す)を測定することができる試験である。
試験のために馴化トレーニングされたマウス(WT n=9、KO n=7、いずれも雄 20週齢以上)を用いた。一般に濃度依存的に嗜好される味質(甘味、旨味)は4時間の絶食、絶水後、濃度が上がるにつれて忌避される味質(苦味、酸味、塩味)は23時間絶水、自由摂食を行った後、5秒間のリック数を測定した。23時間絶水後の水を舐めた回数を1とし、その比率を算出した。
TMC4に対する公知の塩味増強剤の影響を観察するために、humanTMC4(hTMC4)を発現するHEK293T細胞を用いてWhole cell patch clamp assay(全細胞記録)を行った。
1)ヒトTMC4(hTMC4)を発現するHEK293T細胞を用いること、及び
2)ビークル(vehicle)溶液として134 mM NaCl溶液を用い、vehicle溶液に塩味増強剤としてアルギニン塩酸塩(Arg-HCl)100 μMを添加した細胞外液、スクロースまたはマルトース100 μM をそれぞれvehicle溶液に添加した細胞外液(塩味を増強しない対照)を用いること以外は、実施例2と同様にしてWhole cell patch clamp assayを行った。TMC4を介して流入するCl-電流を比較した。
結果を図4及び5に示す。
Claims (5)
- 塩味増強剤の有効成分のスクリーニング方法であって、下記の工程を含むスクリーニング方法:
(i)被験物質が、TMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物であるか否かを判定する工程、および
(ii)前記工程(i)においてTMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物であると判定された被験物質を、塩味増強剤の有効成分として選択する工程。 - TMC4遺伝子又はTMC4タンパク質の機能発現を亢進できる化合物を含む、塩味増強剤。
- 前記化合物が食品由来の成分である請求項2に記載の塩味増強剤。
- TMC4遺伝子がノックアウトされた非ヒト動物である、高塩濃度に対する嗜好性を有するモデル動物。
- マウスである、請求項4に記載のモデル動物。
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NATURE, vol. 494, JPN6017034424, 2013, pages 95 - 99, ISSN: 0005063713 * |
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