「Förster共鳴エネルギー移動」の版間の差分

2013年11月8日 (金) 05:05時点における版

上田善文
金沢医科大学血液免疫内科学
林康紀
独立行政法人理化学研究所脳科学総合研究センター
DOI XXXX/XXXX　原稿受付日：2013年9月18日　原稿完成日：2013年月日
担当編集委員：柚崎通介（慶應義塾大学医学部生理学）

英：Förster resonance energy transfer　英略称：FRET　独：Förster-Resonanzenergietransfer　仏：transfert d'énergie entre molécules fluorescentes

　２つの蛍光分子がごく近接して存在する場合、一つの蛍光分子からもう一つの蛍光分子へ、エネルギーが移行する。これをFörster共鳴エネルギー移動（FRET）という^[1]。FRETの効率は２つの蛍光体のスペクトルの重なりの大きさ、距離と角度により左右される。特に、近年の緑色蛍光タンパク質（green fluorescent protein, GFP）とその色変異体や様々な蛍光スペクトルを持つ近縁のタンパク質の開発・同定により、FRETを用いて、生細胞の中の微小ドメインでのタンパク質相互作用、生化学反応や細胞内シグナル伝達の可視化が可能となった。脳神経研究においても、神経細胞、脳スライスなどの組織および個体レベルで応用されている。

図1:蛍光体が蛍光を発する過程を示したヤブロンスキーダイヤグラム
青色で示した励起光によって、蛍光体の電子が励起状態に到達する。励起された電子は、回転および振動エネルギーを失いながら励起状態の最低準位に行き着く。この電子は緑色で示した蛍光を発して励起状態から基底状態に戻る。実際は、最低準位に行き着く前に基底状態に戻ることもあり、これが蛍光波長の幅に反映される。

図2:励起光によって励起された電子が基底状態に戻る際の減衰曲線
緑の太い線がFRETが起きていない時の減衰曲線。FRETの速度定数が加わることにより速度定数が大きくなり細い緑の線のように減衰曲線の傾斜が大きくなる。

図3:ドナーの蛍光スペクトルとアクセプターの励起スペクトルに重なりがあるときに、FRETが起きる。黒破線で囲まれたスペクトルは、励起スペクトルを示す。緑色のタンパク質がドナー、赤色タンパク質がアクセプターを示す。

Förster共鳴エネルギー移動とは

　２つの蛍光分子がごく近接して存在する場合、一つの蛍光分子からもう一つの蛍光分子へ、エネルギーが移行する事が知られている。この現象は、1946年Theodor Försterによって報告されたことから、Förster共鳴エネルギー移動（FRET）という^[2]^[3]。かつてはFRETは、fluorescence resonance energy transferの略称として用いたが、実際には蛍光を伴わないエネルギー移動であることから、現在ではFörster resonance energy transferと呼ぶ事がIUPACにより推奨されている。　かつてはFRETを用いて生細胞イメージングするのは、非常に煩雑であった。プローブとなるタンパク質を精製、化学的に色素でラベルし、細胞に導入するという操作が必要であり、生物学分野での応用はきわめて限定されたものであった。しかし、GFPとその変異体、類縁タンパク質の発見により今日においては様々な分野において、多くの蛍光タンパク質を基にした完全に遺伝子によってコードされるFRETプローブが使用されている。

FRETの効率を決定する因子

　蛍光分子のうち、エネルギーを受け渡す方をドナー、受け取る方をアクセプターと呼ぶ。FRETの効率はドナーとアクセプター間の次のような因子によって影響される。

ドナーとアクセプター間の距離r

ドナーの発光スペクトルとアクセプターの吸収スペクトルの重なりJ

ドナーの発光双極子モーメントとアクセプターの吸収双極子モーメントとの相対分子配向κ

　ドナーとアクセプター蛍光分子が決定されるとJは次のように計算される。

J=\int f_{\rm {D}}(\lambda )\,\epsilon _{\rm {A}}(\lambda )\,\lambda ^{4}\,d\lambda

　ここでf_D(λ)はピーク値を１としたドナー発光スペクトル、 ε_A(λ)はアクセプターのモル吸光係数である。

　これを用い「Förster距離」R₀が以下のように定義される。これはエネルギー移動効率が50%となるドナーとアクセプターの距離である。通常の蛍光分子の場合、5 nm程度である。

{R_{0}}^{6}={\frac {9\,Q_{0}\,(\ln 10)}{128\,\pi ^{5}\,n^{4}\,N_{A}}}\kappa ^{2}\,J

　相互分子配向κは多くの場合、正確に求める事は困難であるため、しばしばκ² =2/3 と仮定される。この値は、両方の色素が自由に回転しており、励起状態寿命の間は等方的に配向していると考えられる場合に得られる。色素が固定されていたり自由に回転することができないような場合、κ² =2/3 とは仮定できない。Q₀はアクセプターが無い場合の蛍光量子収率、nは媒体の屈折率（水、25 °Cの場合、1.3342）、N_Aはアボガドロ数である。これらの定数を当てはめると、κより前の部分は、8.786 x 10¹¹ mol L^-1 cm nm²となる^[4]。

　R₀を用いると、FRET効率Eは次のように表す事が出来る。

E={\frac {1}{1+(r/R_{0})^{6}}}\!

　蛍光スペクトルが変化しない状態では、ドナーとアクセプター間の距離と角度の変化をFRETの効率の変化として読み取る事が出来る。

FRETの画像検出

　FRETによって蛍光寿命の減少、ドナーの蛍光強度の減少、アクセプターの蛍光の増加などが観察される。液体サンプルであれば蛍光分光光度計を用いる事で検出する事が可能であるが、画像として取得する場合には観察したい対象の特性を考慮しつつ、方法を選択していく。

蛍光強度比イメージング

　ドナーおよびアクセプターの蛍光を取得後、ドナーとアクセプターの蛍光強度比が計算される。FRETが起きると、ドナーの蛍光強度が減少し、アクセプターの蛍光強度が増加する。現在、最も広く使用されている手法である。タイムラプス解析も行える。現在、多数の遺伝子工学的に作製されたタンパク質FRETプローブにおいて、GFPの色彩変異体、シアン色蛍光タンパク質CFPと黄色蛍光タンパク質YFPのFRETペアが広範に用いられている。近年、CloverとmRuby2が開発され、より良いFRETペアであると報告されている^[5]。

　ドナー蛍光強度は、FRET効率Eと次のような関係に有る。

E=1-{F\,'_{\rm {D}}}/{F_{\rm {D}}}\!

　ただし、F'_D、F_Dはそれぞれ、アクセプターがある場合と無い場合でのドナー蛍光強度である。つまり、FRET効率が良い程、F'_D小さくなる、つまり画像が暗くなる。一方で、FRETによりアクセプター画像は明るくなるので、ドナー画像とアクセプター画像の比を計算する事で、FRETを検出する。

　データを取得、解釈する際に注意しなければいけないポイントがある。

　まず、ドナーの蛍光のアクセプターチャネルへの漏れ込みであり、S/N比の減少の原因となる。漏れ込みを極力抑えるには、適切なバンドパスフィルターを用いる。光量を犠牲にしても、ドナー蛍光が漏れ込まない波長を選ぶ方がFRETは特異的に検出できる。

　また、蛍光画像にバックグラウンドノイズがある事があるが、それがFRET変化に影響を与える。バックグラウンドノイズ引き算することで、より正しいFRET効率が得られる。

　次に、2分子間FRETで起きることであるが（以下参照）、ドナーとアクセプターの局在の違いは疑似FRETを生じる。リンカーで連結し1分子にするか、局在しているアクセプターの蛍光強度を補正することで避けることが可能である。

アクセプターブリーチング法

　適切な波長の光によって、アクセプターを退色させることでFRETを解消することができる。この解消度合いより生じていたFRETを算出する。つまり、F'_Dがアクセプターの退色によりF_Dと等しくなる事により、E=0となる。その為、退色前後の画像を比較する事によりEが検出可能である。しかしながら、この手法は不可逆的であるために経時的変化を追うことは困難である。

ドナーの蛍光寿命を測定する方法

　蛍光体が励起されると、図2に示すような減衰曲線に従って蛍光を発する。蛍光寿命は、蛍光の減衰曲線の速度定数 $k\$ と逆数の関係にある。 N₀は励起光によって励起された電子の数、kは励起状態にある電子が基底状態に戻る速度定数であり、蛍光として基底状態に戻る際の速度定数、熱を発して基底状態に戻るなどの無放射遷移の速度定数の和として表される。

　FRETを起こしている時のの速度定数k_fは、以下の式で規定される。

k_{f}(r,\kappa )={\frac {k_{D}Q_{D}\kappa ^{2}}{r^{6}}}\left({\frac {9000In10}{128\pi ^{5}n^{4}N_{A}}}\right)J

　ここで、k_Dはドナーの蛍光の速度定数、Q_Dはドナーの蛍光の量子収率、κはドナーとアクセプターの双極子モーメントの配向、rはドナーとアクセプターの距離、N_Aはアボガドロ数、nは溶媒の屈折率である。

E=1-{\tau '_{\rm {D}}}/{\tau _{\rm {D}}}\!

　ここでτ'_Dとτ_Dはそれぞれ、アクセプターが存在する場合と存在しない場合でのドナー蛍光寿命である。つまり、FRETが起きると、蛍光寿命が減少する(図4)。

　蛍光寿命は、GFPは2.5nsec、YFPでは2.9nsec、mCherryでは1.5nsec程度の値を取る。蛍光寿命プローブとしてはドナーとしてmGFP、アクセプターとしてmRFPもしくはmCherryが用いられる。アクセプターの蛍光は必要ないため、FRETのアクセプターとなるが蛍光を発しないREACh, darkVenus, superREAChなども用いられる。同じ理由により、蛍光寿命は、蛍光強度比測定法に比べて、蛍光の漏れ込み、アクセプターとの局在の違いなどによって生じる疑似陽性を回避できる。

　蛍光寿命の変化を測定する方法は２つある。

時間ドメイン

　励起光によって発生した一つ一つの光子が検出器まで届くまでの時間(数nsec)を計測することで時定数τを計算する。時間を横軸としてヒストグラムを作製することができる。通常蛍光寿命は指数関数に従い減衰していく。FRETを起こしている分子と起こしていない分子が共存する時には二重指数関数になるため、二重指数関数にfittingすることによって、FRETの起きている分子の割合が算出できる。また、得られる光子の数が少ない時には二重指数関数fittingは不正確になりやすい為、単に平均蛍光寿命を計算するだけで済ませる場合も有る。単一指数関数の場合は、平均蛍光寿命はτに等しくなる。

　取得した蛍光を理論上全てデータに反映させることができるが、実際には、光子取得後、再び光子を取得する状態に戻るハードウェアのリセット時間(dead time)などがあり全ての光子を取得するには、改善の余地がある。また、秒単位の経時変化を追うためには、低解像度で画像取得されているのが現状で有り、多数のピクセルから蛍光寿命を取得するためには、処理速度の速いハードウェアが必要となる。さらに、短時間で画像を取得するためには、明るいサンプルであったほうがよい。

　光源にはパルスレーザーを用いる。神経系の研究によく用いられるに光子顕微鏡に後付けする事も可能である。

図4:海馬スライスCA1錐体細胞に発現させたGFPのFLIMイメージおよび減衰曲線
（横軸は時間、縦軸は光子数）をBecker＆Hickl社software、SPC imageにて取得した。実際には、20秒で数千個オーダーの光子を取得する。これらの光子の発生確率分布が減衰曲線を形成し、近似曲線をフィッティングさせることで蛍光寿命を取得する。

周波数ドメイン

　光源の強度を高周波で変調させるのと同時に、検出器も高周波で変調させる。その時に光源と検出器の周波数をずらしておく（heterodyning)。多数のサイクルを繰り返す事により、間接的に蛍光寿命を計算していく。画像の取得にかかる時間がtime domainと比較して短いのが特徴である。

　時間ドメインと同様に光源にはパルスレーザーや光量が高頻度にて変調できるレーザーなどが用いられる。

異方性測定

　一つの蛍光団のストークスシフトが小さい場合、励起スペクトルと蛍光スペクトルの重なりが大きいような蛍光団では、同一の蛍光団同士で、Homo-FRETが生じる。Homo-FRETは、蛍光強度および蛍光寿命は変化しないが、異方性が変わる。この原理を用いて、一般的には、分子同士のクラスターの度合いなどに応用されている。

プローブのデザイン

図5. 様々なフレットプローブの類型

　かつてはFRETを生細胞イメージングするのは、非常に煩雑であった。プローブとなるタンパク質を精製、化学的に色素でラベルし、細胞に導入するという操作が必要であり、神経科学分野での応用はきわめて限定されたものであった。しかし、GFPとその変異体、類縁タンパク質の発見により今日においては様々な細胞生物学の分野において、多くの蛍光タンパク質を基にしたFRETプローブが使用されている。

　これらのプローブを分類すると、以下のように分類される（表１）。

プローブの分解に伴うFRETの変化を検出するプローブ

　この原理は、FRETプローブの最も初期に導入されたデザインである(図6A)。例として、第X因子などのプロテアーゼが挙げられ^[6]、プロテアーゼによって分解される配列の両端にドナーとアクセプターを連結する。プロテアーゼによって、この配列が分解されるとドナーとアクセプターの間に起きていたFRETが解消されることによって、プロテアーゼの活性を評価する。カスパーゼなどの活性を測定するためにも使用されている^[7]^[8]^[9]^[10]。このプローブのデザインの短所としては、反応が不可逆的であるために、一つの実験系で何度も測定することが困難であることである。

二分子間相互作用を利用したFRETプローブ

　興味のあるタンパク質同士の相互作用を測定する際に、この原理が用いられる。一方にドナー、他方にアクセプターを連結する。タンパク質同士が結合していないときにはFRETは起きていないが、結合することによってFRETを生じる。応用例としては蛍光寿命を基にしたGタンパク質の活性化の測定に用いられている^[11]。また、アクチンの重合度を測定するために、アクチンにドナー、アクセプターを連結して測定している例もある^[12]。距離のファクターを生かせるために、比較的大きなシグナルが得られる一方、内在性のタンパク質が反応に関与するために、その分FRET応答が減少する。ドナーとアクセプターの発現量の差によるFRETの応答の変化も問題になる。特に、アクセプターと結合しないドナーが多量に存在するとFRET応答が小さくなる。一般にアクセプターが多い系が、使用に適している。

一分子内FRETプローブ

　一分子内にドナーとアクセプターを連結し、これらの配向および距離の変化を利用する。2分子間FRETに生じるような発現量の違いやドナーとアクセプターの局在の変化によって生じるアーチファクトなどを考慮する必要がない。さらに活性に伴うタンパク質の構造変化などを利用するために、比較的容易に応答するプローブが作製できるが、ドナーとアクセプターを適切な位置に配置するなどの検討が必要である。

タンパク質の構造変化を基にしたFRETプローブ

　興味のあるタンパク質が、活性化の際に構造変化を誘起することが知られている場合には構造変化を利用することができる。タンパク質のC末およびN末にドナーおよびアクセプターを連結する。この手法は、CaMKII^[13]、Calcinulin^[14]、raf^[15]^[16]、膜電位測定^[17]、などに用いられている。

タンパク質結合に伴う構造変化を基にしたFRETプローブ

　ある種のタンパク質は活性化、非活性化に伴い、下流のタンパク質と結合する。このような相互作用を利用してタンパク質の活性化、非活性化を測定することができる。例えばカルシウムFRETプローブ、カメレオンはこの原理を利用している^[18]。また、低分子Gタンパク質の活性化プローブは、低分子Gタンパク質、シグナル伝達下流の結合タンパク質の結合ドメインをドナーとアクセプターで挟んだ形状をしている。低分子Gタンパク質がGDPからGTP結合型になり活性化すると、結合ドメインと相互作用をしFRETが生じる^[19]。

共有結合修飾によって生じる構造変化を測定するプローブ

　このプローブは、ドナー、アクセプター、共有結合修飾を受けるドメイン、これを認識するドメインからなる。プローブが共有結合修飾を受けると、認識するドメインが結合し、ドナーとアクセプターの距離が縮まりFRETが起きる。このプローブは、キナーゼの活性化を測定するために使用される^[20]^[21]。

生体膜上の小分子を測定するFRETプローブ

　このプローブは、主に、脂質分子に応用されてきた。ドナー、脂質結合ドメイン、アクセプターが堅いヘリックス構造で連結され、グリシングリシン配列をその途中に導入することで、そこを中心に一方の蛍光タンパク質が回転することができる。膜結合ドメインを用いて、プローブを結合させる。脂質分子が増えた際に、脂質結合ドメインが脂質分子を認識し、構造変化が起き、ドナートアクセプターの距離が縮まりFRETが生じる。ジアシルグリセロール^[22]、イノシトールリン脂質群^[23]^[24]^[25]^[26]を測定するために用いられている。

表1．
分類	対象	プローブ名	年	プローブデザイン	参考文献
生体内小分子	カルシウム	Cameleon	1997	3-2	^[27]
	サイクリックGMP (cGMP)	CGY, Cygnet, pGES-DE2, cGi	2000, 2001, 2006	3-1	^[28]^[29]^[30]^[31]
	サイクリックAMP (cAMP)	Epac	2000,2004	2, 3-1	^[32]^[33]
	イノシトール3リン酸 (IP₃)	LIBRA, Fretino, FIRE	2004, 2005, 2006	3-1	^[34]^[35]^[36]
	一酸化窒素 (NO)	NOA-1, Piccell	2005, 2006	3-1	^[37]^[38]
	アデノシン3リン酸 (ATP)	A Team 1.03-nD/nA	2012	3-1	^[39]
	エストロゲン	SCCoR	2004	3-3	^[40]
	アンドロゲン	Ficaro	2006	3-3	^[41]
	グルココルチコイド受容体リガンド	GLUCOCOR	2007	3-3	^[42]^[43]
	神経成長因子	ECaus	2008	3-3	^[44]
	核内受容体	conpro	2007	3-2	^[45]
	O-N-アセチルグルコサミン (O-GlcNAc)		2006	3-3	^[46]
	ビタミンA (レチノイン酸)	GEPRAS	2013	3-1	^[47]
	モリブデン酸	MolyProbe	2013	3-1	^[48]
	グルタミン酸	FLIPE	2005	3-1	^[49]
	Zn²⁺	eCALWY-1	2009	2	^[50]
	Cl^-	Clomeleon	2000	other	^[51]
	水素イオン濃度 (pH)	GFpH, YFpH	2001	other	^[52]
	グルコース	FLIPglu	2003	3-1	^[53]
	マルトース	FLIPmal	2002	3-1	^[54]
	リボース	FLIPrib	2003	3-1	^[55]
タンパク質リン酸化酵素	カルシウム/カルモジュリン依存性タンパク質リン酸化酵素II (CaMKII)	Camui α, green-Camui α, Camk2a reporter	2005, 2009, 2011, 2013	3-1	^[56]^[57]^[58]^[59]
	Src	Srcus	2005, 2005, 2007	3-3	^[60]^[61]^[62]
	Ca²⁺／リン脂質依存性タンパク質リン酸化酵素 (Cキナーゼ, プロテインキナーゼC, PKC)	CKAR, CY-PKCdelta	2003, 2005	3-3, 3-1	^[63]^[64]
	タンパク質リン酸化酵素D (Dキナーゼ, プロテインキナーゼD, PKD)	DKAR	2007	3-3	^[65]
	cAMP依存性タンパク質リン酸化酵素 (Aキナーゼ, プロテインキナーゼA, PKA)	ART, AKAR	2000, 2001	3-3	^[66]^[67]
	Abl	Picchu	2001	3-3	^[60]
	Bcr-Abl	Bcr-Abl activity sensor	2010	3-3	^[68]
	c-Raf	Prin-cRaf	2005	3-1	^[69]
	P21 protein-activated kinase 1 (PAK1)	Pakabi	2009	3-1	^[70]
	B-raf	Prin-Braf	2006	3-1	^[71]
	Zeta-chain-associated protein kinase 70 (ZAP-70)	ROZA	2008	3-3	^[72]
	Akt	Aktus, BKAR, Akind	2003, 2005, 2007	3-3	^[73]^[74]^[75]
	細胞外シグナル調節キナーゼ (Extracellular signal-regulated kinases, ERK)	Miu2, Erkus, EKAR	2006, 2007, 2008	3-1,3-3,3-3	^[76]^[77]^[78]
	インシュリン受容体	Phocus	2002	3-3	^[79]
	上皮成長因子受容体 (EGFR)		2001	3-3	^[60]
	Ataxia telangiectasia mutated (ATM)		2007	3-3	^[80]
	オーロラBキナーゼ		2008	3-3	^[81]
	サイクリンB1-サイクリン依存性キナーゼ1		2010	3-3	^[82]
	ミオシン軽鎖キナーゼ	MLCK-FIP	2002	3-1	^[83]
	c-Jun N端末キナーゼ (JNK)	JNKAR1, JUNKAR1EV	2010, 2011	3-3	^[84]^[85]
	リボソームS6キナーゼ (RSK, S6K)	Eevee-RSK, Eevee-S6K	2011	3-3	^[85]
	接着斑キナーゼ (Focal Adhesion Kinase, FAK)	CYFAK413, FERM-sensor	2008, 2009	2, 3-1	^[86]^[87]
	Polo様キナーゼ1 (polo-like kinase1, PLK1)		2008	3-3	^[88]
	ストレス活性化プロテインキナーゼ3 (Stress-Activated Protein Kinase Kinase Kinase, stress-activated protein kinase 3, SAP3K)		2009	3-3	^[89]
	細胞死関連タンパク質キナーゼ (death associated protein kinase 1, DAPK1)	DAPK1(334)-F40	2011	3-1	^[59]
ホスファターゼ	カルシニューリン	CaNAR1	2008, 2013	3-1	^[58]^[90]
低分子量Gタンパク質	Ras	Raichu-Ras, Fras	2001, 2006	3-2,2	^[91]^[92]
	Rap	Raichu-Rap	2001	3-2	^[92]
	Rac	Raichu-Rac1	2004	3-2	^[93]
	Rab5	Raichu-Rab5	2008	3-2	^[94]
	Rho	Raichu-RhoA	2003, 2011	3-2, 2	^[95]^[96]
	Cdc42	Raichu-cdc42	2004, 2011	3-2, 2	^[93]^[95]
	Ral	Raichu-Ral	2004	3-3	^[97]
	TC10	Raichu-TC10	2006	3-2	^[98]
シグナル伝達	RCC1 (Ranに対するGDP, GTP交換因子)	CFP-RCC1-YFP	2008	3-1	^[99]
	CrkII リン酸化	Picchu	2001	3-1	^[100]
	Wiskott-Aldrich syndrome-like (WASL, neuronal Wiskott–Aldrich syndrome protein, N-WASP)	Stinger	2004	3-1	^[101]^[102]
	アドレナリン受容体	α_2AAR-cam	2003	3-1	^[103]
	副甲状腺ホルモン受容体	PTHR-cam	2003	3-1	^[103]
	細胞膜カルシウムポンプ	BFP-PMCA-GFP	2007	3-1	^[104]
アセチル化	ヒストンアセチル化	Histac	2004, 2009	3-3	^[105]^[106]
脂質	ホスファチジルイノシトール-3,4,5-三リン酸 (PIP₃)	Fllip, FLIMPA	2003	3-4	^[107]
	ホスファチジルイノシトール-4,5-二リン酸 (PI(4,5)P₂)	Pippi-PI(4,5)P₂	2008	3-4	^[108]
	ホスファチジルイノシトール-3,4-二リン酸 (PI(3,4)P₂)	Pippi-PI(3,4)P₂	2008	3-4	^[108]
	ホスファチジルイノシトール-4-リン酸 (PI4P)	Pippi-PI(4)P	2008	3-4	^[108]
	ホスファチジン酸	Pii	2010	3-4	^[109]
	ジアシルグリセロール (DAG)	Daglas, DIGDA	2006, 2008	3-4	^[108]^[110]
タンパク質相互作用	アクチン		2004, 2008	2	^[111]^[112]
	3-ホスホイノシチド依存性プロテインキナーゼ1（phosphoinositide-dependent protein kinase 1, PDK1)-タンパク質キナーゼB (protein kinase B, PKB, Akt)相互作用		2007	2	^[75]
	蛋白質チロシン脱リン酸化酵素1B (protein tyrosine phosphatase 1B, PTP 1B)-受容体型チロシンキナーゼ (receptor tyrosine kinases, RTKs)相互作用		2002	2	^[113]
	乳癌耐性タンパク質 (breast cancer resistance protein, BCRP)/ATP結合カセット輸送体 (ATP-binding cassette sub-family G member, ABCG)相互作用		2010	2	^[114]
	コフィリン-アクチン相互作用		2008	2	^[115]
	第10染色体ホスファターゼ・テンシン・ホモログ (Phosphatase and tensin homolog deleted from chromosome 10, PTEN)-ミオシンV相互作用		2009	2	^[116]
プロテアーゼ	カスパーゼ-3	EGFP-DEVD-EBFP	1998	1	^[117]
	カスパーゼ-8	CFP-c3-YFP-c6-mRFP	2002	1	^[118]
	カスパーゼ-9	SCAT9	2011	1	^[119]
	カスパーゼ-7	VDEVDc	2006	1	^[120]
	マトリックスメタロプロテアーゼ (MMP)	YFP-MSS-CFP^display, MTI-MMP-FRET biosensor	2007, 2008	1	^[121]^[122]
	第Xa因子		1996	1	^[123]
	カルパイン活性	pYSCS	2000	1	^[124]
	プレセニリン	GFP-PSI-RFP	2009	3-1	^[125]
その他	細胞膜張力センサー	stFRET	2008	3-1	^[126]
	膜電位	VSFP, Mermaid, ArcLight, VSFP-Butterfly	2001, 2008, 2012	3-1	^[127]^[128]^[129]^[130]
	ミオシンII	GSldCB	1998, 2006	3-1	^[131]^[132]
	ヒト免疫不全ウイルスRevタンパク質	YRGnC-11ad	2005	3-1	^[133]
	酸化還元	Redoxfluor, Gaskins	2010, 2011	3-1	^[134]^[135]

The numbers in the Probe Design column correspond to the section number in the “Strategies of probe design” chapter of the main text. See the webpage by Dr. Michiyuki Matsuda http://www.lif.kyoto-u.ac.jp/labs/fret/e-phogemon/unifret.htm for updated information.

神経科学分野への応用

　1997年、宮脇、Tsienらによって、CFPおよびYFPを利用した、Calcium indicator, Cameleonが開発され^[136]、さらに、cAMP^[137], cGMP^[138], リン酸化^[139]を初めとした主要な細胞内シグナル伝達分子のFRETプローブが次々と作製され、分子のリアルタイムな活性および局在のの活性の解明に大きく貢献した。

　脳神経分野においては、林らが、2000年初期に記憶の形成に必須なシグナル分子、カルシウムカルモデュリンキナーゼII (CaMKII)の活性化を評価するためのFRETプローブ開発し分散培養系にてCaMkIIの可視化に成功した^[140]。1990年代後半、Svobodaらによって、2光子顕微鏡が脳神経科学に導入され、神経回路ネットワークを保持したスライスおよび個体の生きた脳の神経活動を観察可能になった。林らは、神経細胞の連結部位、シナプスのシナプス後膜（スパイン）において、その形態を制御するactinの重合を可視化するためのFRETプローブを開発した^[141]。一方、脳のスライスにおいては、波長依存的な蛍光の吸収が生じるため、ドナーとアクセプターの2波長を測定する蛍光強度比を測定するよりも、蛍光の散乱、吸収によって変化しない蛍光寿命測定法が導入された。安田、Svobodaらは、蛍光寿命測定を基に、スパインの構造的変化を誘導する低分子量Gタンパク質（Ras、cdc42、RhoA）などのシグナル伝達分子の活性化の変化を観察することに成功している^[142]^[143]^[144]。

　個体においてもFRET測定法が導入されている。神経回路ネットワークにおけるシナプスの役割を解明する目的で、フェレットの大脳皮質視覚野にCaMKIIプローブを発現し、片眼剥奪によって、神経回路ネットワークに変化を起こした時のCaMKIIの活性化の変化を観測している^[145]。また、神経活動をモニターする目的で、Knöpfelらは、膜電位プローブを開発しマウスのヒゲ刺激の入力先である体性感覚野 barrel cortexでの入力特異的な神経の活性化を観察している^[146]。

　病態との関係では、神経細胞内のカルシウム濃度を測定するために、オレゴングリーンの蛍光寿命の変化から、カルシウム濃度を測定し、アストロサイトでのカルシウム濃度が、アルツハイマー様マウスと正常マウスで違うことが報告されている^[147]。

　Homo-FRETも応用されている。CaMKIIは12量体を形成しているが、異方性の変化を基に、その構造中にdimerの単位が存在し、活性化に伴うdimer同士の位置関係が変化することをVogelらが明らかにしている^[148]。

将来展望

　脳研究は、生きたままの状態の脳の神経細胞の活動を、広範囲で、より深部で観察したり、逆に神経細胞内の超微細構造を観察する方向に移るであろう。現在、FRETを基にしたin vivoイメージングは、応答の低さ、蛍光の弱さなどの難点はあるものの、蛍光タンパク質の蛍光強度や顕微鏡の性能の改良は日進月歩であり改善されていくであろう。また、神経活動に必要なシグナル伝達を同時に観察するために、マルチカラーイメージングの試みもなされるであろう。その際には、2つの波長を必要とする蛍光強度比変化を基にするFRET測定よりも、蛍光寿命を観察するFLIM測定が適している。

外部リンク

Phogemon Project 京都大学医学部　松田道行よるFRETセンサー開発とイメージング方法の解説。文字化けする時にはブラウザーの設定をShift-JISにするよい。

[1] 表の元となった、FRETセンサーの一覧。松田道行による。

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「Förster共鳴エネルギー移動」の版間の差分

2013年11月8日 (金) 05:05時点における版

目次

Förster共鳴エネルギー移動とは

FRETの効率を決定する因子

FRETの画像検出

蛍光強度比イメージング

アクセプターブリーチング法

ドナーの蛍光寿命を測定する方法

時間ドメイン

周波数ドメイン

異方性測定

プローブのデザイン

プローブの分解に伴うFRETの変化を検出するプローブ

二分子間相互作用を利用したFRETプローブ

一分子内FRETプローブ

タンパク質の構造変化を基にしたFRETプローブ

タンパク質結合に伴う構造変化を基にしたFRETプローブ

共有結合修飾によって生じる構造変化を測定するプローブ

生体膜上の小分子を測定するFRETプローブ

神経科学分野への応用

将来展望

外部リンク

参考文献

案内メニュー

「Förster共鳴エネルギー移動」の版間の差分

2013年11月8日 (金) 05:05時点における版

Förster共鳴エネルギー移動とは

FRETの効率を決定する因子

FRETの画像検出

蛍光強度比イメージング

アクセプターブリーチング法

ドナーの蛍光寿命を測定する方法

時間ドメイン

周波数ドメイン

異方性測定

プローブのデザイン

プローブの分解に伴うFRETの変化を検出するプローブ

二分子間相互作用を利用したFRETプローブ

一分子内FRETプローブ

タンパク質の構造変化を基にしたFRETプローブ

タンパク質結合に伴う構造変化を基にしたFRETプローブ

共有結合修飾によって生じる構造変化を測定するプローブ

生体膜上の小分子を測定するFRETプローブ

神経科学分野への応用

将来展望

外部リンク

参考文献

案内メニュー

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