JP6871165B2 - 新規な電圧依存性イオンチャネル融合物およびその使用方法 - Google Patents
新規な電圧依存性イオンチャネル融合物およびその使用方法 Download PDFInfo
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Description
本発明は、新規な電圧依存性イオンチャネル融合サブユニット、および、候補分子または物理的パラメータを、電圧依存性イオンチャネルを活性化または阻害するそれらの能力についてリアルタイムでスクリーニングし特徴づけるための機能的生物発光共鳴エネルギー移動(BRET)アッセイ、に関する。本発明はまた、少なくとも1つの電圧依存性イオンチャネル融合サブユニットを含む、細胞ベースまたは無細胞の組成物であって、ここで、生物発光ドナー分子および/またはアクセプター分子が、前記チャネルサブユニットのC末端、N末端、またはループのいずれかに結合している、前記組成物にも関する。生物発光ドナーおよび/または蛍光アクセプター分子に結合した電圧依存性イオンチャネル融合サブユニットの組み合わせは、生物発光共鳴エネルギー移動(BRET)を使用して、電圧依存性イオンチャネルサブユニットの立体配座の変化を検出し、これにより前記チャネルの活性化または阻害を示すことを可能にする。
植物および動物細胞における多数の中心的プロセスは、特定イオンの細胞内濃度の変化、例えばプロトン濃度の変化、および膜を横切る膜電位およびイオン勾配の変化を介して、全体的または部分的に制御される。事実上全ての動物細胞は、タンパク質が包埋された脂質二重層から構成される膜によって囲まれている。この膜は、イオンの移動に対する絶縁体および拡散障壁の両方として機能する。イオントランスポーター/ポンプタンパク質は、膜を横切ってイオンを積極的に押し込み、膜を横切る濃度勾配を確立し、イオンチャネルは、イオンが膜を横切ってその濃度勾配の下へと移動することを可能にする。イオンポンプおよびイオンチャネルは、膜に挿入された一組の電池および抵抗器と電気的に等価であり、したがって、膜の両側に電圧差を生成する。イオンチャネルは、活動電位の生成およびタイミング、エネルギー産生、シナプス伝達、ホルモンの分泌および筋肉の収縮などの多様な細胞プロセスに関与し、調節する。
(i)生物発光ドナー分子がチャネルサブユニットのC末端に結合し、アクセプター分子が該チャネルサブユニットのN末端に結合している、
(ii)生物発光ドナー分子がチャネルサブユニットのN末端に結合し、アクセプター分子が該チャネルサブユニットのC末端に結合している、
(iii)生物発光ドナー分子がチャネルサブユニットのC末端に結合し、アクセプター分子が第1または第2細胞内ループの一部を形成する、
(iv)生物発光ドナー分子がチャネルサブユニットのN末端に結合し、アクセプター分子が第1または第2細胞内ループの一部を形成する、
(v)アクセプター分子がチャネルサブユニットのC末端に結合し、生物発光ドナー分子が第1または第2細胞内ループの一部を形成する、
(vi)アクセプター分子がチャネルサブユニットのN末端に結合し、生物発光ドナー分子が第1または第2細胞内ループの一部を形成する、
(vii)生物発光ドナー分子が第1細胞内ループの一部を形成し、アクセプター分子が第2細胞内ループの一部を形成する、
(viii)生物発光ドナー分子が第2細胞内ループの一部を形成し、アクセプター分子が第1細胞内ループの一部を形成する。
ヘマトポルフィリン;Hoechst 33258;Hoechst 33342;Hoechst 34580;HPTS;ヒドロキシクマリン;ヒドロキシスチルバミジン(FluoroGold);ヒドロキシトリプタミン;Indo-1、高カルシウム;Indo-1、低カルシウム;インドジカルボシアニン(DiD);インドトリカルボシアニン(DiR);Intrawhite Cf;JC-1;JO-JO-1;JO-PRO-1;LaserPro;Laurodan;LDS 751(DNA);LDS 751(RNA);Leucophor PAF;Leucophor SF;Leucophor WS;リサミンローダミン;リサミンローダミンB;カルセイン/エチジウムホモダイマー;LOLO-1;LO-PRO-1;ルシファーイエロー;ライソトラッカーブルー;ライソトラッカーブルーホワイト;ライソトラッカーグリーン;ライソトラッカーレッド;ライソトラッカーイエロー;LysoSensor Blue;LysoSensor Green;LysoSensor Yellow/Blue;マググリーン;マグダラレッド(Phloxin B);Mag-Fura Red;Mag-Fura-2;Mag-Fura-5;Mag-Indo-1;マグネシウムグリーン;マグネシウムオレンジ;マラカイトグリーン;Marina Blue;マキシロンブリリアントフラビン10 GFF;マキシロンブリリアントフラビン8 GFF;メロシアニン;メトキシクマリン;Mitotracker Green FM;Mitotracker Orange;Mitotracker Red;ミトラマイシン;モノブロモビマン;モノブロモビマン(mBBr-GSH);モノクロロビマン;MPS(メチルグリーンピロニンスチルベン);NBD;NBDアミン;ナイルレッド;ニトロベンズオキサジドール;ノルアドレナリン;ヌクレアファストレッド;ヌクレアイエロー;Nylosan Brilliant lavin E8G;Oregon Green;Oregon Green 488-X;Oregon Green(商標);Oregon Green(商標)488;Oregon Green(商標)500;Oregon Green(商標)514;Pacific Blue;Pararosaniline(Feulgen);PBFI;PE-Cy5;PE-Cy7;PerCP;PerCP-Cy5.5;PE−Texas Red [Red 613];Phloxin B(マグダラレッド);Phorwite AR;Phorwite BKL;Phorwite Rev;Phorwite RPA;ホスフィン3R;PhotoResist;フィコエリスリンB[PE];フィコエリスリンR[PE];PKH26(Sigma);PKH67;PMIA;ポントクロムブルーブラック;POPO-1;POPO-3;PO-PRO-1;PO-PRO-3;プリムリン;Procion Yellow;ヨウ化プロピジウム(PI);PyMPO;ピレン;ピロニン;ピロニンB;パイロザールブリリアントフラビン7GF;QSY 7;キナクリンマスタード;Red 613 [PE-TexasRed];レゾルフィン;RH 414;Rhod-2;ローダミン;ローダミン110;ローダミン123;ローダミン5GLD;ローダミン6G;ローダミンB;ローダミンB200;ローダミンBエクストラ;ローダミンBB;ローダミンBG;ローダミングリーン;ローダミンファリシジン;ローダミンファロイジン;ローダミンレッド;ローダミンWT;ローズベンガル;R−フィコシアニン;R−フィコエリスリン(PE);S65A;S65C;S65L;S65T;SBFI;セロトニン;セブロンブリリアントレッド2B;セブロンブリリアントレッド4G;セブロンブリリアントレッドB;セブロンオレンジ;セブロンイエローL;SITS;SITS(プリムリン);SITS(スチルベンイソチオスルホン酸);SNAFLカルセイン;SNAFL−1;SNAFL−2;SNARFカルセイン;SNARF1;ナトリウムグリーン;SpectrumAqua;SpectrumGreen;SpectrumOrange;Spectrum Red;SPQ(6−メトキシ−N−(3−スルホプロピル)キノリニウム);スチルベン;スルホローダミンB can C;スルホローダミンエクストラ;SYTO 11;SYTO 12;SYTO 13;SYTO 14;SYTO 15;SYTO 16;SYTO 17;SYTO 18;SYTO 20;SYTO 21;SYTO 22;SYTO 23;SYTO 24;SYTO 25;SYTO 40;SYTO 41;SYTO 42;SYTO 43;SYTO 44;SYTO45;SYTO 59;SYTO 60;SYTO 61;SYTO 62;SYTO 63;SYTO 64;SYTO 80;SYTO 81;SYTO 82;SYTO 83;SYTO 84;SYTO 85;SYTOX Blue;SYTOX Green;SYTOX Orange;テトラサイクリン;テトラメチルローダミン(TRITC);Texas Red(商標);Texas Red X(商標)コンジュゲート;チアジカルボシアニン(DiSC3);チアジンレッドR;チアゾールオレンジ;チオフラビン5;チオフラビンS;チオフラビンTCN;Thiolyte;チオゾールオレンジ;Tinopol CBS(Calcofluor White);TMR;TO-PRO-1;TO-PRO-3;TO-PRO-5;TOTO-1;TOTO-3;TriColor(PE-Cy5);TRITCテトラメチルローダミンイソチオシアネート;True Blue;TrueRed;Ultralite;Uranine B;Uvitex SFC;WW 781;X−ローダミン;XRITC;キシレンオレンジ;Y66F;Y66H;Y66W;YO-PRO-1;YO-PRO-3;YOYO-1;YOYO-3、Sybr Green、チアゾールオレンジ(相互キレート色素)、またはそれらの組み合わせ。
例1.1:生細胞上のTRPチャネル活性化をリアルタイムで分析する方法
TRPV1およびTRPV3などの電圧依存性イオンチャネルを用いて、特異的アゴニストおよび温度上昇の、TRPチャネル活性化に対する効果を調べた。例えば、TRPV1の薬理学は十分に特徴づけられており、その様々な特異的アンタゴニストが市販されている。一方、TRPV1は研究されており、43℃で開くことが知られている。
発現ベクターを、分子内プローブYFP−hTRPV1−RLucおよびYFP−hTRPV3−RLucを用いて構築し、ここで、ヒトチャネルサブユニットTRPV1およびTRPV3(hTRPV1、hTRPV3)のタンパク質配列を、図4に示す戦略に従って、3’のウミシイタケルシフェラーゼと5’のYFPの間に挿入した。
hTRPV1センス(S):配列番号1
5’TGTGTACCGGTGAATTCTGGTGGAGGCGGATCTATGAAGAAATGGAGCAGCACAGACT-3’
hTRPV1アンチセンス(AS): 配列番号2
5’CACCAGAATTCACCGGTACCTTCTCCCCGGAAGCGGCAGGACTC-3’
hTRPV3センス(S):配列番号3
5’TGTGTACCGGTGAATTCTGGTGGAGGCGGATCTATGAAAGCCCACCCCAAGGAGATGG-3’
hTRPV3アンチセンス:配列番号4
5’CACCAGAATTCACCGGTACCACCGAGGTTTCCGGGAATTCCTCG-3’
hTRPM2融合AS:配列番号5
5’ CACCAGAATTCACCGGTACGTAGTGAGCCCCGAACTCAGCGGC- 3’
融合hTRPM2 S:配列番号6
5’TGTGTACCGGTGAATTCTGGTGGAGGCGGATCTATGGAGCCCTCAGCCCTGAGGAAAGC- 3’
hTRPV4融合AS:配列番号7
5’CACCAGAATTCACCGGTACGAGCGGGGCGTCATCAGTCCTCCACTTGCG- 3’
融合hTRPV4 S:配列番号8
5’TGTGTACCGGTGAATTCTGGTGGAGGCGGATCTATGGCGGATTCCAGCGAAGGCCCCCG- 3’
YFPセンス:配列番号9
5’-TGTCTAAGCTTGGATCCGCCACCATGGTGAGCAAGGGCGAGGAGCTGTTCACC-3’
腎臓胚細胞に由来するヒト細胞系HEK293Tを、この実験のために選択した。これらの細胞を、GLUTAmax(Invitrogen)、10%ウシ胎児血清、100単位/mlのペニシリンおよびストレプトマイシン(Invitrogen)、1mMのピルビン酸ナトリウム(Invitrogen)を含有するDMEM培地(ダルベッコ改変イーグル培地)で培養した。これらの細胞を、トランスフェクションの日に培養フラスコT25またはT75中に70〜90%コンフルエンスまで置いた。一過性トランスフェクションは、4:1のPEI:DNA比のOpti-MEM培地(Invitrogen)中のポリエチレンイミン(線状PEI、Polysciences, Inc., Warrington, USA)を用いて行った。T75フラスコ中で培養された細胞のトランスフェクションには、1μg/μlのPEI60μlを添加した700μlのOpti-MEM培地(5分間、RT)中、15μgの全DNAが必要であった。混合物を5秒間ボルテックスし、室温で20分間インキュベートした後、細胞培養物に添加した。翌日、細胞をトリプシン−EDTA1%を用いて収集し、用量反応実験のために96ウェルプラーク(1×105細胞/ウェル)、またはその他の実験のために直径12mmのガラススライドを含む24ウェルプラーク(1×106細胞/ウェル)のいずれかで、24時間培養した。両方の種類の支持体を、L−ポリリジン(Sigma)で処理した。
HEK293T細胞を、野生型TRPV1またはYFP−hTRPV1−rLucをコードするDNAでトランスフェクトした。24時間後、150,000個の細胞を、96ウェルプレートのDMEM培地に播種する。さらに24時間、培地を、2μMのFura 2-AM(Tocris)および0.02%のプルロニック酸(pluronic acid)を含むHBSS緩衝液(140mMのNaCl、4.2mMのKCl、0.4mMのNa2HPO4、0.5mMのNaH2PO4、0.3mMのMgCl2、0.4mMのMgSO4、1mMのCaCl2、20mMのHepes、5mMグルコース、pH7.4)に交換して、細胞を37℃で1時間、光刺激なしでインキュベートした。蛍光シグナルの読み取りは、37℃で予熱した多機能性のFlexstation IIIプラークリーダー(Molecular device)を用いて行った。光シグナルを、プローブを340nmおよび380nmで連続的に励起した後、505nmで1秒間積分した。100秒の読み取り後、1μMのカプサイシンを細胞培地に添加した。図7Aに示された結果は、340nmおよび380nmでの励起中に、505nmで得られた光強度の比を示す(I340/I380)。
用量反応実験におけるBRETシグナルの読み取りは、96個の不透明ウェルプレートにおいて、37℃で予熱された多機能性Flexstation IIIプラークリーダー(Molecular device)を用いて実現された。トランスフェクションの36〜48時間後、細胞培地を、0.2%BSAおよび様々な濃度のカプサイシンリガンド(Tocris)を含有するPBSと交換した。37℃で5分間インキュベートした後、基質であるセレンテラジンH(Nanolight Technology)を最終濃度5μMになるように添加し、光シグナルを480nmおよび530nm(すなわち、それぞれルシフェラーゼおよびYFPの発光の波長)で順番に1秒間積分した。3回目の読み取りは、装置のバックグラウンドシグナルを測定するために300nmで行った。生のBRETシグナルは、以下の式によって算出した:
温度の変動およびFura 2-AMプローブで得られたBRETの結果は、Excel(Microsoft)で分析した。用量反応実験で得られた結果を、GraphPad Prism Software v6.00(GraphPad Software Inc, La Jolla, CA, USA)を用いて分析した。
TRPV1などのファミリーTRPV(バニロイド)チャネルの、電圧依存性カチオンチャネル融合サブユニットの活性化/阻害を、温度または化学的モジュレーターによって研究するために、最初に発現ベクターを、融合チャネルサブユニットをコードするように構築し、ここでTRPV1の配列は、N末端YFP融合サブユニットとC末端RLuc融合サブユニットの間にはさむように取り込まれている。
分子内BRETプローブの挙動、すなわち温度に対するYFP−hTRPV1−rLucを調査するために、HEK293T細胞を、融合サブユニットをコードする発現ベクターを用いてトランスフェクトした。トランスフェクションの24時間後、細胞をペルチェサーモスタットで29℃から50℃まで徐々に加熱し、BRETシグナルを既知の技術を用いて測定した。
プローブYFP−hTRPV3−rLucの、化学的アクチベーターに対する感受性を評価した。YFP−hTRPV3−rLuc融合タンパク質を発現するHEK293T細胞におけるBRETシグナルの発生の動態を、33℃で測定した。規定の時間に、2−アミノエチルジフェニルボリナート(2−APB)などのTRPV3アクチベーターを培地中に加え、数秒以内にBRET値の増加を生じさせた(図8)。
例3.1:分子間TRPV1 BRETプローブの特徴付け
RLucがTRPV1サブユニットのC末端部分に融合され、かつYFPがカルモジュリン(これはTRPVチャネルにカルシウム依存的に結合することが知られている)に融合された、分子間TRPV1 BRETプローブを使用した(図9B)。したがってかかる分子間プローブは、細胞内での活性化およびカルシウム侵入後の、カルモジュリンの、TRPV1細胞内部分へのドッキングを測定することを可能にした。次いで、TRPV1チャネル活性化を、この分子間BRETプローブならびに例2.1に記載の分子内TRPV1 BRETプローブを用いて、モニタリングした(図9A)。
YFP−hTRPV3−rLuc BRETプローブの機能および感度を、TRPV3の2つのアゴニスト、すなわち2−アミノエチルジフェニルボリナート(2−APB)およびカルバクロールで処理した、YFP−hTRPV3−rLuc融合タンパク質を発現するHEK293T細胞において確認した。図12は、BRETシグナルの動態および、カルバクロールと2−APBの、YFP−TRPV3−Luc BRETプローブを発現するHEK293T細胞に対する効果を示し、それによって融合タンパク質の機能性を確認する。
RLucがTRPV4のC末端に融合され、YFPがカルモジュリンのN末端部分に融合された分子間TRPV4 BRETプローブ。TRPV4アゴニストGSK1016790Aの、TRPV4−Luc/YFP−CaM構築物を発現するHEK293T細胞に対する、動態(図14A)および用量反応曲線(図14B)を得た。図14Aにおいて、細胞は、1μMのアゴニストにより矢印で示された時間に活性化された。図14Bにおいて、試験は、TRPV阻害剤ルテニウムレッド(10μM)の存在下(正方形)または不在下で行った。対照条件について、LogEC50=−4,89±0.12Mであることが判明した。ルテニウムレッドの存在下で、BRET増加を測定することはできなかった。
Claims (20)
- 生物発光ドナー分子に結合しかつ少なくとも1つの蛍光アクセプター分子に結合した電圧依存性カチオンチャネルサブユニットを含む電圧依存性イオンチャネル融合サブユニットをコードするヌクレオチド配列を含む核酸であって、ここで電圧依存性カチオンチャネルサブユニットが、TRPA1、TRPM1、TRPM3、TRPM4、TRPM5、TRPM6、TRPM7、TRPM8、TRPV1、TRPV2、TRPV3、TRPV4、TRPV5、およびTRPV6からなる群から選択される一過性受容体電位(TRP)チャネルのサブユニットであり、およびここで、生物発光ドナー分子およびアクセプター分子が、生物発光ドナー分子の発光スペクトルがアクセプター分子の吸光度スペクトルと重複するように選択され、そのため、生物発光ドナー分子によって送達される光エネルギーが、アクセプター分子を励起することができる波長である、前記核酸。
- 電圧依存性カチオンチャネルサブユニットが、6つの膜貫通ドメイン、2つの細胞内ループ、1つの膜貫通ループ、および細胞内N末端およびC末端を含むチャネルのサブユニットである、請求項1に記載の核酸。
- サブユニットが、一過性受容体電位チャネルTRPV(バニロイド)チャネルサブファミリーのメンバーに属する、請求項1に記載の核酸。
- サブユニットが、TRPV1、TRPV3、またはTRPV4チャネルに属する、請求項1〜3のいずれか一項に記載の核酸。
- 電圧依存性イオンチャネル融合サブユニットをコードするヌクレオチド配列と、少なくとも1つの生物発光ドナー分子をコードするヌクレオチド配列および/または少なくとも1つの蛍光アクセプター分子をコードするヌクレオチド配列との間に、リンカー配列をさらに含む、請求項1〜4のいずれか一項に記載の核酸。
- 生物発光ドナー分子およびアクセプター分子が、C末端、N末端のいずれか、またはチャネルサブユニットのループに結合している、請求項1〜5のいずれか一項に記載の核酸。
- (i)生物発光ドナー分子がチャネルサブユニットのC末端に結合し、アクセプター分子が該チャネルサブユニットのN末端に結合している、
(ii)生物発光ドナー分子がチャネルサブユニットのN末端に結合し、アクセプター分子が該チャネルサブユニットのC末端に結合している、
(iii)生物発光ドナー分子がチャネルサブユニットのC末端に結合し、アクセプター分子が第1または第2細胞内ループの一部を形成する、
(iv)生物発光ドナー分子がチャネルサブユニットのN末端に結合し、アクセプター分子が第1または第2細胞内ループの一部を形成する、
(v)アクセプター分子がチャネルサブユニットのC末端に結合し、生物発光ドナー分子が第1または第2細胞内ループの一部を形成する、
(vi)アクセプター分子がチャネルサブユニットのN末端に結合し、生物発光ドナー分子が第1または第2細胞内ループの一部を形成する、
(vii)生物発光ドナー分子が第1細胞内ループの一部を形成し、アクセプター分子が第2細胞内ループの一部を形成するか、または
(viii)生物発光ドナー分子が第2細胞内ループの一部を形成し、アクセプター分子が第1細胞内ループの一部を形成する、
請求項1〜6のいずれか一項に記載の核酸。 - 生物発光ドナー分子が、ウミシイタケルシフェラーゼ、ホタルルシフェラーゼ、腔腸動物ルシフェラーゼ、北アメリカグローワームルシフェラーゼ、クリックビートルルシフェラーゼ、鉄道虫ルシフェラーゼ、ガウシアルシフェラーゼ、エクオリン、アラクノカンパルシフェラーゼ、またはそれらのいずれかの生物学的に活性なバリアントもしくは断片から選択されるルシフェラーゼから選択されるタンパク質である、請求項1〜7のいずれか一項に記載の核酸。
- 生物発光ドナー分子が、β−ガラクトシダーゼ、ラクタマーゼ、西洋ワサビペルオキシダーゼ、アルカリホスファターゼ、β−グルクロニダーゼまたはβ−グルコシダーゼから選択される非ルシフェラーゼ生物発光タンパク質である、請求項1〜7のいずれか一項に記載の核酸。
- アクセプター分子が、緑色蛍光タンパク質(GFP)、緑色蛍光タンパク質のバリアント(GFP10)、青色蛍光タンパク質(BFP)、シアン蛍光タンパク質(CFP)、黄色蛍光タンパク質(YFP)、増強GFP(EGFP)、増強CFP(ECFP)、増強YFP(EYFP)、GFPS65T、mAmetrine、LSS-mOrange、LSS-mKate、Emerald、Topaz、GFPuv、不安定化EGFP(dEGFP)、不安定化ECFP(dECFP)、不安定化EYFP(dEYFP)、HcRed、t-HcRed、DsRed、DsRed2、mRFP1、pocilloporin、ウミシイタケGFP、Monster GFP(商標)、paGFP、Kaedeタンパク質もしくはフィコビリタンパク質から選択されるタンパク質である、請求項1〜9のいずれか一項に記載の核酸。
- アクセプター分子が、Alexa(商標)、Bodipy色素(商標)、Cy色素(商標)、フルオレセイン、ダンシル、ウンベリフェロン、蛍光マイクロスフェア、発光ナノ結晶、Marina blue(商標)、Cascade blue(商標)、Cascade yellow(商標)、Pacific blue(商標)、Oregon green(商標)、テトラメチルローダミン、ローダミン、Texas red(商標)、希土類元素キレート、またはそれらの任意の組み合わせである、請求項1〜10のいずれか一項に記載の核酸。
- 請求項1〜11のいずれか一項に記載のTRPチャネル融合サブユニットをコードするヌクレオチド配列を含む、プロモーターに作動可能に連結された発現ベクターであって、ここで前記プロモーターは、CMVプロモーター、RSVプロモーター、SV40プロモーター、アデノウイルスプロモーター、アデノウイルスE1A、熱ショックタンパク質プロモーター、Mycobacteriaの遺伝子およびRNAからのプロモーター、Mycobacterium bovisMPB70、MPB59またはMPB64抗原プロモーター、バクテリオファージラムダ由来のP1プロモーター、tacプロモーター、trpプロモーター、lacプロモーター、lacUV5プロモーター、Ippプロモーター、PLλプロモーター、PRλプロモーター、rac5プロモーター、β−ラクタマーゼ、recAプロモーター、SP6プロモーター、T7プロモーター、メタロチオネインプロモーター、成長ホルモンプロモーター、真核生物プロモーターと原核生物プロモーターとの間のハイブリッドプロモーター、ユビキチンプロモーター、E2F、CEA、MUC1/DF3、α−フェトプロテイン、erb−B2、界面活性剤、チロシナーゼ、PSA、TK、p21、hTERT、hKLK2、プロバシンまたはサイクリン遺伝子由来プロモーターであり、または、ここで前記発現ベクターは、真核生物宿主細胞を形質転換し、かつチャネル融合サブユニットの安定なまたは一過性の発現をもたらすことができる、DNAまたはRNAベクターであり、ここで前記ベクターは、プラスミド、またはアデノウイルス、アデノ随伴ウイルス(AVV)、レンチウイルス、エプスタイン−バール、単純ヘルペス、パピローマ、ポリオーマ、レトロ、SV40、ワクシニアなどのウイルス、任意のレトロウイルスベクター、またはインフルエンザウイルスベクターである、前記発現ベクター。
- 請求項12に記載の発現ベクターを含む組換え細胞であって、TRPチャネル融合サブユニットが発現されている、前記組換え細胞。
- 請求項1〜11のいずれか一項に記載のTRPチャネル融合サブユニットを生産するための方法であって、請求項13に記載の組換え細胞を培養すること、および、請求項1〜11のいずれか一項に記載のTRPチャネル融合サブユニットを発現すること、を含む、前記方法。
- 請求項1〜11のいずれか1項に記載の、核酸によってコードされるTRPチャネル融合サブユニットであって、前記サブユニットの少なくとも1つのN末端先端部、C末端先端部、またはループが、少なくとも1つの生物発光ドナータンパク質および少なくとも1つのアクセプタータンパク質に結合している、前記TRPチャネル融合サブユニット。
- 請求項15に記載の融合サブユニットを含む無細胞組成物であって、機能性融合チャネルまたは融合チャネルサブユニットが、脂質二重層、またはリポソームの二重層中に埋め込まれている、前記無細胞組成物。
- 請求項13に記載の組換え細胞を得ること、および細胞の膜を破壊することを含む、請求項16に記載の無細胞組成物の調製方法。
- チャネルを活性化または阻害することができる化合物候補をリアルタイムでスクリーニングする方法であって、
−候補を、請求項13の組換え宿主細胞、または請求項16の無細胞組成物と接触させること、
−生物発光ドナー分子の基質を提供すること;および
−BRETシグナルの変化を測定すること、
を含む、前記方法。 - 基質が、ホタルルシフェリン、細菌ルシフェリン、渦鞭毛藻類ルシフェリン、イミダゾロピラジンバルグリン、またはセレンテラジンである、請求項18に記載の方法。
- 請求項1〜11のいずれか一項に記載の核酸、請求項12のベクター、請求項13の組換え宿主細胞、または請求項16の無細胞組成物を含む、TRPチャネルのアゴニストまたは阻害剤化合物候補をスクリーニングするためのキット。
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JP2009505642A (ja) | 2005-08-19 | 2009-02-12 | コモンウェルス サイエンティフィック アンド インダストリアル リサーチ オーガニゼイション | アラクノカンパのルシフェラーゼ |
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CA2975652A1 (en) | 2016-08-25 |
EP3056902B1 (en) | 2020-04-01 |
EP3056902A1 (en) | 2016-08-17 |
WO2016131832A1 (en) | 2016-08-25 |
JP2018504917A (ja) | 2018-02-22 |
EP3259595A1 (en) | 2017-12-27 |
US20180030108A1 (en) | 2018-02-01 |
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