Биосенсоры активных форм кислорода и других редокс-активных соединений: создание и применение в живых системах тема диссертации и автореферата по ВАК РФ 03.01.03, доктор биологических наук Белоусов, Всеволод Вадимович

• Белоусов, Всеволод Вадимович
• доктор биологических наук
• 2013

Оглавление диссертации доктор биологических наук Белоусов, Всеволод Вадимович

Введение

Обзор литературы

Компартментализация передачи сигналов, опосредованных активными 5 формами кислорода

Источники АФК: НАДФН оксидазы

Источники АФК: митохондрии

Методы детекции АФК

Генетически кодируемые флуоресцентные индикаторы

Цель работы

Материалы и методы

Результаты

Создание генетически кодируемого флуоресцентного индикатора для 109 детекции пероксида водорода

НуРег-2, сенсор Н202 с увеличенным динамическим диапазоном

НуРег-3: Сочетание преимуществ НуРег и НуРег

Исследование микродоменов пероксида водорода с помощью 133 локализованных сенсоров

Создание двойного биосенсора для одновременной детекции 149 фосфатидилинозитол-(3,4,5)-трифосфата (PIP3) и пероксида водорода

Исследование динамики и функции Н202 при фагоцитозе

Создание красного флуоресцентного белка HyPer-RED

Генетически кодируемый сенсор для детекции соотношения НАД+/НАДН

Обсуждение

Выводы

Заключение диссертации по теме «Молекулярная биология», Белоусов, Всеволод Вадимович

ВЫВОДЫ:

1. Создан генетически кодируемый флуоресцентный сенсор для внутриклеточной детекции пероксида водорода НуРег. Сенсор демонстрирует рациометрические изменения спектра возбуждения, реагирует специфично с пероксидом водорода и не взаимодействует с другими протестированными оксидантами.

2. Получен и охарактеризован сенсор НуРег-2, имеющий увеличенный в два раза, по сравнению с НуРег, динамический диапазон. Мутация A406V, отличающая НуРег-2 от НуРег, локализована в димеризационном интерфейсе OxyR, делая НуРег-2 строгим димером по сравнению с мономерным НуРег. Однако НуРег-2 характеризуется более медленным, по сравнению с НуРег, окислением и восстановлением в клетке.

3. Сенсор НуРег-3, несущий мутацию H34Y, также локализованную в димеризационном интерфейсе OxyR, сочетает высокий динамический диапазон характерный для НуРег-2 и высокие скорости окисления и восстановления, характерные для НуРег. Высокий динамический диапазон НуРег-3 существенно упрощает детекцию Н202 в тканях in vivo.

4. Сенсоры на основе одного флуорофора способны менять время жизни флуоресценции при активации, что позволяет наблюдать за ними с помощью микроскопии с детекцией времени жизни флуоресценции (FLIM).

5. Создан красный флуоресцентный генетически кодируемый индикатор пероксида водорода HyPer-RED. Параметры взаимодействия сенсора с Н202 сходны с таковыми для НуРег.

6. Локализация НуРег на цитоплазматической поверхности клеточных мембран путем создания химер НуРег с мембранными белками позволяет существенно увеличить пространственное разрешение детекции Н202.

Пероксид водорода, образующийся в клетке при активации тирозинкиназных каскадов, локализован в микродоменах, ассоциированных с плазматической мембраной, эндосомами и мембраной эндоплазматического ретикулума. Диффузия Н202 в клетке строго ограничена, пероксид водорода окисляет тиолаты лишь в пределах микродоменов.

Получен двойной биосенсор, позволяющий детектировать одновременно продукцию фосфатидилинозитол-3,4,5-трифосфата (по транслокации сенсора из цитоплазмы на плазматическую мембрану) и динамику [Н202] (по изменению рациометрического сигнала сенсора). С помощью данного сенсора продемонстрирована поляризация активности Р13-киназы и пероксида водорода в ТЬ-лимфоцитах при образовании иммунологического синапса.

Исследована продукция Н202 в фагоцитирующих макрофагах. При наблюдении за динамикой Н202 на уровне отдельных клеток видно, что всплеск НАДФН-оксидазной активности носит кратковременный и контролируемый характер.

Пероксид водорода в макрофагах регулирует активацию МАР-киназ при фагоцитозе. Одна из функций Н202 в макрофагах состоит в предотвращении повторных событий фагоцитоза одной и той же клеткой.

Получен генетически кодируемый флуоресцентный индикатор для детекции соотношения НАД+/НАДН в различных компартментах клетки и разработана стратегия использования сенсоров на базе срУРР в условиях сильных колебаний рН.

Заключение

В настоящей работе впервые были созданы генетически кодируемые индикаторы пероксида водорода. Биосенсор НуРег стал первым в мире инструментом, позволившим отслеживать динамику пероксида водорода в живых клетках и тканях. Его специфичность и обратимость делает НуРег незаменимым в исследованиях физиологических и патологических состояний, ассоциированных с продукцией АФК. Преимуществами сенсора НуРег являются также рациометрический сигнал и полностью белковая природа самого сенсора, что позволяет локализовать его в различных внутриклеточных компартментах и предоставляет широкие возможности создания трансгенных животных, экспрессирующих сенсор.

Вслед за НуРег, были получены сенсоры НуРег-2 и НуРег-3, отличающиеся увеличенным, по сравнению с НуРег, динамическим диапазоном. Использование этих сенсоров существенно упрощает детекцию небольших концентраций Н2О2. Был также создан красный флуоресцентный индикатор Н202, HyPer-Red.

На примере сенсоров НуРег и НуРег-3 впервые было продемонстрировано, что сенсоры на базе одного флуорофора (пермутированного флуоресцентного белка) способны менять время жизни флуоресценции. Сенсоры были успешно применены для детекции Н2С>2 in vivo в режиме детекции времени жизни флуоресценции FLIM.

Белковая природа сенсора НуРег позволила нам создать метод детекции локальных изменений концентрации Н2Ог на уровне суб-компартментов. Сшивая НуРег с белками, локализованными на различных клеточных мембранах, мы впервые продемонстрировали существование микродоменов Н2О2, ассоциированных с активированной рецепторными тирозинкиназами и резидентной ретикулярной тирозинфосфатазой РТР-1В. В ходе выполнения данной части работы мы впервые получили прямое доказательство того, что пероксид водорода локализован вблизи мест его производства и его диффузия в цитоплазме существенно ограничена.

Путем комбинирования биосенсора НуРег в одном химерном белке с РН-доменом киназы ВТК нам удалось создать сенсор, позволяющий одновременно детектировать Н2О2 (по изменению соотношения пиков возбуждения сенсора НуРег) и фосфатидилинозитол-3,4,5-трифосфат (по транслокации сенсора из цитоплазмы на плазматическую мембрану). С помощью данного сенсора нам впервые удалось наблюдать активность обеих сигнальных систем, липидной и окислительно-восстановительной, в иммунологическом синапсе, образуемом Th-лимфоцитом в процессе активации Т-клеточного рецептора антиген-презентирующими структурами. Мы показали, что не только активность Р13-киназы, но и продукция Н202 поляризованы в активируемых Т-клетках.

Биосенсор НуРег позволил нам впервые пронаблюдать за динамикой Н202 в фагоцитирующих макрофагах. Мы установили, что пероксид водорода, генерируемый макрофагами, участвует в регуляции МАР-киназ и служит для перепрограммирования фагоцитировавших клеток.

Получен генетически кодируемый флуоресцентный сенсор соотношения НАДТРІАДН, первый сенсор, способный детектировать редокс-состояние данной пары в компартментах, сильно различающихся по количеству НАДН: в цитоплазме и митохондриальном матриксе.

Методическая платформа для детекции АФК и других редокс-активных веществ, созданная в данной работе, применяется в настоящее время сотнями лабораторий в мире, являясь, фактически, безальтернативной в экспериментах, исследующих динамику окислительных процессов. Принципы конструирования биосенсоров, разработанные нами при создании индикаторов семейства НуРег, успешно применяются в других лабораториях при создании биосенсоров. Ведутся работы по созданию на базе биосенсоров Н202 систем скрининга лекарственных препаратов, направленных на ингибирование ферментативных систем, генерирующих АФК.

СПИСОК ПУБЛИКАЦИЙ ПО ТЕМЕ ДИССЕРТАЦИИ

Обзоры

1. Зоров ДБ., Банникова С.Ю., Белоусов В.В., Высоких М.Ю., Зорова Л.Д., Исаев Н.К., Красников Б.Ф., Плотников Е Ю. Друзья или враги. Активные формы кислорода и азота. Биохимия, 2005; 70 (2), 265-272.

2. Murphy MP, Holmgren A, Larsson N.-G., Halliwell В, Chang С, Kalyanaraman В, Rhee S.-G., Thornalley P, Partridge L, Gems D, Nystrôm T, Belousov V, Schumacker P, and Winterbourn C. Unravelling the Biological Roles of Reactive Oxygen Species. Cell Metabolism. 2011; 13(4), 361-366.

3. Lukyanov KA, Belousov VV. Biophotonics: The slow fade of cell fluorescence. Nature Photonics. 2012; 6, 641-643.

4. Ткачук В.А., Тюрин-Кузьмин П.А., Белоусов B.B., Воротников А.В. Пероксид водорода как новый вторичный посредник. Биологические мембраны. 2012; 29 (1-2), 1-17.

5. Белоусов В.В., Ениколопов Т.Н., Мишина Н.М. Компартментализация передачи сигналов, опосредованных активными формами кислорода. Биоорганическая химия. 2013; 39 (4), 1-17.

Статьи

6. Belousov VV, Fradkov AF, Lukyanov KA, Staroverov DB, Shakhbazov KS, Terskikh AV, Lukyanov S. Genetically encoded fluorescent indicator for intracellular hydrogen peroxide. Nature Methods. 2006 Apr;3(4):281-286.

7. Chudakov DM, Chepurnykh TV, Belousov VV, Lukyanov S, Lukyanov KA. Fast and precise protein tracking using repeated reversible photoactivation. Traffic. 2006;7(10): 1304-1310.

8. Souslova EA, Belousov VV, Lock JG, Strômblad S, Kasparov S, Bolshakov AP, Pinelis VG, Labas YA, Lukyanov S, Mayr LM, Chudakov DM. Single fluorescent protein-based Ca2+ sensors with increased dynamic range. BMC Biotechnology. 2007. 29;7:37.

9. Markvicheva KN, Bogdanova EA, Staroverov DB, Lukyanov S, Belousov VV. Imaging of intracellular hydrogen peroxide production with HyPer upon stimulation of HeLa cells with epidermal growth factor. Methods in Molecular Biology. 2009;476:76-83.

10. Bogdanov AM, Mishin AS, Yampolsky IV, Belousov VV, Chudakov DM, Subach FV, Verkhusha VV, Lukyanov S, Lukyanov KA. Green fluorescent proteins are light-induced electron donors. Nature Chemical Biology. 2009;5(7):459-461.

11. Марквичева K.H., Гороховатский А.Ю., Мишина H.M., Мудрик Н.Н., Винокуров Л.М., Лукьянов С.А., Белоусов В.В. Сигнальная функция фагоцитарной НАДФН-оксидазы: активация МАР-киназных каскадов при фагоцитозе. Биоорганическая химия. 2010; 36: 133-138.

12. Тюрин-Кузьмин П.А., Агаронян К.М., Морозов Я.И., Мишина Н.М., Белоусов В.В., Воротников А.В. НАД(Ф)Н оксидаза регулирует EGF-зависимую пролиферацию клеток по механизму, отличному от активации ERK1/2 МАР-киназ. Биофизика. 2010; 55: 1048-1056.

13. Malinouski М, Zhou Y, Belousov VV, Hatfield DL, Gladyshev VN. Hydrogen peroxide probes directed to different cellular compartments. PLoS One. 2011; 6(1): el4564.

14. Mishina NM, Tyurin-Kuzmin PA, Markvicheva KN, Vorotnikov AV, Tkachuk VA, Laketa V, Schultz C, Lukyanov S, Belousov VV. Does cellular hydrogen peroxide diffuse or act locally? Antioxidants & Redox Signaling. 2011; 14(1): 1-7.

15. Markvicheva KN, Bilan DS, Mishina NM, Gorokhovatsky AY, Vinokurov LM, Lukyanov S, Belousov VV. A genetically encoded sensor for H202 with expanded dynamic range. Bioorganic & Medicinal Chemistry. 2011; 19(3): 10791084.

16. Mishina NM, Bogeski I, Bolotin DA, Hoth M, Niemeyer BA, Schultz C, Zagaynova EV, Lukyanov S, Belousov W. Can We See PIP(3) and Hydrogen Peroxide with a Single Probe? Antioxidants & Redox Signaling. 2012; 17(3): 505512.

17. Bilan DS, Pase L, Joosen L, Gorokhovatsky AY, Ermakova YG, Grabher C, Gadella TWJ, Schultz C, Lukyanov S, Belousov VV. HyPer-3: a genetically encoded

H202 probe with improved performance for ratiometric and fluorescence lifetime imaging. ACS Chemical Biology. 2013 Mar 15; 8(3): 535-542.

18. Mishina NM, Markvicheva KN, Bilan DS, Matlashov ME, Shirmanova MV, Liebl D, Schultz C, Lukyanov S, Belousov VV. Visualization of intracellular hydrogen peroxide with HyPer, a genetically encoded fluorescent probe. Methods in Enzymology. 2013; 526: 45-59.

19. Mishina NM, Markvicheva KN, Fradkov AF, Zagaynova EV, Schultz C, Lukyanov S, Belousov VV. Imaging H202 microdomains in receptor tyrosine kinases signaling. Methods in Enzymology. 2013; 526: 175-187.

Список литературы диссертационного исследования доктор биологических наук Белоусов, Всеволод Вадимович, 2013 год

1. V В Djordjevic, Free radicals in cell biology, Int Rev Cytol, 237 (2004) 57-89

2. W Droge, Free radicals in the physiological control of cell function, Physiol Rev, 82 (2002) 47-95

3. L Moldovan, N1 Moldovan, Oxygen free radicals and redox biology of organelles, Histochem Cell Biol, 122 (2004) 395-412

4. P A Riley, Free radicals in biology oxidative stress and the effects of ionizing radiation, Int J Radiat Biol, 65 (1994) 27-33

5. С С Winterbourn, D Metodiewa, Reaction of superoxide with glutathione and other thiols , Methods in enzymology, 251 (1995) 81-86

6. H J Forman, I Fridovich, Superoxide dismutase a comparison of rate constants , Archives of biochemistry and biophysics, 158 (1973) 396-400

7. M Fujikawa, К Kobayashi, T Kozawa, Direct Oxidation of the 2Fe-2S] Cluster in SoxR Protein by Superoxide DISTINCT DIFFERENTIAL SENSITIVITY TO SUPEROXIDE-MEDIATED SIGNAL TRANSDUCTION , The Journal of biological chemistry, 287 (2012) 35702-35708

8. E Hidalgo, J M Bollinger, Jr , T M Bradley, С T Walsh, В Demple, Binuclear 2Fe-2S] clusters in the Escherichia coll SoxR protein and role of the metal centers in transcription, J Biol Chem, 270 (1995) 20908-20914

9. E Hidalgo, В Demple, An iron-sulfur center essential for transcriptional activation by the redox-sensing SoxR protein, EMBO J, 13 (1994) 138-146

10. PR Gardner, Superoxide-driven aconitase FE-S center cycling, Biosci Rep, 17 (1997)33-42

11. PR Gardner, I Fridovich, Inactivation-reactivation of aconitase in Escherichia coli A sensitive measure of superoxide radical, J Biol Chem, 267 (1992) 8757-8763

12. PR Gardner, I Raineri, LB Epstein, С W White, Superoxide radical and iron modulate aconitase activity in mammalian cells, J Biol Chem, 270 (1995) 1339913405

13. C.P. Anderson, M. Shen, R.S. Eisenstein, E.A. Leibold, Mammalian iron metabolism and its control by iron regulatory proteins., Biochimica et biophysica acta, 1823 (2012) 1468-1483.

14. K. Bedard, K.H. Krause, The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology, Physiol Rev, 87 (2007) 245-313.

15. E.A. Veal, A.M. Day, B.A. Morgan, Hydrogen peroxide sensing and signaling., Molecular cell, 26 (2007) 1-14.

16. D R. Mumbengegwi, Q. Li, C. Li, C.E. Bear, J.F. Engelhardt, Evidence for a superoxide permeability pathway in endosomal membranes, Мої Cell Biol, 28 (2008) 3700-3712.

17. M. Bertolotti, S. Bestetti, J.M. Garcia-Manteiga, I. Medrano-Fernandez, A. Dal Mas, M.L. Malosio, R. Sitia, Tyrosine kinase signal modulation, a matter of H202 membrane permeability?, Antioxid Redox Signal, (2013).

18. G.P. Bienert, A.L.B. М0І1ег, K.A. Kristiansen, A. Schulz, I.M. Mailer, J.K. Schjoerring, T.P. Jahn, Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes., The Journal of biological chemistry, 282 (2007) 11831192.

19. E.W. Miller, B.C. Dickinson, C.J. Chang, Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling, Proc Natl Acad Sci U S A, 107 (2010) 15681-15686.

20. S R. Lee, K.S. Kwon, S.R. Kim, S.G. Rhee, Reversible inactivation of protein-tyrosine phosphatase IB in A431 cells stimulated with epidermal growth factor, J Biol Chem, 273 (1998) 15366-15372.

21. Y.W. Lou, Y.Y. Chen, S.F. Hsu, R.K. Chen, C.L. Lee, K.H. Khoo, N.K. Tonks, T.C. Meng, Redox regulation of the protein tyrosine phosphatase PTP1B in cancer cells, FEBS J, 275 (2008) 69-88.

22. T.C. Meng, D A. Buckley, S. Galic, T. Tiganis, N.K. Tonks, Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B, J Biol Chem, 279 (2004) 37716-37725.

23. A. Salmeen, J.N. Andersen, M.P. Myers, T.C. Meng, J.A. Hmks, N.K. Tonks, D. Barford, Redox regulation of protein tyrosine phosphatase IB involves a sulphenyl-amide intermediate, Nature, 423 (2003) 769-773.

24. G. Storz, L.A. Tartaglia, B.N. Ames, Transcriptional regulator of oxidative stress-inducible genes: direct activation by oxidation, Science, 248 (1990) 189-194.

25. M. Zheng, F. Aslund, G. Storz, Activation of the OxyR transcription factor by reversible disulfide bond formation, Science, 279 (1998) 1718-1721.

26. Z.A. Wood, L.B. Poole, P. A. Karplus, Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling., Science (New York, NY.), 300 (2003) 650-653.

27. J.R. Stone, An assessment of proposed mechanisms for sensing hydrogen peroxide in mammalian systems., Archives of biochemistry and biophysics, 422 (2004) 119-124.

28. F. Aslund, M. Zheng, J. Beckwith, G. Storz, Regulation of the OxyR transcription factor by hydrogen peroxide and the cellular thiol-disulfide status, Proc Natl Acad Sci USA, 96(1999)6161-6165.

29. L.B. Poole, P.A. Karplus, A. Claiborne, Protein sulfenic acids in redox signaling., Annual review of pharmacology and toxicology, 44 (2004) 325-347.

30. H.A. Woo, H.Z. Chae, S.C. Hwang, K.-S. Yang, S.W. Kang, K. Kim, S.G. Rhee, Reversing the inactivation of peroxiredoxins caused by cysteine sulfinic acid formation., Science (New York, N.Y.), 300 (2003) 653-656.

31. B. Biteau, J. Labarre, M.B. Toledano, ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin., Nature, 425 (2003) 980-984.

32. P. Ghezzi, Oxidoreduction of protein thiols in redox regulation., Biochemical Society transactions, 33 (2005) 1378-1381.

33. F.Q. Schafer, G.R. Buettner, Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple., Free radical biology & medicine, 30 (2001) 1191-1212.

34. D M. Ziegler, Role of reversible oxidation-reduction of enzyme thiols-disulfides in metabolic regulation., Annual review of biochemistry, 54 (1985) 305-329.

35. S.A. Gravina, J.J. Mieyal, Thioltransferase is a specific glutathionyl mixed disulfide oxidoreductase., Biochemistry, 32 (1993) 3368-3376.

36. B Chance, H Sies, A Bovens, Hydroperoxide metabolism in mammalian organs , Physiological reviews, 59 (1979) 527-605

37. S G Rhee, SW Kang, W Jeong, TS Chang, KS Yang, HA Woo, Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins, Curr Opin Cell Biol, 17 (2005) 183-189

38. AM Day, JD Brown, SR Taylor, JD Rand, BA Morgan, EA Veal, Inactivation of a peroxiredoxin by hydrogen peroxide is critical for thioredoxin-mediated repair of oxidized proteins and cell survival, Mol Cell, 45 (2012) 398-408

39. J M Denu, KG Tanner, Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide evidence for a sulfenic acid intermediate and implications for redox regulation, Biochemistry, 37 (1998) 5633-5642

40. J Sohn, J Rudolph, Catalytic and chemical competence of regulation of cdc25 phosphatase by oxidation/reduction , Biochemistry, 42 (2003) 10060-10070

41. C C Winterbourn, D Metodiewa, Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide , Free radical biology & medicine, 27 (1999) 322-328

42. S G Rhee, Cell signaling H202, a necessary evil for cell signaling, Science, 312 (2006)1882-1883

43. M Ushio-Fukai, Localizing NADPH oxidase-denved ROS, Sci STKE, 2006 (2006) re 8

44. H S Park, S H Lee, D Park, J S Lee, S H Ryu, W J Lee, S G Rhee, Y S Bae, Sequential activation of phosphatidylinositol 3-kinase, beta Pix, Racl, and Noxl in growth factor-induced production of H202 , Molecular and cellular biology, 24 (2004) 4384-4394

45. R.F. Wu, Y.C. Xu, Z. Ma, F.E. Nwariaku, G.A. Sarosi, L.S. Terada, Subcellular targeting of oxidants during endothelial cell migration., The Journal of cell biology, 171 (2005) 893-904.

46. J. Kwon, S R. Lee, K.S. Yang, Y. Ahn, Y.J. Kim, E.R. Stadtman, S.G. Rhee, Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors, Proc Natl Acad Sci U S A, 101 (2004) 1641916424.

47. S. Funamoto, R. Meili, S. Lee, L. Parry, R.A. Firtel, Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis., Cell, 109 (2002)611-623.

48. N R. Leslie, X. Yang, C P. Downes, C.J. Weijer, The regulation of cell migration by PTEN., Biochemical Society transactions, 33 (2005) 1507-1508.

49. J.D. Van Buul, M. Fernandez-Borja, E.C. Anthony, P.L. Hordijk, Expression and localization of NOX2 and NOX4 in primary human endothelial cells., Antioxidants & redox signaling, 7 (2005) 308-317.

50. C. Huang, Z. Rajfur, C. Borchers, M.D. Schaller, K. Jacobson, JNK phosphorylates paxillin and regulates cell migration., Nature, 424 (2003) 219-223.

51. R.F. Wu, Y. Gu, Y.C. Xu, F.E. Nwariaku, L.S. Terada, Vascular endothelial growth factor causes translocation of p47phox to membrane ruffles through WAVE1., The Journal of biological chemistry, 278 (2003) 36830-36840.

52. T. Harder, K. Simons, Caveolae, DIGs, and the dynamics of sphingolipid-cholesterol microdomains., Current opinion in cell biology, 9 (1997) 534-542.

53. K. Simons, D. Toomre, Lipid rafts and signal transduction., Nature reviews. Molecular cell biology, 1 (2000) 31-39.

54. F. Vilhardt, B. van Deurs, The phagocyte NADPH oxidase depends on cholesterol-enriched membrane microdomains for assembly., The EMBO journal, 23 (2004) 739-748.

55. A. Navarro, B. Anand-Apte, M.-O. Parat, A role for caveolae in cell migration., FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 18(2004) 1801-1811.

56. S. Mañes, C. Martinez-A, Cholesterol domains regulate the actin cytoskeleton at the leading edge of moving cells., Trends in cell biology, 14 (2004) 275-278.

57. M.A. del Pozo, N.B. Alderson, W.B. Kiosses, H.-H. Chiang, R.G.W. Anderson, M.A. Schwartz, Integrins regulate Rac targeting by internalization of membrane domains., Science (New York, N.Y.), 303 (2004) 839-842.

58. A.Y. Zhang, F. Yi, G. Zhang, E. Gulbins, P.-L. Li, Lipid raft clustering and redox signaling platform formation in coronary arterial endothelial cells., Hypertension, 472006) 74-80.

59. L.L. Hilenski, R.E. Clempus, M.T. Quinn, J.D. Lambeth, K.K. Griendling, Distinct subcellular localizations of Noxl and Nox4 in vascular smooth muscle cells., Arteriosclerosis, thrombosis, and vascular biology, 24 (2004) 677-683.

60. K D Martyn, L M Frederick, K von Loehneysen, M C Dinauer, U G Knaus, Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases , Cellular signalling, 18 (2006) 69-82

61. K Chen, M T Kirber, H Xiao, Y Yang, J F Keaney, Jr, Regulation of ROS signal transduction by NADPH oxidase 4 localization, J Cell Biol, 181 (2008) 11291139

62. JV Frangioni, PH Beahm, V Shifnn, CA Jost, BG Neel, The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence , Cell, 68 (1992) 545-560

63. F G Haj, P J Verveer, A Squire, B G Neel, P I Bastiaens, Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum, Science, 295 (2002) 1708-1711

64. B M Babior, R S Kipnes, J T Curnutte, Biological defense mechanisms The production by leukocytes of superoxide, a potential bactericidal agent, J Clin Invest, 52(1973) 741-744

65. B M Babior, J D Lambeth, W Nauseef, The neutrophil NADPH oxidase, Arch Biochem Biophys, 397 (2002) 342-344

66. P Behe, A W Segal, The function of the NADPH oxidase of phagocytes, and its relationship to other NOXs, Biochem Soc Trans, 35 (2007) 1100-1103

67. A B Fisher, Redox signaling across cell membranes , Antioxidants & redox signaling, 11 (2009) 1349-1356

68. T L Leto, S Morand, D Hurt, T Ueyama, Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases, Antioxid Redox Signal, 11 (2009) 2607-2619

69. AR Cross, AW Segal, The NADPH oxidase of professional phagocytes-prototype of the NOX electron transport chain systems, Biochim Biophys Acta, 1657 (2004) 1-22

70. J G Moreland, AP Davis, G Bailey, WM Nauseef, F S Lamb, Anion channels, including C1C-3, are required for normal neutrophil oxidative function, phagocytosis, and transendothelial migration, J Biol Chem, 281 (2006) 12277-12288

71. GP Bienert, JK Schjoerring, TP Jahn, Membrane transport of hydrogen peroxide, Biochim Biophys Acta, 1758 (2006) 994-1003

72. B Banfi, F Tirone, I Durussel, J Knisz, P Moskwa, GZ Molnar, KH Krause, J A Cox, Mechanism of Ca2+ activation of the NADPH oxidase 5 (NOX5), J Biol Chem, 279 (2004) 18583-18591

73. T Kawahara, JD Lambeth, Phosphatidylinositol (4,5)-bisphosphate modulates Nox5 localization via an N-terminal polybasic region, Mol Biol Cell, 19 (2008) 40204031

74. T Ueyama, M Geiszt, T L Leto, Involvement of Racl in activation of multicomponent Noxl- and Nox3-based NADPH oxidases, Mol Cell Biol, 26 (2006) 2160-2174

75. I Helmcke, S Heumuller, R Tikkanen, K Schroder, R P Brandes, Identification of structural elements in Noxl and Nox4 controlling localization and activity, Antioxid Redox Signal, 11 (2009) 1279-1287

76. S Morand, T Ueyama, S Tsujibe, N Saito, A Korzeniowska, T L Leto, Duox maturation factors form cell surface complexes with Duox affecting the specificity of reactive oxygen species generation, FASEB J, 23 (2009) 1205-1218

77. X De Deken, D Wang, M C Many, S Costagliola, F Libert, G Vassart, J E Dumont, F Miot, Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family, J Biol Chem, 275 (2000) 23227-23233

78. R.K. Ambasta, P. Kumar, K.K. Griendling, H.H. Schmidt, R. Busse, R.P. Brandes, Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase, J Biol Chem, 279 (2004) 4593545941.

79. N. Ueno, R. Takeya, K. Miyano, H. Kikuchi, H. Sumimoto, The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators, J Biol Chem, 280 (2005) 2332823339.

80. M. Geiszt, K. Lekstrom, J. Witta, T.L. Leto, Proteins homologous to p47phox and p67phox support superoxide production by NAD(P)H oxidase 1 in colon epithelial cells, J Biol Chem, 278 (2003) 20006-20012.

81. R. Takeya, N. Ueno, K. Kami, M. Taura, M. Kohjima, T. Izaki, H. Nunoi, H. Sumimoto, Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases, J Biol Chem, 278 (2003) 25234-25246.

82. T. Ueyama, K. Lekstrom, S. Tsujibe, N. Saito, T.L. Leto, Subcellular localization and function of alternatively spliced Noxol isoforms, Free Radic Biol Med, 42 (2007) 180-190.

83. G. Cheng, J.D. Lambeth, NOXOl, regulation of lipid binding, localization, and activation of Noxl by the Phox homology (PX) domain, J Biol Chem, 279 (2004) 4737-4742.

84. G. Cheng, J.D. Lambeth, Alternative mRNA splice forms of NOXOl: differential tissue expression and regulation of Noxl and Nox3, Gene, 356 (2005) 118-126.

85. N. Borregaard, J.M. Heiple, E.R. Simons, R.A. Clark, Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation, J Cell Biol, 97 (1983) 52-61.

86. D. Rotrosen, T.L. Leto, Phosphorylation of neutrophil 47-kDa cytosolic oxidase factor. Translocation to membrane is associated with distinct phosphorylation events, J Biol Chem, 265 (1990) 19910-19915.

87. A.W. Segal, P.G. Heyworth, S. Cockcroft, MM. Barrowman, Stimulated neutrophils from patients with autosomal recessive chronic granulomatous disease fail to phosphorylate a Mr-44,000 protein, Nature, 316 (1985) 547-549.

88. K. Lapouge, S.J. Smith, Y. Groemping, K. Rittinger, Architecture of the p40-p47-p67phox complex in the resting state of the NADPH oxidase. A central role for p67phox, J Biol Chem, 277 (2002) 10121-10128.

89. A. Abo, E. Pick, A. Hall, N. Totty, C.G. Teahan, A.W. Segal, Activation of the NADPH oxidase involves the small GTP-binding protein p21racl, Nature, 353 (1991) 668-670.

90. A. Fontayne, P.M. Dang, M.A. Gougerot-Pocidalo, J. El-Benna, Phosphorylation of p47phox sites by PKC alpha, beta II, delta, and zeta: effect on binding to p22phox and on NADPH oxidase activation, Biochemistry, 41 (2002) 77437750.

91. P.G. Heyworth, BP. Bohl, G.M. Bokoch, J.T. Curnutte, Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its interaction with flavocytochrome b558, J Biol Chem, 269 (1994) 30749-30752.

92. X. De Deken, D. Wang, J.E. Dumont, F. Miot, Characterization of ThOX proteins as components of the thyroid H(2)0(2)-generating system, Exp Cell Res, 273 (2002) 187-196.

93. H. Grasberger, S. Refetoff, Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent, J Biol Chem, 281 (2006) 18269-18272.

94. K Rokutan, T Kawahara, Y Kuwano, K Tominaga, K Nishida, S Teshima-Kondo, Nox enzymes and oxidative stress in the immunopathology of the gastrointestinal tract, Semin Immunopathol, 30 (2008) 315-327

95. M Geiszt, J B Kopp, P Varnai, T L Leto, Identification of renox, an NAD(P)H oxidase in kidney, Proc Natl Acad Sci U S A, 97 (2000) 8010-8014

96. S Sorce, KH Krause, NOX enzymes in the central nervous system from signaling to disease, Antioxid Redox Signal, 11 (2009) 2481-2504

97. K Rokutan, T Kawahara, Y Kuwano, K Tominaga, A Sekiyama, S Teshima-Kondo, NADPH oxidases in the gastrointestinal tract a potential role of Noxl in innate immune response and carcinogenesis, Antioxid Redox Signal, 8 (2006) 15731582

98. Y Adachi, Y Shibai, J Mitsushita, WH Shang, K Hirose, T Kamata, Oncogenic Ras upregulates NADPH oxidase 1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6, Oncogene, 27 (2008) 4921-4932

99. D Gianni, B Bohl, S A Courtneidge, GM Bokoch, The involvement of the tyrosine kinase c-Src in the regulation of reactive oxygen species generation mediated by NADPH oxidase-1, Mol Biol Cell, 19 (2008) 2984-2994

100. C Cheret, A Gervais, A Lelli, C Colin, L Amar, P Ravassard, J Mallet, A Cumano, K H Krause, M Mallat, Neurotoxic activation of microglia is promoted by a noxl-dependent NADPH oxidase, J Neurosci, 28 (2008) 12039-12051

101. M Ibi, M Katsuyama, C Fan, K Iwata, T Nishinaka, T Yokoyama, C Yabe-Nishimura, NOX1/NADPH oxidase negatively regulates nerve growth factor-induced neunte outgrowth, Free Radic Biol Med, 40 (2006) 1785-1795

102. IR Hanna, L L Hilenski, A Dikalova, Y Tamyama, S Dikalov, A Lyle, M T Quinn, B Lassegue, K K Griendling, Functional association of noxl with p22phox in vascular smooth muscle cells, Free Radic Biol Med, 37 (2004) 1542-1549

103. T Kawahara, D Ritsick, G Cheng, JD Lambeth, Point mutations in the prohne-nch region of p22phox are dominant inhibitors of Noxl- and Nox2-dependent reactive oxygen generation, J Biol Chem, 280 (2005) 31859-31869

104. B Banfi, RA Clark, K Steger, KH Krause, Two novel proteins activate superoxide generation by the NADPH oxidase NOX1, J Biol Chem, 278 (2003) 35103513

105. G. Cheng, B.A. Diebold, Y. Hughes, J.D. Lambeth, Noxl -dependent reactive oxygen generation is regulated by Racl, J Biol Chem, 281 (2006) 1771817726.

106. H. Sumimoto, K. Miyano, R. Takeya, Molecular composition and regulation of the Nox family NAD(P)H oxidases, Biochem Biophys Res Commun, 338 (2005) 677686.

107. A. Yamamoto, K. Kami, R. Takeya, H. Sumimoto, Interaction between the SH3 domains and C-terminal proline-rich region in NADPH oxidase organizer 1 (Noxol), Biochem Biophys Res Commun, 352 (2007) 560-565.

108. M. Taura, K. Miyano, R. Minakami, S. Kamakura, R. Takeya, H. Sumimoto, A region N-terminal to the tandem SH3 domain of p47phox plays a crucial role in the activation of the phagocyte NADPH oxidase, Biochem J, 419 (2009) 329-338.

109. A.J. Valente, A. El Jamali, T.K. Epperson, M.J. Gamez, D.W. Pearson, R.A. Clark, NOX1 NADPH oxidase regulation by the NOXA1 SH3 domain, Free Radic Biol Med, 43 (2007) 384-396.

110. M. Ushio-Fukai, R.W. Alexander, M. Akers, Q. Yin, Y. Fujio, K. Walsh, K.K. Griendling, Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells, J Biol Chem, 274 (1999) 22699-22704.

111. P.N. Seshiah, D.S. Weber, P. Rocic, L. Valppu, Y. Taniyama, K.K. Griendling, Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators, Circ Res, 91 (2002) 406-413.

112. B.J. Hawkins, M. Madesh, C.J. Kirkpatrick, A.B. Fisher, Superoxide flux in endothelial cells via the chloride channel-3 mediates intracellular signaling, Mol Biol Cell, 18(2007) 2002-2012.

113. B. Lassegue, How does the chloride/proton antiporter C1C-3 control NADPH oxidase?, Circ Res, 101 (2007) 648-650.

114. K.K. Griendling, C.A. Mimeri, J.D. Ollerenshaw, R.W. Alexander, Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells, Circ Res, 74 (1994) 1141-1148.

115. T. Adachi, D.R. Pimentel, T. Heibeck, X. Hou, Y.J. Lee, B. Jiang, Y. Ido, R.A. Cohen, S-glutathiolation of Ras mediates redox-sensitive signaling by angiotensin II in vascular smooth muscle cells, J Biol Chem, 279 (2004) 29857-29862.

116. A.M. Zafari, M. Ushio-Fukai, M. Akers, Q. Yin, A. Shah, D.G. Harrison, W.R. Taylor, K.K. Griendling, Role of NADH/NADPH oxidase-derived H202 in angiotensin II-induced vascular hypertrophy, Hypertension, 32 (1998) 488-495.

117. A.N. Lyle, K.K. Griendling, Modulation of vascular smooth muscle signaling by reactive oxygen species, Physiology (Bethesda), 21 (2006) 269-280.

118. D.I. Brown, K.K. Griendling, Nox proteins in signal transduction, Free Radic Biol Med, 47 (2009) 1239-1253.

119. K. Schroder, I. Helmcke, K. Palfi, K.H. Krause, R. Busse, R.P. Brandes, Noxl mediates basic fibroblast growth factor-induced migration of vascular smooth muscle cells, Arterioscler Thromb Vase Biol, 27 (2007) 1736-1743.

120. A. Sadok, V. Bourgarel-Rey, F. Gattacceca, C. Penel, M. Lehmann, H. Kovacic, Noxl-dependent superoxide production controls colon adenocarcinoma cell migration, Biochim Biophys Acta, 1783 (2008) 23-33.

121. P.M. Burch, N.H. Heintz, Redox regulation of cell-cycle re-entry: cyclin D1 as a primary target for the mitogenic effects of reactive oxygen and nitrogen species, Antioxid Redox Signal, 7 (2005) 741-751.

122. P. Ranjan, V. Anathy, P.M. Burch, K. Weirather, J.D. Lambeth, N.H. Heintz, Redox-dependent expression of cyclin D1 and cell proliferation by Noxl in mouse lung epithelial cells, Antioxid Redox Signal, 8 (2006) 1447-1459.

123. J. Mitsushita, J.D. Lambeth, T. Kamata, The superoxide-generating oxidase Noxl is functionally required for Ras oncogene transformation, Cancer Res, 64 (2004) 3580-3585.

124. D. Komatsu, M. Kato, J. Nakayama, S. Miyagawa, T. Kamata, NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor expression, Oncogene, 27 (2008) 4724-4732.

125. E. Laurent, J.W. McCoy, 3rd, R.A. Macina, W. Liu, G. Cheng, S. Robine, J. Papkoff, J.D. Lambeth, Noxl is over-expressed in human colon cancers and correlates with activating mutations in K-Ras, Int J Cancer, 123 (2008) 100-107.

126. Y.S. Kim, M.J. Morgan, S. Choksi, Z.G. Liu, TNF-induced activation of the Noxl NADPH oxidase and its role in the induction of necrotic cell death, Mol Cell, 262007) 675-687.

127. B. Rada, C. Hably, A. Meczner, C. Timar, G. Lakatos, P. Enyedi, E. Ligeti, Role of Nox2 in elimination of microorganisms, Semin Immunopathol, 30 (2008) 237-253.

128. K. Bedard, B. Lardy, K.H. Krause, NOX family NADPH oxidases: not just in mammals, Biochimie, 89 (2007) 1107-1112.

129. R. Dworakowski, S.P. Alom-Ruiz, A.M. Shah, NADPH oxidase-derived reactive oxygen species in the regulation of endothelial phenotype, Pharmacol Rep, 60 (2008) 21-28.

130. A.W. Segal, Biochemistry and molecular biology of chronic granulomatous disease, J Inherit Metab Dis, 15 (1992) 683-686.

131. A.W. Segal, The NADPH oxidase and chronic granulomatous disease, Mol Med Today, 2(1996) 129-135.

132. U. Zor, E. Ferber, P. Gergely, K. Szucs, V. Dombradi, R. Goldman, Reactive oxygen species mediate phorbol ester-regulated tyrosine phosphorylation and phospholipase A2 activation: potentiation by vanadate, Biochem J, 295 ( Pt 3) (1993) 879-888.

133. K. Chen, S.E. Craige, J.F. Keaney, Jr., Downstream targets and intracellular compartmentalization in Nox signaling, Antioxid Redox Signal, 11 (2009) 2467-2480.

134. T. Noguchi, K. Ishii, H. Fukutomi, I. Naguro, A. Matsuzawa, K. Takeda, H. Ichijo, Requirement of reactive oxygen species-dependent activation of ASKl-p38

135. MAPK pathway for extracellular ATP- induced apoptosis in macrophage, J Biol Chem, 283 (2008) 7657-7665.

136. Q. Li, N.Y. Spencer, F.D. Oakley, GR. Buettner, J.F. Engelhardt, Endosomal Nox2 facilitates redox-dependent induction of NF-kappaB by TNF-alpha, Antioxid Redox Signal, 11 (2009) 1249-1263.

137. H.M. Shen, Y. Lin, S. Choksi, J. Tran, T. Jin, L. Chang, M. Karin, J. Zhang, Z.G. Liu, Essential roles of receptor-interacting protein and TRAF2 in oxidative stress-induced cell death, Mol Cell Biol, 24 (2004) 5914-5922.

138. M. Ushio-Fukai, VEGF signaling through NADPH oxidase-derived ROS, Antioxid Redox Signal, 9 (2007) 731-739.

139. R. Harfouche, N.A. Malak, R.P. Brandes, A. Karsan, K. Irani, S.N. Hussain, Roles of reactive oxygen species in angiopoietin-l/tie-2 receptor signaling, FASEB J, 19(2005) 1728-1730.

140. F.D. Oakley, D. Abbott, Q. Li, J.F. Engelhardt, Signaling components of redox active endosomes: the redoxosomes, Antioxid Redox Signal, 11 (2009) 1313-1333.

141. I. Diebold, T. Djordjevic, A. Petry, A. Hatzelmann, H. Tenor, J. Hess, A. Gorlach, Phosphodiesterase 2 mediates redox-sensitive endothelial cell proliferation and angiogenesis by thrombin via Racl and NADPH oxidase 2, Circ Res, 104 (2009) 1169-1177.

142. M. Ushio-Fukai, Redox signaling in angiogenesis: role of NADPH oxidase, Cardiovasc Res, 71 (2006) 226-235.

143. G. Cheng, Z. Cao, X. Xu, E.G. van Meir, J.D. Lambeth, Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5, Gene, 269 (2001) 131-140.

144. Y. Nakano, C.M. Longo-Guess, D.E. Bergstrom, W.M. Nauseef, S.M. Jones, B. Banfi, Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice, J Clin Invest, 118 (2008) 1176-1185.

145. P.J. Kiss, J. Knisz, Y. Zhang, J. Baltrusaitis, C.D. Sigmund, R. Thalmann, R.J. Smith, E. Verpy, B. Banfi, Inactivation of NADPH oxidase organizer 1 results in severe imbalance, Curr Biol, 16 (2006) 208-213.

146. X. Zhang, P. Shan, G. Jiang, L. Cohn, P.J. Lee, Toll-like receptor 4 deficiency causes pulmonary emphysema, J Clin Invest, 116 (2006) 3050-3059.

147. A. Shiose, J. Kuroda, K. Tsuruya, M. Hirai, H. Hirakata, S. Naito, M. Hattori, Y. Sakaki, H. Sumimoto, A novel superoxide-producing NAD(P)H oxidase in kidney, J Biol Chem, 276 (2001) 1417-1423.

148. B. Banfi, B. Malgrange, J. Knisz, K. Steger, M. Dubois-Dauphin, K.H. Krause, NOX3, a superoxide-generating NADPH oxidase of the inner ear, J Biol Chem, 279 (2004) 46065-46072.

149. G. Cheng, D. Ritsick, J.D. Lambeth, Nox3 regulation by NOXOl, p47phox, and p67phox, J Biol Chem, 279 (2004) 34250-34255.

150. Y. Nakano, B. Banfi, A.J. Jesaitis, M.C. Dinauer, L.A. Allen, W.M. Nauseef, Critical roles for p22phox in the structural maturation and subcellular targeting of Nox3, Biochem J, 403 (2007) 97-108.

151. Y. Gorin, J.M. Ricono, N.H. Kim, B. Bhandari, G.G. Choudhury, H E. Abboud, Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells, Am J Physiol Renal Physiol, 285 (2003) F219-229.

152. I. Cucoranu, R. Clempus, A. Dikalova, P.J. Phelan, S. Ariyan, S. Dikalov, D. Sorescu, NAD(P)H oxidase 4 mediates transforming growth factor-beta 1-induced differentiation of cardiac fibroblasts into myofibroblasts, Circ Res, 97 (2005) 900-907.

153. W. Chamulitrat, W. Stremmel, T. Kawahara, K. Rokutan, H. Fujii, K. Wingler, H.H. Schmidt, R. Schmidt, A constitutive NADPH oxidase-like system containinggp91phox homologs in human keratinocytes, J Invest Dermatol, 122 (2004) 1000-1009.

154. P. Vallet, Y. Charnay, K. Steger, E. Ogier-Denis, E. Kovari, F. Herrmann, J.P. Michel, I. Szanto, Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia, Neuroscience, 132 (2005) 233-238.

155. K.H. Krause, Tissue distribution and putative physiological function of NOX family NADPH oxidases, Jpn J Infect Dis, 57 (2004) S28-29.

156. K. Schroder, K. Wandzioch, I. Helmcke, R.P. Brandes, Nox4 acts as a switch between differentiation and proliferation in preadipocytes, Arterioscler Thromb Vase Biol, 29 (2009) 239-245.

157. D. Meng, D.D. Lv, J. Fang, Insulin-like growth factor-I induces reactive oxygen species production and cell migration through Nox4 and Racl in vascular smooth muscle cells, Cardiovasc Res, 80 (2008) 299-308.

158. H. Peshavariya, F. Jiang, C.J. Taylor, S. Selemidis, C.W. Chang, G.J. Dusting, Translation-linked mRNA destabilization accompanying serum-induced Nox4 expression in human endothelial cells, Antioxid Redox Signal, 11 (2009) 23992408.

159. A.N. Lyle, N.N. Deshpande, Y. Taniyama, B. Seidel-Rogol, L. Pounkova, P. Du, C. Papaharalambus, B. Lassegue, K.K. Griendling, Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells, Circ Res, 105 (2009) 249259.

160. R.F. Wu, Z. Ma, Z. Liu, L.S. Terada, Nox4-derived H202 mediates endoplasmic reticulum signaling through local Ras activation, Mol Cell Biol, 30 (2010) 3553-3568.

161. M.J. Haurani, M.E. Cifuentes, A.D. Shepard, P.J. Pagano, Nox4 oxidase overexpression specifically decreases endogenous Nox4 mRNA and inhibits angiotensin II-induced adventitial myofibroblast migration, Hypertension, 52 (2008) 143-149.

162. R.S. BelAiba, T. Djordjevic, A. Petry, K. Diemer, S. Bonello, B. Banfi, J. Hess, A. Pogrebniak, C. Bickel, A. Gorlach, NOX5 variants are functionally active in endothelial cells, Free Radic Biol Med, 42 (2007) 446-459.

163. B. Banfi, G. Molnar, A. Maturana, K. Steger, B. Hegedus, N. Demaurex, K.H. Krause, A Ca(2+)-activated NADPH oxidase in testis, spleen, and lymph nodes, J Biol Chem, 276 (2001) 37594-37601.

164. D.B. Jay, C.A. Papaharalambus, B. Seidel-Rogol, A.E. Dikalova, B. Lassegue, K.K. Griendling, Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells, Free Radic Biol Med, 45 (2008) 329-335.

165. A.S. Kamiguti, L. Serrander, K. Lin, R.J. Harris, J.C. Cawley, D.J. Allsup, J.R. Slupsky, K.H. Krause, M. Zuzel, Expression and activity of NOX5 in the circulating malignant B cells of hairy cell leukemia, J Immunol, 175 (2005) 8424-8430.

166. J. Si, J. Behar, J. Wands, D.G. Beer, D. Lambeth, Y.E. Chin, W. Cao, STAT5 mediates PAF-induced NADPH oxidase NOX5-S expression in Barrett's esophageal adenocarcinoma cells, Am J Physiol Gastrointest Liver Physiol, 294 (2008) G174-183.

167. F Tirone, J A Cox, NADPH oxidase 5 (N0X5) interacts with and is regulated by calmodulin, FEBS Lett, 581 (2007) 1202-1208

168. D Jagnandan, J E Church, B Banfi, D J Stuehr, M B Marrero, D J Fulton, Novel mechanism of activation of NADPH oxidase 5 calcium sensitization via phosphorylation, J Biol Chem, 282 (2007) 6494-6507

169. A El Jamah, A J Valente, J D Lechleiter, M J Gamez, D W Pearson, W M Nauseef, R A Clark, Novel redox-dependent regulation of NOX5 by the tyrosine kinase c-Abl, Free Radic Biol Med, 44 (2008) 868-881

170. L Serrander, V Jaquet, K Bedard, O Piastre, O Hartley, S Arnaudeau, N Demaurex, W Schlegel, K H Krause, NOX5 is expressed at the plasma membrane and generates superoxide in response to protein kinase C activation, Biochimie, 892007) 1159-1167

171. P Sharma, R Chakraborty, L Wang, B Min, M L Tremblay, T Kawahara, J D Lambeth, S J Haque, Redox regulation of interleukin-4 signaling, Immunity, 292008)551-564

172. C Dupuy, R Ohayon, A Valent, M S Noel-Hudson, D Deme, A Virion, Purification of a novel flavoprotein involved in the thyroid NADPH oxidase Cloning of the porcine and human cdnas, J Biol Chem, 274 (1999) 37265-37269

173. RW Harper, C Xu, M McManus, A Heidersbach, JP Eisench, Duox2 exhibits potent heme peroxidase activity in human respiratory tract epithelium, FEBS Lett, 580 (2006)5150-5154

174. C Ris-Stalpers, Physiology and pathophysiology of the DUOXes, Antioxid Redox Signal, 8 (2006) 1563-1572

175. RW Harper, C Xu, JP Eisench, Y Chen, C Y Kao, P Thai, H Setiadi, R Wu, Differential regulation of dual NADPH oxidases/peroxidases, Duoxl and Duox2, by Thl and Th2 cytokines in respiratory tract epithelium, FEBS Lett, 579 (2005) 4911-4917

176. C. Dupuy, J. Kaniewski, D. Deme, J. Pommier, A. Virion, NADPH-dependent H202 generation catalyzed by thyroid plasma membranes. Studies with electron scavengers, Eur J Biochem, 185 (1989) 597-603.

177. C. Dupuy, A. Virion, R. Ohayon, J. Kaniewski, D. Deme, J. Pommier, Mechanism of hydrogen peroxide formation catalyzed by NADPH oxidase in thyroid plasma membrane, J Biol Chem, 266 (1991) 3739-3743.

178. H. Fischer, Mechanisms and function of DUOX in epithelia of the lung, Antioxid Redox Signal, 11 (2009) 2453-2465.

179. S. Pacquelet, M. Lehmann, S. Luxen, K. Regazzoni, M. Frausto, D. Noack, U.G. Knaus, Inhibitory action of NoxAl on dual oxidase activity in airway cells, J Biol Chem, 283 (2008) 24649-24658.

180. J.C. Moreno, H. Bikker, M.J. Kempers, A.S. van Trotsenburg, F. Baas, J.J. de Vijlder, T. Vulsma, C. Ris-Stalpers, Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism, N Engl J Med, 347 (2002) 95102.

181. N. Pfarr, E. Korsch, S. Kaspers, A. Herbst, A. Stach, C. Zimmer, J. Pohlenz, Congenital hypothyroidism caused by new mutations in the thyroid oxidase 2 (THOX2) gene, Clin Endocrinol (Oxf), 65 (2006) 810-815.

182. N. Anilkumar, R. Weber, M. Zhang, A. Brewer, A.M. Shah, Nox4 and nox2 NADPH oxidases mediate distinct cellular redox signaling responses to agonist stimulation, Arterioscler Thromb Vase Biol, 28 (2008) 1347-1354.

183. J.A. Badwey, M.L. Karnovsky, Active oxygen species and the functions of phagocytic leukocytes, Annu Rev Biochem, 49 (1980) 695-726.

184. D.B. Drath, M L. Karnovsky, Superoxide production by phagocytic leukocytes, J Exp Med, 141 (1975) 257-262.

185. J. Schrenzel, L. Serrander, B. Banfi, O. Nusse, R. Fouyouzi, D.P. Lew, N. Demaurex, K.H. Krause, Electron currents generated by the human phagocyte NADPH oxidase, Nature, 392 (1998) 734-737.

186. D. Morgan, V.V. Cherny, R. Murphy, W. Xu, L.L. Thomas, T.E. DeCoursey, Temperature dependence of NADPH oxidase in human eosinophils, J Physiol, 550 (2003) 447-458.

187. D. Morgan, V.V. Cherny, R. Murphy, B.Z. Katz, T.E. DeCoursey, The pH dependence of NADPH oxidase in human eosinophils, J Physiol, 569 (2005) 419-431.

188. V.V. Cherny, L.M. Henderson, W. Xu, L.L. Thomas, T.E. DeCoursey, Activation of NADPH oxidase-related proton and electron currents in human eosinophils by arachidonic acid, J Physiol, 535 (2001) 783-794.

189. D. Morgan, T.E. DeCoursey, Analysis of electrophysiological properties and responses of neutrophils, Methods Mol Biol, 412 (2007) 139-175.

190. I.S. Ramsey, M.M. Moran, J.A. Chong, D.E. Clapham, A voltage-gated proton-selective channel lacking the pore domain, Nature, 440 (2006) 1213-1216.

191. I.S. Ramsey, E. Ruchti, J.S. Kaczmarek, D.E. Clapham, Hvl proton channels are required for high-level NADPH oxidase-dependent superoxide production during the phagocyte respiratory burst, Proc Natl Acad Sci U S A, 106 (2009) 7642-7647.

192. L.M. Henderson, J.B. Chappell, O.T. Jones, The superoxide-generating NADPH oxidase of human neutrophils is electrogenic and associated with an H+ channel, Biochem J, 246 (1987) 325-329.

193. N. Demaurex, G.L. Petheo, Electron and proton transport by NADPH oxidases, Philos Trans R Soc Lond B Biol Sci, 360 (2005) 2315-2325.

194. B. Banfi, J. Schrenzel, O. Nusse, D.P. Lew, E. Ligeti, K.H. Krause, N. Demaurex, A novel H(+) conductance in eosinophils: unique characteristics and absence in chronic granulomatous disease, J Exp Med, 190 (1999) 183-194.

195. S. Grinstein, W. Furuya, Amiloride-sensitive Na+/H+ exchange in human neutrophils: mechanism of activation by chemotactic factors, Biochem Biophys Res Commun, 122 (1984) 755-762.

196. L. Simchowitz, Chemotactic factor-induced activation of Na+/H+ exchange in human neutrophils. II. Intracellular pH changes, J Biol Chem, 260 (1985) 1324813255.

197. D. Morgan, M. Capasso, B. Musset, V.V. Cherny, E. Rios, M.J. Dyer, T.E. DeCoursey, Voltage-gated proton channels maintain pH in human neutrophils during phagocytosis, Proc Natl Acad Sci U S A, 106 (2009) 18022-18027.

198. M B. Hampton, A.J. Kettle, C.C. Winterbourn, Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing, Blood, 92 (1998) 3007-3017.

199. E.P. Reeves, H. Lu, H.L. Jacobs, C.G. Messina, S. Bolsover, G. Gabella, E.O. Potma, A. Warley, J. Roes, A.W. Segal, Killing activity of neutrophils is mediated through activation of proteases by K+ flux, Nature, 416 (2002) 291-297.

200. R. Murphy, T.E. DeCoursey, Charge compensation during the phagocyte respiratory burst, Biochim Biophys Acta, 1757 (2006) 996-1011.

201. J.G. Hirsch, Z.A. Cohn, Degranulation of polymorphonuclear leucocytes following phagocytosis of microorganisms, J Exp Med, 112 (1960) 1005-1014.

202. C.C. Winterbourn, M.B. Hampton, J.H. Livesey, A.J. Kettle, Modeling the reactions of superoxide and myeloperoxidase in the neutrophil phagosome: implications for microbial killing, J Biol Chem, 281 (2006) 39860-39869.

203. T.E. DeCoursey, D. Morgan, V.V. Cherny, The voltage dependence of NADPH oxidase reveals why phagocytes need proton channels, Nature, 422 (2003) 531-534.

204. L.J. Wu, G. Wu, M R. Akhavan Sharif, A. Baker, Y. Jia, F.H. Fahey, H.R. Luo, E.P. Feener, D.E. Clapham, The voltage-gated proton channel Hvl enhances brain damage from ischemic stroke, Nat Neurosci, 15 (2012) 565-573.

205. A.M. Brennan, S.W. Suh, S.J. Won, P. Narasimhan, T.M. Kauppinen, H. Lee, Y. Edling, PH. Chan, R.A. Swanson, NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation, Nat Neurosci, 12 (2009) 857-863.

206. A.Y. Andreyev, Y.E. Kushnareva, A.A. Starkov, Mitochondrial metabolism of reactive oxygen species, Biochemistry (Mosc), 70 (2005) 200-214.

207. R. Vogel, H. Wiesinger, B. Hamprecht, R. Dringen, The regeneration of reduced glutathione in rat forebrain mitochondria identifies metabolic pathways providing the NADPH required, Neurosci Lett, 275 (1999) 97-100.

208. M.E. Tischler, P. Hecht, J.R. Williamson, Effect of ammonia on mitochondrial and cytosolic NADH and NADPH systems in isolated rat liver cells, FEBS Lett, 76 (1977) 99-104.

209. J.R. Williamson, B.E. Corkey, Assay of citric acid cycle intermediates and related compounds—update with tissue metabolite levels and intracellular distribution, Methods Enzymol, 55 (1979) 200-222.

210. O.W. Griffith, A. Meister, Origin and turnover of mitochondrial glutathione, Proc Natl Acad Sei U S A, 82 (1985) 4668-4672.

211. I. Rebrin, S. Kamzalov, R.S. Sohal, Effects of age and caloric restriction on glutathione redox state in mice, Free Radic Biol Med, 35 (2003) 626-635.

212. A. Wahllander, S. Soboll, H. Sies, I. Linke, M. Muller, Hepatic mitochondrial and cytosolic glutathione content and the subcellular distribution of GSH-S-transferases, FEBS Lett, 97 (1979) 138-140.

213. C. Chinopoulos, L. Tretter, V. Adam-Vizi, Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals: inhibition of alpha-ketoglutarate dehydrogenase, JNeurochem, 73 (1999) 220-228.

214. D. Kang, N. Hamasaki, Mitochondrial oxidative stress and mitochondrial DNA, Clin Chem Lab Med, 41 (2003) 1281-1288.

215. S P. LeDoux, N.M. Druzhyna, S.B. Hollensworth, J.F. Harrison, G.L. Wilson, Mitochondrial DNA repair: a critical player in the response of cells of the CNS to genotoxic insults, Neuroscience, 145 (2007) 1249-1259.

216. B. Van Houten, V. Woshner, J.H. Santos, Role of mitochondrial DNA in toxic responses to oxidative stress, DNA Repair (Amst), 5 (2006) 145-152.

217. J.F. Turrens, Mitochondrial formation of reactive oxygen species, J Physiol, 552 (2003) 335-344.

218. V. Adam-Vizi, C. Chinopoulos, Bioenergetics and the formation of mitochondrial reactive oxygen species, Trends Pharmacol Sei, 27 (2006) 639-645.

219. A.A. Starkov, G. Fiskum, C. Chinopoulos, B.J. Lorenzo, S.E. Browne, M.S. Patel, M.F. Beal, Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species, J Neurosci, 24 (2004) 7779-7788.

220. L. Tretter, V. Adam-Vizi, Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase, J Neurosci, 24 (2004) 7771-7778.

221. D.G. Nicholls, The effective proton conductance of the inner membrane of mitochondria from brown adipose tissue. Dependency on proton electrochemical potential gradient, Eur J Biochem, 77 (1977) 349-356.

222. D.G. Nicholls, Mitochondrial membrane potential and aging, Aging Cell, 3 (2004) 35-40.

223. G. Benzi, O. Pastoris, M. Dossena, Relationships between gamma-aminobutyrate and succinate cycles during and after cerebral ischemia, J Neurosci Res, 7(1982) 193-201.

224. Y. Kakinuma, T. Matsubara, T. Hashimoto, N. Sakamoto, Myocardial metabolic markers of total ischemia in vitro, Nagoya J Med Sci, 57 (1994) 35-42.

225. R.J. Wiesner, P. Rosen, M.K. Grieshaber, Pathways of succinate formation and their contribution to improvement of cardiac function in the hypoxic rat heart, Biochem Med Metab Biol, 40 (1988) 19-34.

226. F. Zoccarato, L. Cavallini, S. Bortolami, A. Alexandre, Succinate modulation of H202 release at NADH:ubiquinone oxidoreductase (Complex I) in brain mitochondria, Biochem J, 406 (2007) 125-129.

227. A.J. Lambert, M.D. Brand, Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane, Biochem J, 382 (2004) 511-517.

228. K. Takeshige, S. Minakami, NADH- and NADPH-dependent formation of superoxide anions by bovine heart submitochondrial particles and NADH-ubiquinone reductase preparation, Biochem J, 180 (1979) 129-135.

229. J.F. Turrens, A. Boveris, Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria, Biochem J, 191 (1980) 421-427.

230. A. Boveris, B. Chance, The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen, Biochem J, 134 (1973) 707-716.

231. V.P. Skulachev, Nonphosphorylating respiration as the mechanism preventing the formation of active forms of oxygen], Mol Biol (Mosk), 291995) 1199-1209.

232. V.P. Skulachev, Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants, Q Rev Biophys, 291996) 169-202.

233. D.L. Hoffman, J.D. Salter, P.S. Brookes, Response of mitochondrial reactive oxygen species generation to steady-state oxygen tension, implications for hypoxic cell signaling, Am J Physiol Heart Circ Physiol, 292 (2007) H101-108.

234. P. Wardman, Fluorescent and luminescent probes for measurement of oxidative and nitrosative species in cells and tissues: progress, pitfalls, and prospects, Free Radie Biol Med, 43 (2007) 995-1022.

235. M. Burkitt, C. Jones, A. Lawrence, P. Wardman, Activation of cytochrome c to a peroxidase compound I-type intermediate by H202: relevance to redox signalling in apoptosis, Biochem Soc Symp, (2004) 97-106.

236. M.J. Burkitt, P. Wardman, Cytochrome C is a potent catalyst of dichlorofluorescin oxidation: implications for the role of reactive oxygen species in apoptosis, Biochem Biophys Res Commun, 282 (2001) 329-333.

237. A.A. Starkov, The role of mitochondria in reactive oxygen species metabolism and signaling, Ann N Y Acad Sci, 1147 (2008) 37-52.

238. D.T. Johnson, RA. Harris, P.V. Blair, R.S. Balaban, Functional consequences of mitochondrial proteome heterogeneity, Am J Physiol Cell Physiol, 292 (2007) C698-707.

239. D.T. Johnson, R.A. Harris, S. French, P.V. Blair, J. You, K G. Bemis, M. Wang, R.S. Balaban, Tissue heterogeneity of the mammalian mitochondrial proteome, Am J Physiol Cell Physiol, 292 (2007) C689-697.

240. B.H. Robinson, The role of manganese superoxide dismutase in health and disease, J Inherit Metab Dis, 21 (1998) 598-603.

241. C.R. Hackenbrock, B. Chazotte, S.S. Gupte, The random collision model and a critical assessment of diffusion and collision in mitochondrial electron transport, J Bioenerg Biomembr, 18 (1986) 331-368.

242. J.M. McCord, I. Fridovich, Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein), J Biol Chem, 244 (1969) 6049-6055.

243. K. Mailer, Superoxide radical as electron donor for oxidative phosphorylation of ADP, Biochem Biophys Res Commun, 170 (1990) 59-64.

244. F. Zoccarato, L. Cavallini, A. Alexandre, Respiration-dependent removal of exogenous H202 in brain mitochondria: inhibition by Ca2+, J Biol Chem, 279 (2004) 4166-4174.

245. S. Fourquet, M.E. Huang, B. D'Autreaux, M.B. Toledano, The dual functions of thiol-based peroxidases in H202 scavenging and signaling, Antioxid Redox Signal, 10 (2008) 1565-1576.

246. T. Tamura, H.W. McMicken, C.V. Smith, T.N. Hansen, Gene structure for mouse glutathione reductase, including a putative mitochondrial targeting signal, Biochem Biophys Res Commun, 237 (1997) 419-422.

247. L A. Esposito, J.E. Kokoszka, K G. Waymire, B. Cottrell, G.R. MacGregor, D.C. Wallace, Mitochondrial oxidative stress in mice lacking the glutathione peroxidase-1 gene, Free Radic Biol Med, 28 (2000) 754-766.

248. C. Godeas, G. Sandri, E. Panfili, Distribution of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in rat testis mitochondria, Biochim Biophys Acta, 1191 (1994) 147-150.

249. C.H. Jung, J.A. Thomas, S-glutathiolated hepatocyte proteins and insulin disulfides as substrates for reduction by glutaredoxin, thioredoxin, protein disulfide isomerase, and glutathione, Arch Biochem Biophys, 335 (1996) 61-72.

250. V.N. Gladyshev, A. Liu, S.V. Novoselov, K. Krysan, Q.A. Sun, V.M. Kryukov, G.V. Kryukov, M.F. Lou, Identification and characterization of a new mammalian glutaredoxin (thioltransferase), Grx2, J Biol Chem, 276 (2001) 30374-30380.

251. I. Dalle-Donne, A. Milzani, N. Gagliano, R. Colombo, D. Giustarini, R. Rossi, Molecular mechanisms and potential clinical significance of S-glutathionylation, Antioxid Redox Signal, 10 (2008) 445-473.

252. E.M. Hanschmann, M.E. Lonn, L.D. Schutte, M. Funke, J.R. Godoy, S. Eitner, C. Hudemann, C.H. billig, Both thioredoxin 2 and glutaredoxin 2 contribute to the reduction of the mitochondrial 2-Cys peroxiredoxin Prx3, J Biol Chem, 285 40699-40705.

253. J.H. Bushweiler, F. Aslund, K. Wuthrich, A. Holmgren, Structural and functional characterization of the mutant Escherichia coli glutaredoxin (CI4—S) and its mixed disulfide with glutathione, Biochemistry, 31 (1992) 9288-9293.

254. A. Holmgren, Thioredoxin, Annu Rev Biochem, 54 (1985) 237-271.

255. P.Y. Gasdaska, M.M. Berggren, M.J. Berry, G. Powis, Cloning, sequencing and functional expression of a novel human thioredoxin reductase, FEBS Lett, 442 (1999) 105-111.

256. S.G. Rhee, HZ. Chae, K. Kim, Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling, Free Radic Biol Med, 38 (2005) 1543-1552.

257. S.G. Rhee, S.W. Kang, T.S. Chang, W. Jeong, K. Kim, Peroxiredoxin, a novel family of peroxidases, IUBMB Life, 52 (2001) 35-41.

258. S.G. Rhee, S.W. Kang, L.E. Netto, M.S. Seo, E.R. Stadtman, A family of novel peroxidases, peroxiredoxins, Biofactors, 10 (1999) 207-209.

259. S. Watabe, T. Hiroi, Y. Yamamoto, Y. Fujioka, H. Hasegawa, N. Yago, S.Y. Takahashi, SP-22 is a thioredoxin-dependent peroxide reductase in mitochondria, Eur J Biochem, 249 (1997) 52-60.

260. A.G. Cox, C.C. Winterbourn, MB. Hampton, Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling, Biochem J, 425 (2009) 313325.

261. A.G. Cox, A.V. Peskin, L.N. Paton, C.C. Winterbourn, M B. Hampton, Redox potential and peroxide reactivity of human peroxiredoxin 3, Biochemistry, 48 (2009) 6495-6501.

262. H.A. Woo, H Z. Chae, S C. Hwang, K S. Yang, S.W. Kang, K. Kim, S.G. Rhee, Reversing the inactivation of peroxiredoxins caused by cysteine sulfinic acid formation, Science, 300 (2003) 653-656.

263. Y.H. Noh, J.Y. Baek, W. Jeong, S.G. Rhee, T.S. Chang, Sulfiredoxin Translocation into Mitochondria Plays a Crucial Role in Reducing Hyperoxidized Peroxiredoxin III, J Biol Chem, 284 (2009) 8470-8477.

264. R.O. Olojo, R.H. Xia, J.J. Abramson, Spectrophotometric and fluorometric assay of superoxide ion using 4-chloro-7-nitrobenzo-2-oxa-l,3-diazole, Anal Biochem, 339 (2005) 338-344.

265. E. Pick, Y. Keisari, A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture, J Immunol Methods, 38 (1980) 161170.

266. S C. Richer, W.C. Ford, A critical investigation of NADPH oxidase activity in human spermatozoa, Mol Hum Reprod, 7 (2001) 237-244.

267. J. De la Harpe, C.F. Nathan, A semi-automated micro-assay for H202 release by human blood monocytes and mouse peritoneal macrophages, J Immunol Methods, 78 (1985) 323-336.

268. M.J. Black, R.B. Brandt, Spectrofluorometric analysis of hydrogen peroxide, Anal Biochem, 58 (1974) 246-254.

269. A.S. Keston, R. Brandt, THE FLUOROMETRIC ANALYSIS OF ULTRAMICRO QUANTITIES OF HYDROGEN PEROXIDE, Anal Biochem, 11 (1965) 1-5.

270. R. Cathcart, E. Schwiers, B.N. Ames, Detection of picomole levels of lipid hydroperoxides using a dichlorofluorescein fluorescent assay, Methods Enzymol, 105 (1984) 352-358.

271. В. Halliwell, М. Whiteman, Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean?, Br J Pharmacol, 142 (2004) 231-255.

272. A. Keller, A. Mohamed, S. Drose, U. Brandt, I. Fleming, R.P. Brandes, Analysis of dichlorodihydrofluorescein and dihydrocalcein as probes for the detection of intracellular reactive oxygen species, Free Radic Res, 38 (2004) 1257-1267.

273. H. Ischiropoulos, A. Gow, S.R. Thorn, N.W. Kooy, J.A. Royall, J.P. Crow, Detection of reactive nitrogen species using 2,7-dichlorodihydrofluorescein and dihydrorhodamine 123, Methods Enzymol, 301 (1999) 367-373.

274. N.W. Kooy, J.A. Royall, H. Ischiropoulos, Oxidation of 2',7'-dichlorofluorescin by peroxynitrite, Free Radic Res, 27 (1997) 245-254.

275. N.W. Kooy, J.A. Royall, H. Ischiropoulos, J.S. Beckman, Peroxynitrite-mediated oxidation of dihydrorhodamine 123, Free Radic Biol Med, 16 (1994) 149156.

276. C P. LeBel, H. Ischiropoulos, S C. Bondy, Evaluation of the probe 2',7'-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress, Chem Res Toxicol, 5 (1992) 227-231.

277. JF Kalinich, N Ramakrishnan, DE McClain, The antioxidant Trolox enhances the oxidation of 2',7'-dichlorofluorescin to 2',7'-dichlorofluorescein, Free Radic Res, 26(1997)37-47

278. YQ O'Malley, KJ Reszka, BE Bntigan, Direct oxidation of 2',7'-dichlorodihydrofluorescein by pyocyanin and other redox-active compounds independent of reactive oxygen species production, Free Radic Biol Med, 36 (2004) 90-100

279. H Zhang, J Joseph, J Vasquez-Vivar, H Karoui, C Nsanzumuhire, P Martasek, P Tordo, B Kalyanaraman, Detection of superoxide anion using an isotopically labeled nitrone spin trap potential biological applications, FEBS Lett, 473 (2000) 58-62

280. K Setsukinai, Y Urano, K Kakinuma, H J Majima, T Nagano, Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species, J Biol Chem, 278 (2003) 3170-3175

281. G Rothe, G Valet, Flow cytometric analysis of respiratory burst activity in phagocytes with hydroethidine and 2',7'-dichlorofluorescin, J Leukoc Biol, 47 (1990) 440-448

282. H Kojima, N Nakatsubo, K Kikuchi, S Kawahara, Y Kinno, H Nagoshi, Y Hirata, T Nagano, Detection and imaging of nitric oxide with novel fluorescent indicators diaminofluoresceins, Anal Chem, 70 (1998) 2446-2453

283. H Kojima, Y Urano, K Kikuchi, T Higuchi, Y Hirata, T Nagano, Fluorescent Indicators for Imaging Nitric Oxide Production, Angew Chem Int Ed Engl, 38 (1999) 3209-3212

284. S Roychowdhury, A Luthe, G Keilhoff, G Wolf, TF Horn, Oxidative stress in glial cultures detection by DAF-2 fluorescence used as a tool to measure peroxynitnte rather than nitric oxide, Glia, 38 (2002) 103-114

285. X Zhang, WS Kim, N Hatcher, K Potgieter, LL Moroz, R Gillette, JV Sweedler, Interfering with nitric oxide measurements 4,5-diaminofluorescein reacts with dehydroascorbic acid and ascorbic acid, J Biol Chem, 277 (2002) 48472-48478

286. D Jourd'heuil, Increased nitric oxide-dependent nitrosylation of 4,5-diaminofluorescein by oxidants implications for the measurement of intracellular nitric oxide, Free Radic Biol Med, 33 (2002) 676-684

287. N. Nagata, K. Momose, Y. Ishida, Inhibitory effects of catecholamines and anti-oxidants on the fluorescence reaction of 4,5-diaminofluorescein, DAF-2, a novel indicator of nitric oxide, J Biochem, 125 (1999) 658-661.

288. Y. Li, H. Zhu, M.A. Trush, Detection of mitochondria-derived reactive oxygen species production by the chemilumigenic probes lucigenin and luminol, Biochim Biophys Acta, 1428 (1999) 1-12.

289. O. Myhre, J.M. Andersen, H. Aarnes, F. Fonnum, Evaluation of the probes 2',7'-dichlorofluorescin diacetate, luminol, and lucigenin as indicators of reactive species formation, Biochem Pharmacol, 65 (2003) 1575-1582.

290. N.W. Kooy, J.A. Royall, Agonist-induced peroxynitrite production from endothelial cells, Arch Biochem Biophys, 310 (1994) 352-359.

291. L. Castro, M.N. Alvarez, R. Radi, Modulatory role of nitric oxide on superoxide-dependent luminol chemiluminescence, Arch Biochem Biophys, 333 (1996) 179-188.

292. B. Oldenburg, H. van Kats-Renaud, J.C. Koningsberger, G.P. van Berge Henegouwen, B.S. van Asbeck, Chemiluminescence in inflammatory bowel disease patients: a parameter of inflammatory activity, Clin Chim Acta, 310 (2001) 151-156.

293. B. Gunaydin, A.T. Demiryurek, Interaction of lidocaine with reactive oxygen and nitrogen species, Eur J Anaesthesiol, 18 (2001) 816-822.

294. K. Teranishi, T. Nishiguchi, Cyclodextrin-bound 6-(4-methoxyphenyl)imidazol,2-alpha+/-]pyrazin-3(7H)-ones with fluorescein as green chemiluminescent probes for superoxide anions, Anal Biochem, 325 (2004) 185-195.

295. Y. Kambayashi, K. Ogino, Reestimation of Cypridina luciferin analogs (MCLA) as a chemiluminescence probe to detect active oxygen species—cautionary note for use of MCLA, J Toxicol Sci, 28 (2003) 139-148.

296. J. Vasquez-Vivar, N. Hogg, K.A. Pritchard, Jr., P. Martasek, B. Kalyanaraman, Superoxide anion formation from lucigenin: an electron spin resonance spin-trapping study, FEBS Lett, 403 (1997) 127-130.

297. I. Spasojevic, S.I. Liochev, I. Fridovich, Lucigenin: redox potential in aqueous media and redox cycling with 0-(2) production, Arch Biochem Biophys, 373 (2000) 447-450.

298. C. Rota, Y.C. Fann, R.P. Mason, Phenoxyl free radical formation during the oxidation of the fluorescent dye 2',7'-dichlorofluorescein by horseradish peroxidase.

299. Possible consequences for oxidative stress measurements, J Biol Chem, 274 (1999)28161-28168.

300. F. Petrat, S. Pindiur, M. Kirsch, H. de Groot, NAD(P)H, a primary target of 102 in mitochondria of intact cells, J Biol Chem, 278 (2003) 3298-3307.

301. S. Dikalov, K.K. Griendling, D.G. Harrison, Measurement of reactive oxygen species in cardiovascular studies, Hypertension, 49 (2007) 717-727.

302. A.E. Dikalova, A.T. Bikineyeva, K. Budzyn, R.R. Nazarewicz, L. McCann, W. Lewis, D.G. Harrison, S.I. Dikalov, Therapeutic targeting of mitochondrial superoxide in hypertension, Circ Res, 107 106-116.

303. K M. Robinson, M.S. Janes, M. Pehar, J.S. Monette, M.F. Ross, T.M. Hagen, M.P. Murphy, J.S. Beckman, Selective fluorescent imaging of superoxide in vivo using ethidium-based probes, ProcNatl Acad Sci USA, 103 (2006) 15038-15043.

304. J. Zielonka, J. Vasquez-Vivar, B. Kalyanaraman, Detection of 2-hydroxyethidium in cellular systems: a unique marker product of superoxide and hydroethidine, Nat Protoc, 3 (2008) 8-21.

305. E.W. Miller, A.E. Albers, A. Pralle, E.Y. Isacoff, C.J. Chang, Boronate-based fluorescent probes for imaging cellular hydrogen peroxide, J Am Chem Soc, 127 (2005) 16652-16659.

306. E.W. Miller, O. Tulyathan, E.Y. Isacoff, C.J. Chang, Molecular imaging of hydrogen peroxide produced for cell signaling, Nat Chem Biol, 3 (2007) 263-267.

307. A.H. Coons, H.J. Creech, R.N. Jones, E.J. Berliner, The Demonstration of Pneumococcal Antigen in Tissues by the Use of Fluorescent Antibody, J Immunol, 45 (1942) 159-170.

308. B.J. Trask, Human cytogenetics: 46 chromosomes, 46 years and counting, Nat Rev Genet, 3 (2002) 769-778.

309. R.Y. Tsien, The green fluorescent protein, Annu Rev Biochem, 67 (1998) 509544.

310. M. Zimmer, Green fluorescent protein (GFP): applications, structure, and related photophysical behavior, Chem Rev, 102 (2002) 759-781.

311. D.M. Chudakov, M.V. Matz, S. Lukyanov, K.A. Lukyanov, Fluorescent proteins and their applications in imaging living cells and tissues, Physiol Rev, 90 (2010) 11031163.

312. D.M. Chudakov, S. Lukyanov, K.A. Lukyanov, Fluorescent proteins as a toolkit for in vivo imaging, Trends Biotechnol, 23 (2005) 605-613.

313. S.J. Remington, Fluorescent proteins: maturation, photochemistry and photophysics, Curr Opin Struct Biol, 16 (2006) 714-721.

314. O. Shimomura, The discovery of aequorin and green fluorescent protein, J Microsc, 217 (2005) 1-15.

315. M.V. Matz, A.F. Fradkov, Y.A. Labas, A.P. Savitsky, AG. Zaraisky, M.L. Markelov, S.A. Lukyanov, Fluorescent proteins from nonbioluminescent Anthozoa species, Nat Biotechnol, 17 (1999) 969-973.

316. D. Baumann, M. Cook, L. Ma, A. Mushegian, E. Sanders, J. Schwartz, C.R. Yu, A family of GFP-like proteins with different spectral properties in lancelet Branchiostoma floridae, Biol Direct, 3 (2008) 28.

317. N.C. Shaner, G.G. Lambert, A. Chammas, Y. Ni, P.J. Cranfill, M A. Baird, B.R. Sell, J.R. Allen, R.N. Day, M. Israelsson, M.W. Davidson, J. Wang, A bright monomeric green fluorescent protein derived from Branchiostoma lanceolatum, Nat Methods, (2013).

318. M. Ormo, A.B. Cubitt, K. Kallio, L A. Gross, R.Y. Tsien, S.J. Remington, Crystal structure of the Aequorea victoria green fluorescent protein, Science, 273 (1996) 1392-1395.

319. D.P. Barondeau, C.D. Putnam, C.J. Kassmann, J.A. Tainer, ED. Getzoff, Mechanism and energetics of green fluorescent protein chromophore synthesis revealed by trapped intermediate structures, Proc Natl Acad Sci USA, 100 (2003) 12111-12116.

320. D.P. Barondeau, J.A. Tainer, E.D. Getzoff, Structural evidence for an enolate intermediate in GFP fluorophore biosynthesis, J Am Chem Soc, 128 (2006) 31663168.

321. R.M. Wachter, Chromogenic cross-link formation in green fluorescent protein, Acc Chem Res, 40 (2007) 120-127.

322. A.B. Cubitt, R. Heim, S.R. Adams, A.E. Boyd, L A. Gross, R.Y. Tsien, Understanding, improving and using green fluorescent proteins, Trends Biochem Sci, 20(1995) 448-455.

323. H. Niwa, S. Inouye, T. Hirano, T. Matsuno, S. Kojima, M. Kubota, M. Ohashi, F.I. Tsuji, Chemical nature of the light emitter of the Aequorea green fluorescent protein, Proc Natl Acad Sci U S A, 93 (1996) 13617-13622.

324. X. Shu, N.C. Shaner, C.A. Yarbrough, R.Y. Tsien, S.J. Remington, Novel chromophores and buried charges control color in mFruits, Biochemistry, 45 (2006) 9639-9647.

325. V.V. Verkhusha, K.A. Lukyanov, The molecular properties and applications of Anthozoa fluorescent proteins and chromoproteins, Nat Biotechnol, 22 (2004) 289296.

326. M. Kondo, I.A. Heisler, D. Stoner-Ma, P.J. Tonge, SR. Meech, Ultrafast dynamics of protein proton transfer on short hydrogen bond potential energy surfaces: S65T/H148D GFP, J Am Chem Soc, 132 (2010) 1452-1453.

327. S.R. Meech, Excited state reactions in fluorescent proteins, Chem Soc Rev, 38 (2009) 2922-2934.

328. D. Stoner-Ma, A.A. Jaye, P. Matousek, M. Towrie, S.R. Meech, P.J. Tonge, Observation of excited-state proton transfer in green fluorescent protein using ultrafast vibrational spectroscopy, J Am Chem Soc, 127 (2005) 2864-2865.

329. G.S. Baird, D.A. Zacharias, R.Y. Tsien, Biochemistry, mutagenesis, and oligomerization of DsRed, a red fluorescent protein from coral, Proc Natl Acad Sci U SA, 97 (2000) 11984-11989.

330. RE. Campbell, O. Tour, A.E. Palmer, P A. Steinbach, G.S. Baird, D.A. Zacharias, R.Y. Tsien, A monomeric red fluorescent protein, Proc Natl Acad Sci U S A, 99 (2002) 7877-7882.

331. M. Fischer, I. Haase, E. Simmeth, G. Gerisch, A. Muller-Taubenberger, A brilliant monomeric red fluorescent protein to visualize cytoskeleton dynamics in Dictyostelium, FEBS Lett, 577 (2004) 227-232.

332. S. Karasawa, T. Araki, M. Yamamoto-Hino, A. Miyawaki, A green-emitting fluorescent protein from Galaxeidae coral and its monomeric version for use in fluorescent labeling, J Biol Chem, 278 (2003) 34167-34171.

333. A. Muller-Taubenberger, M.J. Vos, A. Bottger, M. Lasi, F.P. Lai, M. Fischer, K. Rottner, Monomeric red fluorescent protein variants used for imaging studies in different species, Eur J Cell Biol, 85 (2006) 1119-1129.

334. N.C. Shaner, R E. Campbell, P A. Steinbach, B.N. Giepmans, A.E. Palmer, R.Y. Tsien, Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein, Nat Biotechnol, 22 (2004) 1567-1572.

335. M.A. Hink, R.A. Griep, J.W. Borst, A. van Hoek, M.H. Eppink, A. Schots, A.J. Visser, Structural dynamics of green fluorescent protein alone and fused with a single chain Fv protein, J Biol Chem, 275 (2000) 17556-17560.

336. O. Dyachok, Y. Isakov, J. Sagetorp, A. Tengholm, Oscillations of cyclic AMP in hormone-stimulated insulin-secreting beta-cells, Nature, 439 (2006) 349-352.

337. J. Enninga, J. Mounier, P. Sansonetti, G. Tran Van Nhieu, Secretion of type III effectors into host cells in real time, Nat Methods, 2 (2005) 959-965.

338. D.L. Sheridan, T.E. Hughes, A faster way to make GFP-based biosensors: two new transposons for creating multicolored libraries of fluorescent fusion proteins, BMC Biotechnol, 4 (2004) 17.

339. S.E. Tillo, T.E. Hughes, N.S. Makarov, A. Rebane, M. Drobizhev, A new approach to dual-color two-photon microscopy with fluorescent proteins, BMC Biotechnol, 10 (2010) 6.

340. R. Mealer, H. Butler, T. Hughes, Functional fusion proteins by random transposon-based GFP insertion, Methods Cell Biol, 85 (2008) 23-44.

341. T.T. Yang, L. Cheng, S.R. Kain, Optimized codon usage and chromophore mutations provide enhanced sensitivity with the green fluorescent protein, Nucleic Acids Res, 24 (1996) 4592-4593.

342. S. Zolotukhin, M. Potter, W.W. Hauswirth, J. Guy, N. Muzyczka, A "humanized" green fluorescent protein cDNA adapted for high-level expression in mammalian cells, J Virol, 70 (1996) 4646-4654.

343. M. Kozak, The scanning model for translation: an update, J Cell Biol, 108 (1989)229-241.

344. B P. Cormack, R.H. Valdivia, S. Falkow, FACS-optimized mutants of the green fluorescent protein (GFP), Gene, 173 (1996) 33-38.

345. J.D. Pedelacq, S. Cabantous, T. Tran, T.C. Terwilliger, G.S. Waldo, Engineering and characterization of a superfolder green fluorescent protein, Nat Biotechnol, 24 (2006) 79-88.

346. M.A. Rizzo, G.H. Springer, B. Granada, D.W. Piston, An improved cyan fluorescent protein variant useful for FRET, Nat Biotechnol, 22 (2004) 445-449.

347. M.A. Mena, T.P. Treynor, S.L. Mayo, P.S. Daugherty, Blue fluorescent proteins with enhanced brightness and photostability from a structurally targeted library, Nat Biotechnol, 24 (2006) 1569-1571.

348. O.M. Subach, I.S. Gundorov, M. Yoshimura, F.V. Subach, J. Zhang, D. Gruenwald, E.A. Souslova, D.M. Chudakov, V.V. Verkhusha, Conversion of red fluorescent protein into a bright blue probe, Chem Biol, 15 (2008) 1116-1124.

349. R.Y. Tsien, New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures, Biochemistry, 19 (1980) 2396-2404.

350. G. Grynkiewicz, M. Poenie, R.Y. Tsien, A new generation of Ca2+ indicators with greatly improved fluorescence properties, J Biol Chem, 260 (1985) 3440-3450.

351. O. Griesbeck, Fluorescent proteins as sensors for cellular functions, Curr Opin Neurobiol, 14 (2004) 636-641.

352. D. Arosio, G. Garau, F. Ricci, L. Marchetti, R. Bizzarri, R. Nifosi, F. Beltram, Spectroscopic and structural study of proton and halide ion cooperative binding to gfp, Biophys J, 93 (2007) 232-244.

353. R. Bizzarri, C. Arcangeli, D. Arosio, F. Ricci, P. Faraci, F. Cardarelli, F. Beltram, Development of a novel GFP-based ratiometric excitation and emission pH indicator for intracellular studies, Biophys J, 90 (2006) 3300-3314.

354. R. Bizzarri, M. Serresi, S. Luin, F. Beltram, Green fluorescent protein based pH indicators for in vivo use: a review, Anal Bioanal Chem, 393 (2009) 1107-1122.

355. G. Miesenböck, D.A. De Angelis, J.E. Rothman, Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins, Nature, 394 (1998) 192-195.

356. M. Kneen, J. Farinas, Y. Li, A.S. Verkman, Green fluorescent protein as a noninvasive intracellular pH indicator, Biophys J, 74 (1998) 1591-1599.

357. J. Llopis, J.M. McCaffery, A. Miyawaki, M.G. Farquhar, R.Y. Tsien, Measurement of cytosolic, mitochondrial, and Golgi pH in single living cells with green fluorescent proteins, Proc Natl Acad Sei U S A, 95 (1998) 6803-6808.

358. D. Poburko, J. Santo-Domingo, N. Demaurex, Dynamic regulation of the mitochondrial proton gradient during cytosolic calcium elevations, J Biol Chem, 286 (2011) 11672-11684.

359. M.F. Abad, G. Di Benedetto, P.J. Magalhaes, L. Filippin, T. Pozzan, Mitochondrial pH monitored by a new engineered green fluorescent protein mutant, J Biol Chem, 279 (2004) 11521-11529.

360. A.M. Porcelli, A. Ghelli, C. Zanna, P. Pinton, R. Rizzuto, M. Rugolo, pH difference across the outer mitochondrial membrane measured with a green fluorescent protein mutant, Biochem Biophys Res Commun, 326 (2005) 799-804.

361. S. Jayaraman, P. Haggie, R.M. Wächter, S.J. Remington, AS. Verkman, Mechanism and cellular applications of a green fluorescent protein-based halide sensor, J Biol Chem, 275 (2000) 6047-6050.

362. L.J. Galietta, P.M. Haggie, A S. Verkman, Green fluorescent protein-based halide indicators with improved chloride and iodide affinities, FEBS Lett, 499 (2001) 220-224.

363. K.J. Rhoden, S. Cianchetta, V. Stivani, C. Portulano, L.J. Galietta, G. Romeo, Cell-based imaging of sodium iodide symporter activity with the yellow fluorescent protein variant YFP-H148Q/I152L, Am J Physiol Cell Physiol, 292 (2007) C814-823.

364. T. Kuner, G.J. Augustine, A genetically encoded ratiometric indicator for chloride: capturing chloride transients in cultured hippocampal neurons, Neuron, 27 (2000) 447-459.

365. O. Markova, M. Mukhtarov, E. Real, Y. Jacob, P. Bregestovski, Genetically encoded chloride indicator with improved sensitivity, J Neurosci Methods, 170 (2008) 67-76.

366. G. Halet, Imaging phosphoinositide dynamics using GFP-tagged protein domains, Biol Cell, 97 (2005) 501-518.

367. T. Balla, Z. Szentpetery, Y.J. Kim, Phosphoinositide signaling: new tools and insights, Physiology (Bethesda), 24 (2009) 231-244.

368. T. Balla, P. Varnai, Visualizing cellular phosphoinositide pools with GFP-fused protein-modules, Sci STKE, 2002 (2002) pl3.

369. T. Tamguney, D. Stokoe, New insights into PTEN, J Cell Sci, 120 (2007) 40714079.

370. G. Servant, O.D. Weiner, P. Herzmark, T. Balla, J.W. Sedat, H.R. Bourne, Polarization of chemoattractant receptor signaling during neutrophil chemotaxis, Science, 287 (2000) 1037-1040.

371. P. Varnai, T. Balla, Live cell imaging of phosphoinositide dynamics with fluorescent protein domains, Biochim Biophys Acta, 1761 (2006) 957-967.

372. P. Varnai, T. Balla, Visualization and manipulation of phosphoinositide dynamics in live cells using engineered protein domains, Pflugers Arch, 455 (2007) 69-82.

373. T. Yeung, G.E. Gilbert, J. Shi, J. Silvius, A. Kapus, S. Grinstein, Membrane phosphatidylserine regulates surface charge and protein localization, Science, 319 (2008)210-213.

374. T. Yeung, B. Heit, J.F. Dubuisson, G.D. Fairn, B. Chiu, R. Inman, A. Kapus, M. Swanson, S. Grinstein, Contribution of phosphatidylserine to membrane surfacecharge and protein targeting during phagosome maturation, J Cell Biol, 185 (2009) 917-928

375. S R Bolsover, J C Gomez-Fernandez, S Corbalan-Garcia, Role of the Ca2+/phosphatidylsenne binding region of the C2 domain in the translocation of protein kinase Calpha to the plasma membrane, J Biol Chem, 278 (2003) 1028210290

376. T Forster, Zwischenmolekulare Energiewanderung und Fluoreszenz, Ann Phys 437(1948) 55-75

377. G H Patterson, DW Piston, BG Bansas, Forster distances between green fluorescent protein pairs, Anal Biochem, 284 (2000) 438-440

378. H W Ai, K L Hazelwood, M W Davidson, R E Campbell, Fluorescent protein FRET pairs for ratiometric imaging of dual biosensors, Nat Methods, 5 (2008) 401403

379. A J Lam, F St-Pierre, Y Gong, J D Marshall, P J Cranfill, M A Baird, M R

380. McKeown, J Wiedenmann, M W Davidson, M J Schnitzer, R Y Tsien, M Z Lin,1.proving FRET dynamic range with bright green and red fluorescent proteins, Nat Methods, 9 (2012) 1005-1012

381. A W Nguyen, P S Daugherty, Evolutionary optimization of fluorescent proteins for intracellular FRET, Nat Biotechnol, 23 (2005) 355-360

382. D Shcherbo, E A Souslova, J Goedhart, T V Chepurnykh, A Gaintzeva, Shemiakina, II, T W Gadella, S Lukyanov, D M Chudakov, Practical and reliable FRET/FLIM pair of fluorescent proteins, BMC Biotechnol, 9 (2009) 24

383. A Miyawaki, J Llopis, R Heim, J M McCaffery, J A Adams, M Ikura, R Y Tsien, Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin, Nature, 388 (1997) 882-887

384. T Porumb, P Yau, T S Harvey, M Ikura, A calmodulin-target peptide hybrid molecule with unique calcium-binding properties, Protein Eng, 7 (1994) 109-115

385. T Nagai, A Sawano, E S Park, A Miyawaki, Circularly permuted green fluorescent proteins engineered to sense Ca2+, Proc Natl Acad Sci U S A, 98 (2001) 3197-3202

386. J Nakai, M Ohkura, K Imoto, A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein, Nat Biotechnol, 19 (2001) 137-141

387. E. Emmanouilidou, A.G. Teschemacher, A.E. Pouli, L.I. Nicholls, E.P. Seward, G.A. Rutter, Imaging Ca2+ concentration changes at the secretory vesicle surface with a recombinant targeted cameleon, Curr Biol, 9 (1999) 915-918.

388. M. Isshiki, Y.S. Ying, T. Fujita, R.G. Anderson, A molecular sensor detects signal transduction from caveolae in living cells, J Biol Chem, 277 (2002) 4338943398.

389. R. Foyouzi-Youssefi, S. Arnaudeau, C. Borner, W.L. Kelley, J. Tschopp, D P. Lew, N. Demaurex, K.H. Krause, Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum, Proc Natl Acad Sci U S A, 97 (2000) 5723-5728.

390. N. Heim, O. Griesbeck, Genetically encoded indicators of cellular calcium dynamics based on troponin C and green fluorescent protein, J Biol Chem, 279 (2004) 14280-14286.

391. A.E. Palmer, M. Giacomello, T. Kortemme, S.A. Hires, V. Lev-Ram, D. Baker, R.Y. Tsien, Ca2+ indicators based on computationally redesigned calmodulin-peptide pairs, Chem Biol, 13 (2006) 521-530.

392. M. Mank, O. Griesbeck, Genetically encoded calcium indicators, Chem Rev, 108 (2008) 1550-1564.

393. M. Mank, D.F. Reiff, N. Heim, M.W. Friedrich, A. Borst, O. Griesbeck, A FRET-based calcium biosensor with fast signal kinetics and high fluorescence change, Biophys J, 90 (2006) 1790-1796.

394. L.H. Tay, O. Griesbeck, D.T. Yue, Live-cell transforms between Ca2+ transients and FRET responses for a troponin-C-based Ca2+ sensor, Biophys J, 93 (2007) 40314040.

395. N. Heim, O. Garaschuk, M.W. Friedrich, M. Mank, R.I. Milos, Y. Kovalchuk, A. Konnerth, O. Griesbeck, Improved calcium imaging in transgenic mice expressing a troponin C-based biosensor, Nat Methods, 4 (2007) 127-129.

396. D.J. Wallace, S.M. Zum Alten Borgloh, S. Aston, Y. Yang, M. Bausen, S. Kugler, A.E. Palmer, R.Y. Tsien, R. Sprengel, J.N. Kerr, W. Denk, M.T. Hasan, Single-spike detection in vitro and in vivo with a genetic Ca(2+) sensor, Nat Methods, (2008).

397. J.S. Hayes, L.L. Brunton, S.E. Mayer, Selective activation of particulate cAMP-dependent protein kinase by isoproterenol and prostaglandin El, J Biol Chem, 255 (1980) 5113-5119.

398. I.L. Buxton, L.L. Brunton, Compartments of cyclic AMP and protein kinase in mammalian cardiomyocytes, J Biol Chem, 258 (1983) 10233-10239.

399. I.L. Buxton, L.L. Brunton, Alpha-adrenergic receptors on rat ventricular myocytes: characteristics and linkage to cAMP metabolism, Am J Physiol, 251 (1986) H307-313.

400. M. Zaccolo, F. De Giorgi, C.Y. Cho, L. Feng, T. Knapp, P A. Negulescu, S.S. Taylor, R.Y. Tsien, T. Pozzan, A genetically encoded, fluorescent indicator for cyclic AMP in living cells, Nat Cell Biol, 2 (2000) 25-29.

401. M. Zaccolo, T. Pozzan, Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes, Science, 295 (2002) 1711-1715.

402. V.O. Nikolaev, M. Bunemann, L. Hein, A. Hannawacker, M.J. Lohse, Novel single chain cAMP sensors for receptor-induced signal propagation, J Biol Chem, 279 (2004)37215-37218.

403. G. Di Benedetto, A. Zoccarato, V. Lissandron, A. Terrin, X. Li, M.D. Houslay, G.S. Baillie, M. Zaccolo, Protein kinase A type I and type II define distinct intracellular signaling compartments, Circ Res, 103 (2008) 836-844.

404. L.M. DiPilato, X. Cheng, J. Zhang, Fluorescent indicators of cAMP and Epac activation reveal differential dynamics of cAMP signaling within discrete subcellular compartments, Proc Natl Acad Sci U S A, 101 (2004) 16513-16518.

405. L.M. DiPilato, J. Zhang, The role of membrane microdomains in shaping beta2-adrenergic receptor-mediated cAMP dynamics, Mol Biosyst, 5 (2009) 832-837.

406. H. Rehmann, В. Prakash, Е. Wolf, A. Rueppel, J. de Rooij, J.L. Bos, A. Wittinghofer, Structure and regulation of the cAMP-binding domains of Epac2, Nat Struct Biol, 10 (2003) 26-32.

407. H. Rehmann, A. Rueppel, J.L. Bos, A. Wittinghofer, Communication between the regulatory and the catalytic region of the cAMP-responsive guanine nucleotide exchange factor Epac, J Biol Chem, 278 (2003) 23508-23514.

408. D. Calebiro, V.O. Nikolaev, M.C. Gagliani, T. de Filippis, C. Dees, C. Tacchetti, L. Persani, M.J. Lohse, Persistent cAMP-signals triggered by internalized G-protein-coupled receptors, PLoS Biol, 7 (2009) ЄІ000172.

409. S. Ferrandon, T.N. Feinstein, M. Castro, B. Wang, R. Bouley, J.T. Potts, T.J. Gardella, J.P. Vilardaga, Sustained cyclic AMP production by parathyroid hormone receptor endocytosis, Nat Chem Biol, 5 (2009) 734-742.

410. M. Sato, N. Hida, Y. Umezawa, Imaging the nanomolar range of nitric oxide with an amplifier-coupled fluorescent indicator in living cells, Proc Natl Acad Sci U S A, 102 (2005) 14515-14520.

411. A. Honda, S.R. Adams, C.L. Sawyer, V. Lev-Ram, R.Y. Tsien, W.R. Dostmann, Spatiotemporal dynamics of guanosine 3',5'-cyclic monophosphate revealed by a genetically encoded, fluorescent indicator, Proc Natl Acad Sci U S A, 98 (2001) 24372442.

412. A. Honda, C.L. Sawyer, S.M. Cawley, W.R. Dostmann, Cygnets: in vivo characterization of novel cGMP indicators and in vivo imaging of intracellular cGMP, Methods Мої Biol, 307 (2005) 27-43.

413. V.O. Nikolaev, S. Gambaryan, M.J. Lohse, Fluorescent sensors for rapid monitoring of intracellular cGMP, Nat Methods, 3 (2006) 23-25.

414. S.M. Cawley, C.L. Sawyer, K.F. Brunelle, A. van der Vliet, W.R. Dostmann, Nitric oxide-evoked transient kinetics of cyclic GMP in vascular smooth muscle cells, Cell Signal, 19 (2007) 1023-1033.

415. M. Russwurm, F. Mullershausen, A. Friebe, R. Jager, C. Russwurm, D. Koesling, Design of fluorescence resonance energy transfer (FRET)-based cGMP indicators: a systematic approach, Biochem J, 407 (2007) 69-77.

416. M. Sato, Y. Ueda, T. Takagi, Y. Umezawa, Production of PtdInsP3 at endomembranes is triggered by receptor endocytosis, Nat Cell Biol, 5 (2003) 10161022.

417. B. Ananthanarayanan, Q. Ni, J. Zhang, Signal propagation from membrane messengers to nuclear effectors revealed by reporters of phosphoinositide dynamics and Akt activity, Proc Natl Acad Sci U S A, 102 (2005) 15081-15086.

418. R. Heim, R.Y. Tsien, Engineering green fluorescent protein for improved brightness, longer wavelengths and fluorescence resonance energy transfer, Curr Biol, 6(1996) 178-182.

419. R.D. Mitra, C.M. Silva, D.C. Youvan, Fluorescence resonance energy transfer between blue-emitting and red-shifted excitation derivatives of the green fluorescent protein, Gene, 173 (1996) 13-17.

420. X. Xu, A.L. Gerard, B.C. Huang, D.C. Anderson, D.G Payan, Y. Luo, Detection of programmed cell death using fluorescence energy transfer, Nucleic Acids Res, 26 (1998) 2034-2035.

421. Q. Ni, D.V. Titov, J. Zhang, Analyzing protein kinase dynamics in living cells with FRET reporters, Methods, 40 (2006) 279-286.

422. J. Zhang, M.D. Allen, FRET-based biosensors for protein kinases: illuminating the kinome, Mol Biosyst, 3 (2007) 759-765.

423. M.D. Allen, J. Zhang, A tunable FRET circuit for engineering fluorescent biosensors, AngewChem Int Ed Engl, 47 (2008) 500-502.

424. J. Zhang, C.J. Hupfeld, S.S. Taylor, J.M. Olefsky, R.Y. Tsien, Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes, Nature, 437 (2005) 569573.

425. J. Zhang, Y. Ma, S.S. Taylor, R.Y. Tsien, Genetically encoded reporters of protein kinase A activity reveal impact of substrate tethering, Proc Natl Acad Sci U S A, 98 (2001) 14997-15002.

426. A. Schleifenbaum, G. Stier, A. Gasch, M. Sattler, C. Schultz, Genetically encoded FRET probe for PKC activity based on pleckstrin, J Am Chem Soc, 126 (2004)11786-11787.

427. J.D. Violin, J. Zhang, R.Y. Tsien, A.C. Newton, A genetically encoded fluorescent reporter reveals oscillatory phosphorylation by protein kinase C, J Cell Biol, 161 (2003) 899-909.

428. M.T. Kunkel, Q. Ni, R.Y. Tsien, J. Zhang, AC. Newton, Spatio-temporal dynamics of protein kinase B/Akt signaling revealed by a genetically encoded fluorescent reporter, J Biol Chem, 280 (2005) 5581-5587.

429. M. Sato, Y. Umezawa, Imaging protein phosphorylation by fluorescence in single living cells, Methods, 32 (2004) 451-455.

430. AY. Ting, K.H. Kain, R.L. Klemke, R.Y. Tsien, Genetically encoded fluorescent reporters of protein tyrosine kinase activities in living cells, Proc Natl Acad Sci U S A, 98 (2001) 15003-15008.

431. Y. Wang, E.L. Botvinick, Y. Zhao, M.W. Berns, S. Usami, R.Y. Tsien, S. Chien, Visualizing the mechanical activation of Src, Nature, 434 (2005) 1040-1045.

432. C D. Harvey, A G. Ehrhardt, C. Cellurale, H. Zhong, R. Yasuda, R.J. Davis, K. Svoboda, A genetically encoded fluorescent sensor of ERK activity, Proc Natl Acad Sci U S A, 105 (2008) 19264-19269.

433. M. Fosbrink, NN. Aye-Han, R. Cheong, A. Levchenko, J. Zhang, Visualization of JNK activity dynamics with a genetically encoded fluorescent biosensor, Proc Natl Acad Sci USA, 107 5459-5464.

434. R.E. Itoh, K. Kurokawa, A. Fujioka, A. Sharma, B.J. Mayer, M. Matsuda, A FRET-based probe for epidermal growth factor receptor bound non-covalently to a pair of synthetic amphipathic helixes, Exp Cell Res, 307 (2005) 142-152.

435. M. Offterdinger, V. Georget, A. Girod, P.I. Bastiaens, Imaging phosphorylation dynamics of the epidermal growth factor receptor, J Biol Chem, 279 (2004) 3697236981.

436. G.S. Baird, D.A. Zacharias, R.Y. Tsien, Circular permutation and receptor insertion within green fluorescent proteins, Proc Natl Acad Sci U S A, 96 (1999) 11241-11246.

437. Y. Li, A.M. Sierra, H.W. Ai, R E. Campbell, Identification of sites within a monomeric red fluorescent protein that tolerate peptide insertion and testing of corresponding circular permutations, Photochem Photobiol, 84 (2008) 111-119.

438. V.V. Belousov, A.F. Fradkov, K.A. Lukyanov, D.B. Staroverov, K.S. Shakhbazov, A.V. Terskikh, S. Lukyanov, Genetically encoded fluorescent indicator for intracellular hydrogen peroxide, Nat Methods, 3 (2006) 281-286.

439. M. Ohkura, M. Matsuzaki, H. Kasai, K. Imoto, J. Nakai, Genetically encoded bright Ca2+ probe applicable for dynamic Ca2+ imaging of dendritic spines, Anal Chem, 77 (2005) 5861-5869.

440. M.J. Berridge, Calcium microdomains: organization and function, Cell Calcium, 40 (2006)405-412.

441. H. Cheng, W.J. Lederer, Calcium sparks, Physiol Rev, 88 (2008) 1491-1545.

442. E. Dreosti, B. Odermatt, M.M. Dorostkar, L. Lagnado, A genetically encoded reporter of synaptic activity in vivo, Nat Methods, 6 (2009) 883-889.

443. L.H. Tay, I.E. Dick, W. Yang, M. Mank, O. Griesbeck, D.T. Yue, Nanodomain Ca(2)(+) of Ca(2)(+) channels detected by a tethered genetically encoded Ca(2)(+) sensor, Nat Commun, 3 (2012) 778.

444. Y. Zhao, S. Araki, J. Wu, T. Teramoto, Y.F. Chang, M. Nakano, A.S. Abdelfattah, M. Fujiwara, T. Ishihara, T. Nagai, R.E. Campbell, An expanded palette of genetically encoded Ca(2)(+) indicators, Science, 333 (2011) 1888-1891.

445. J. Berg, Y.P. Hung, G. Yellen, A genetically encoded fluorescent reporter of ATP:ADP ratio, Nat Methods, 6 (2009) 161-166.

446. N. Pollak, C. Dolle, M. Ziegler, The power to reduce: pyridine nucleotides— small molecules with a multitude of functions, Biochem J, 402 (2007) 205-218.

447. A. Holmgren, C. Johansson, C. Berndt, M.E. Lonn, C. Hudemann, C.H. Lillig, Thiol redox control via thioredoxin and glutaredoxin systems, Biochem Soc Trans, 33 (2005) 1375-1377.

448. Y. Zhao, J. Jin, Q. Hu, H.M. Zhou, J. Yi, Z. Yu, L. Xu, X. Wang, Y. Yang, J. Loscalzo, Genetically encoded fluorescent sensors for intracellular NADH detection, Cell Metab, 14 (2012) 555-566.

449. Y.P. Hung, J.G. Albeck, M. Tantama, G. Yellen, Imaging Cytosolic NADH-NAD(+) Redox State with a Genetically Encoded Fluorescent Biosensor, Cell Metab, 14(2011)545-554.

450. K.J. McLaughlin, C.M. Strain-Damerell, K. Xie, D. Brekasis, A S. Soares, M.S. Paget, C.L. Kielkopf, Structural basis for NADH/NAD+ redox sensing by a Rex family repressor, Mol Cell, 38 (2010) 563-575.

451. E.A. Sickmier, D. Brekasis, S. Paranawithana, J.B. Bonanno, M.S. Paget, S.K. Burley, C.L. Kielkopf, X-ray structure of a Rex-family repressor/NADH complex insights into the mechanism of redox sensing, Structure, 13 (2005) 43-54.

452. E. Wang, M.C. Bauer, A. Rogstam, S. Linse, D.T. Logan, C. von Wachenfeldt, Structure and functional properties of the Bacillus subtilis transcriptional repressor Rex, Mol Microbiol, 69 (2008) 466-478.

453. E.C. Schwarz, C. Kummerow, A.S. Wenning, K. Wagner, A. Sappok, K. Waggershauser, D. Griesemer, B. Strauss, M.J. Wolfs, A. Quintana, M. Hoth, Calcium dependence of T cell proliferation following focal stimulation, Eur J Immunol, 37 (2007) 2723-2733.

454. S.N. Ho, H.D. Hunt, R.M. Horton, J.K. Pullen, L.R. Pease, Site-directed mutagenesis by overlap extension using the polymerase chain reaction, Gene, 77 (1989) 51-59.

455. F.S. Wouters, P.I. Bastiaens, Fluorescence lifetime imaging of receptor tyrosine kinase activity in cells, Curr Biol, 9 (1999) 1127-1130.

456. I. Anderie, I. Schulz, A. Schmid, Characterization of the C-terminal ER membrane anchor of PTP1B, Exp Cell Res, 313 (2007) 3189-3197.

457. E.B. Van Munster, T.W. Gadella, Jr., phiFLIM: a new method to avoid aliasing in frequency-domain fluorescence lifetime imaging microscopy, J Microsc, 213 (2004) 29-38.

458. E. Oancea, T. Meyer, Protein kinase C as a molecular machine for decoding calcium and diacylglycerol signals, Cell, 95 (1998) 307-318.

459. J.D. Helmann, OxyR: a molecular code for redox sensing?, Science's STKE : signal transduction knowledge environment, 2002 (2002) pe46.

460. C. Lee, S.M. Lee, P. Mukhopadhyay, S.J. Kim, S.C. Lee, W.S. Ahn, M.H. Yu, G. Storz, S.E. Ryu, Redox regulation of OxyR requires specific disulfide bond formation involving a rapid kinetic reaction path, Nat Struct Mol Biol, 11 (2004) 1179-1185.

461. T. Nagai, K. Ibata, E.S. Park, M. Kubota, K. Mikoshiba, A. Miyawaki, A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications, Nat Biotechnol, 20 (2002) 87-90.

462. H. Choi, S. Kim, P. Mukhopadhyay, S. Cho, J. Woo, G. Storz, S. Ryu, Structural basis of the redox switch in the OxyR transcription factor, Cell, 105 (2001) 103-113.

463. A. Hausladen, C.T. Privalle, T. Keng, J. DeAngelo, J.S. Stamler, Nitrosative stress: activation of the transcription factor OxyR, Cell, 86 (1996) 719-729.

464. S. Fulda, E. Meyer, K.M. Debatin, Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression, Oncogene, 21 (2002) 2283-2294.

465. O.W. Rokhlin, N. Guseva, A. Tagiyev, C M. Knudson, MB. Cohen, Bcl-2 oncoprotein protects the human prostatic carcinoma cell line PC3 from TRAIL-mediated apoptosis, Oncogene, 20 (2001) 2836-2843.

466. S.A. Keogh, H. Walczak, L. Bouchier-Hayes, S.J. Martin, Failure of Bcl-2 to block cytochrome c redistribution during TRAIL-induced apoptosis, FEBS Lett, 471 (2000) 93-98.

467. H. Walczak, A. Bouchon, H. Stahl, P.H. Krammer, Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-xL-overexpressing chemotherapy-resistant tumor cells, Cancer Res, 60 (2000) 3051-3057.

468. K. Suzukawa, K. Miura, J. Mitsushita, J. Resau, K. Hirose, R. Crystal, T. Kamata, Nerve growth factor-induced neuronal differentiation requires generation of Racl-regulated reactive oxygen species, J Biol Chem, 275 (2000) 13175-13178.

469. I. Kullik, J. Stevens, M B. Toledano, G. Storz, Mutational analysis of the redox-sensitive transcriptional regulator OxyR: regions important for DNA binding and multimerization, J Bacterid, 177 (1995) 1285-1291.

470. I. Kullik, M.B. Toledano, L.A. Tartaglia, G. Storz, Mutational analysis of the redox-sensitive transcriptional regulator OxyR: regions important for oxidation and transcriptional activation, J Bacteriol, 177 (1995) 1275-1284.

471. P. Niethammer, C. Grabher, A.T. Look, T.J. Mitchison, A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish, Nature, 459 (2009) 996-999.

472. L. Pase, J.E. Layton, C. Wittmann, F. Ellett, C.J. Nowell, C.C. Reyes-Aldasoro, S. Varma, K.L. Rogers, C.J. Hall, M.C. Keightley, P S. Crosier, C. Grabher, J.K.

473. Heath, S.A. Renshaw, G.J. Lieschke, Neutrophil-delivered myeloperoxidase dampens the hydrogen peroxide burst after tissue wounding in zebrafish, Curr Biol, 22 (2012) 1818-1824.

474. P.I. Bastiaens, A. Squire, Fluorescence lifetime imaging microscopy: spatial resolution of biochemical processes in the cell, Trends Cell Biol, 9 (1999) 48-52.

475. E.B. van Munster, T.W. Gadella, Fluorescence lifetime imaging microscopy (FLIM), Adv Biochem Eng Biotechnol, 95 (2005) 143-175.

476. T. Nakabayashi, H.P. Wang, M. Kinjo, N. Ohta, Application of fluorescence lifetime imaging of enhanced green fluorescent protein to intracellular pH measurements, Photochem Photobiol Sci, 7 (2008) 668-670.

477. C.C. Winterbourn, Reconciling the chemistry and biology of reactive oxygen species, Nat Chem Biol, 4 (2008) 278-286.

478. M. Gutscher, M.C. Sobotta, G.H. Wabnitz, S. Ballikaya, A.J. Meyer, Y. Samstag, T.P. Dick, Proximity-based protein thiol oxidation by H202-scavenging peroxidases, J Biol Chem, 284 (2009) 31532-31540.

479. J. Schlessinger, Cell signaling by receptor tyrosine kinases, Cell, 103 (2000) 211-225.

480. K. Roepstorff, M.V. Grandal, L. Henriksen, S.L. Knudsen, M. Lerdrup, L. Grovdal, B.M. Willumsen, B. van Deurs, Differential effects of EGFR ligands on endocytic sorting of the receptor, Traffic, 10 (2009) 1115-1127.

481. A. Ostman, F.D. Bohmer, Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases, Trends Cell Biol, 11 (2001) 258-266.

482. A. Ostman, C. Hellberg, F.D. Bohmer, Protein-tyrosine phosphatases and cancer, Nat Rev Cancer, 6 (2006) 307-320.

483. A.J. Flint, T. Tiganis, D. Barford, N.K. Tonks, Development of "substrate-trapping" mutants to identify physiological substrates of protein tyrosine phosphatases, Proc Natl Acad Sci U S A, 94 (1997) 1680-1685.

484. I.A. Yudushkin, A. Schleifenbaum, A. Kinkhabwala, B.G. Neel, C. Schultz, P.I. Bastiaens, Live-cell imaging of enzyme-substrate interaction reveals spatial regulation ofPTPlB, Science, 315 (2007) 115-119.

485. D.P. Jones, Intracellular diffusion gradients of 02 and ATP, Am J Physiol, 250 (1986) C663-675.

486. D.P. Jones, F.G. Kennedy, Intracellular 02 gradients in cardiac myocytes. Lack of a role for myoglobin in facilitation of intracellular 02 diffusion, Biochem Biophys Res Commun, 105 (1982) 419-424.

487. D.P. Jones, H.S. Mason, Gradients of 02 concentration in hepatocytes, J Biol Chem, 253 (1978) 4874-4880.

488. Y.M. Go, D.M. Duong, J. Peng, D.P. Jones, Protein Cysteines Map to Functional Networks According to Steady-state Level of Oxidation, J Proteomics Bioinform, 4 (2012) 196-209.

489. H.J. Carlson, R.E. Campbell, Genetically encoded FRET-based biosensors for multiparameter fluorescence imaging, Curr Opin Biotechnol, 20 (2009) 19-27.

490. C. Schultz, A. Schleifenbaum, J. Goedhart, T.W. Gadella, Jr., Multiparameter imaging for the analysis of intracellular signaling, Chembiochem, 6 (2005) 1323-1330.

491. J. Brumbaugh, A. Schleifenbaum, A. Gasch, M. Sattler, C. Schultz, A dual parameter FRET probe for measuring PKC and PKA activity in living cells, J Am Chem Soc, 128 (2006) 24-25.

492. Y.S. Bae, J.Y. Sung, O S. Kim, Y.J. Kim, K.C. Hur, A. Kazlauskas, S.G. Rhee, Platelet-derived growth factor-induced H(2)0(2) production requires the activation of phosphatidylinositol 3-kinase, J Biol Chem, 275 (2000) 10527-10531.

493. X. Xu, M. Meier-Schellersheim, J. Yan, T. Jin, Locally controlled inhibitory mechanisms are involved in eukaryotic GPCR-mediated chemosensing, J Cell Biol, 178 (2007) 141-153.

494. W. Kolanus, B. Seed, Integrins and inside-out signal transduction: converging signals from PKC and PIP3, Curr Opin Cell Biol, 9 (1997) 725-731.

495. P. Varnai, T. Balla, Live cell imaging of phosphoinositides with expressed inositide binding protein domains, Methods, 46 (2008) 167-176.

496. F. Kanai, H. Liu, S.J. Field, H. Akbary, T. Matsuo, G.E. Brown, L.C. Cantley, M.B. Yaffe, The PX domains of p47phox and p40phox bind to lipid products of PI(3)K, Nat Cell Biol, 3 (2001) 675-678.

497. SR. Lee, K.S. Yang, J. Kwon, C. Lee, W. Jeong, S.G. Rhee, Reversible inactivation of the tumor suppressor PTEN by H202, J Biol Chem, 277 (2002) 2033620342.

498. M. Mentel, V. Laketa, D. Subramanian, H. Gillandt, C. Schultz, Photoactivatable and cell-membrane-permeable phosphatidylinositol 3,4,5-trisphosphate, Angew Chem Int Ed Engl, 50 (2011) 3811-3814.

499. C.R. Monks, B.A. Freiberg, H. Kupfer, N. Sciaky, A. Kupfer, Three-dimensional segregation of supramolecular activation clusters in T cells, Nature, 395 (1998) 82-86.

500. A. Quintana, C. Schwindling, A.S. Wenning, U. Becherer, J. Rettig, E C. Schwarz, M. Hoth, T cell activation requires mitochondrial translocation to the immunological synapse, ProcNatl Acad Sci U S A, 104 (2007) 14418-14423.

501. J. Harriague, G. Bismuth, Imaging antigen-induced PI3K activation in T cells, Nat Immunol, 3 (2002) 1090-1096.

502. P.S. Costello, M. Gallagher, D A. Cantrell, Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse, Nat Immunol, 3 (2002) 1082-1089.

503. J. Kwon, K.E. Shatynski, H. Chen, S. Morand, X. de Deken, F. Miot, T.L. Leto, M.S. Williams, The nonphagocytic NADPH oxidase Duoxl mediates a positive feedback loop during T cell receptor signaling, Sci Signal, 3 (2010) ra59.

504. M.G. Bonini, C. Rota, A. Tomasi, R.P. Mason, The oxidation of 2',7'-dichlorofluorescin to reactive oxygen species: a self-fulfilling prophesy?, Free Radic Biol Med, 40 (2006) 968-975.

505. R.S. Flannagan, G. Cosio, S. Grinstein, Antimicrobial mechanisms of phagocytes and bacterial evasion strategies, Nat Rev Microbiol, 7 (2009) 355-366.

506. R.M. Smith, J.T. Curnutte, Molecular basis of chronic granulomatous disease, Blood, 77 (1991) 673-686.

507. Y.A. Suh, R.S. Arnold, B. Lassegue, J. Shi, X. Xu, D. Sorescu, A.B. Chung, K.K. Griendling, J.D. Lambeth, Cell transformation by the superoxide-generating oxidase Moxl, Nature, 401 (1999) 79-82.

508. A.R. Reynolds, C. Tischer, P.J. Verveer, O. Rocks, P.I. Bastiaens, EGFR activation coupled to inhibition of tyrosine phosphatases causes lateral signal propagation, Nat Cell Biol, 5 (2003) 447-453.

509. H.J. Forman, M. Torres, Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling, Am J Respir Crit Care Med, 166 (2002) S4-8.

510. S.M. Zughaier, W.M. Shafer, D.S. Stephens, Antimicrobial peptides and endotoxin inhibit cytokine and nitric oxide release but amplify respiratory burst response in human and murine macrophages, Cell Microbiol, 7 (2005) 1251-1262.

511. W. Ying, NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences, Antioxid Redox Signal, 10 (2008) 179206.

512. S. Bruzzone, S. Kunerth, E. Zocchi, A. De Flora, A.H. Guse, Spatio-temporal propagation of Ca2+ signals by cyclic ADP-ribose in 3T3 cells stimulated via purinergic P2Y receptors, J Cell Biol, 163 (2003) 837-845.

513. A. De Flora, E. Zocchi, L. Guida, L. Franco, S. Bruzzone, Autocrine and paracrine calcium signaling by the CD38/NAD+/cyclic ADP-ribose system, Ann N Y Acad Sci, 1028 (2004) 176-191.

514. A.H. Guse, Second messenger function and the structure-activity relationship of cyclic adenosine diphosphonbose (cADPR), FEBS J, 272 (2005) 4590-4597.

515. H. Higashida, M. Hashn, S. Yokoyama, N. Hoshi, K. Asai, T. Kato, Cyclic ADP-ribose as a potential second messenger for neuronal Ca2+ signaling, J Neurochem, 76 (2001) 321-331.

516. T. Inoue, M. Hiratsuka, M. Osaki, M. Oshimura, The molecular biology of mammalian SIRT proteins: SIRT2 in cell cycle regulation, Cell Cycle, 6 (2007) 10111018.

517. W. Xie, A. Xu, E.S. Yeung, Determination of NAD(+) and NADH in a single cell under hydrogen peroxide stress by capillary electrophoresis, Anal Chem, 81 (2009) 1280-1284.

518. D.H. Williamson, P. Lund, H.A. Krebs, The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver, Biochem J, 103 (1967) 514-527.

519. W. Ying, NAD+ and NADH in cellular functions and cell death, Front Biosci, 11 (2006)3129-3148.

520. B. Liang, H.R. Petty, Imaging neutrophil activation: analysis of the translocation and utilization of NAD(P)H-associated autofluorescence during antibody-dependent target oxidation, J Cell Physiol, 152 (1992) 145-156.

521. L. Pan, X. Zhang, K. Song, B. Tang, W. Cai, X. Wu, R.A. Rupp, J. Xu, Realtime imaging of autofluorescence NAD(P)H in single human neutrophils, Appl Opt, 48 (2009) 1042-1046.

522. D.W. Piston, B.R. Masters, W.W. Webb, Three-dimensionally resolved NAD(P)H cellular metabolic redox imaging of the in situ cornea with two-photon excitation laser scanning microscopy, J Microsc, 178 (1995) 20-27.

523. J.V. Rocheleau, W.S. Head, D.W. Piston, Quantitative NAD(P)H/flavoprotein autofluorescence imaging reveals metabolic mechanisms of pancreatic islet pyruvate response, J Biol Chem, 279 (2004) 31780-31787.

524. M. Malinouski, Y. Zhou, V.V. Belousov, D.L. Hatfield, V.N. Gladyshev, Hydrogen peroxide probes directed to different cellular compartments, PLoS ONE, 6 (2011)el4564.

525. N.M. Mishina, P.A. Tyurin- Kuzmin, K.N. Markvicheva, A.V. Vorotnikov, V.A. Tkachuk, V. Laketa, C. Schultz, S. Lukyanov, V.V. Belousov, Does cellular hydrogen peroxide diffuse or act locally?, Antioxid Redox Signal, 14 (2011) 1-7.

526. A. Costa, I. Drago, S. Behera, M. Zottini, P. Pizzo, J.I. Schroeder, T. Pozzan, F. Lo Schiavo, H202 in plant peroxisomes: an in vivo analysis uncovers a Ca(2+)-dependent scavenging system, Plant J, 62 (2010) 760-772.

527. M. Eisner, W. Gehrmann, S. Lenzen, Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells, Diabetes, 60 (2011) 200-208.

528. B. Enyedi, P. Varnai, M. Geiszt, Redox state of the endoplasmic reticulum is controlled by ErolL-alpha and intraluminal calcium, Antioxid Redox Signal, 13 (2010)721-729.

529. K. Brejc, T.K. Sixma, P.A. Kitts, SR. Kain, R.Y. Tsien, M. Ormo, S.J. Remington, Structural basis for dual excitation and photoisomerization of the Aequorea victoria green fluorescent protein, Proc Natl Acad Sci U S A, 94 (1997) 2306-2311.

530. M.A. Elsliger, R.M. Wachter, G.T. Hanson, K. Kallio, S.J. Remington, Structural and spectral response of green fluorescent protein variants to changes in pH, Biochemistry, 38 (1999) 5296-5301.

531. M. Tantama, Y.P. Hung, G. Yellen, Imaging intracellular pH in live cells with a genetically encoded red fluorescent protein sensor, J Am Chem Soc, 133 (2011) 10034-10037.

532. Y. Li, R.W. Tsien, pHTomato, a red, genetically encoded indicator that enables multiplex interrogation of synaptic activity, NatNeurosci, 15 (2012) 1047-1053.

533. H. Ostergaard, A. Henriksen, F.G. Hansen, JR. Winther, Shedding light on disulfide bond formation: engineering a redox switch in green fluorescent protein, EMBO J, 20 (2001) 5853-5862.

534. H. Ostergaard, C. Tachibana, J R. Winther, Monitoring disulfide bond formation in the eukaryotic cytosol, J Cell Biol, 166 (2004) 337-345.

535. O. Bjornberg, H. Ostergaard, J.R. Winther, Mechanistic insight provided by glutaredoxin within a fusion to redox-sensitive yellow fluorescent protein, Biochemistry, 45 (2006) 2362-2371.

536. M. Gutscher, A.L. Pauleau, L. Marty, T. Brach, G.H. Wabnitz, Y. Samstag, A.J. Meyer, T.P. Dick, Real-time imaging of the intracellular glutathione redox potential, Nat Methods, 5 (2008) 553-559.

537. C.T. Dooley, T.M. Dore, G.T. Hanson, W.C. Jackson, S.J. Remington, R.Y. Tsien, Imaging dynamic redox changes in mammalian cells with green fluorescent protein indicators, J Biol Chem, 279 (2004) 22284-22293.

538. G.T. Hanson, R. Aggeler, D. Oglesbee, M. Cannon, R.A. Capaldi, R.Y. Tsien, S.J. Remington, Investigating mitochondrial redox potential with redox-sensitive green fluorescent protein indicators, J Biol Chem, 279 (2004) 13044-13053.

539. A.J. Meyer, T.P. Dick, Fluorescent protein-based redox probes, Antioxid Redox Signal, 13 (2010) 621-650.

540. A.J. Meyer, T. Brach, L. Marty, S. Kreye, N. Rouhier, J.P. Jacquot, R. Hell, Redox-sensitive GFP in Arabidopsis thaliana is a quantitative biosensor for the redox potential of the cellular glutathione redox buffer, Plant J, 52 (2007) 973-986.

541. B. Morgan, M.C. Sobotta, T.P. Dick, Measuring E(GSH) and H202 with roGFP2-based redox probes, Free Radic Biol Med, 51 (2012) 1943-1951.

542. A. Delaunay, D. Pflieger, M.B. Barrault, J. Vinh, MB. Toledano, A thiol peroxidase is an H202 receptor and redox-transducer in gene activation, Cell, 111 (2002)471-481.

543. V.L. Kolossov, B.Q. Spring, A. Sokolowski, J.E. Conour, R.M. Clegg, P.J. Kenis, H.R. Gaskins, Engineering redox-sensitive linkers for genetically encoded FRET-based biosensors, Exp Biol Med (Maywood), 233 (2008) 238-248.

544. V.L. Kolossov, B.Q. Spring, R.M. Clegg, J.J. Henry, A. Sokolowski, P.J. Kenis, H.R. Gaskins, Development of a high-dynamic range, GFP-based FRET probe sensitive to oxidative microenvironments, Exp Biol Med (Maywood), 236 (2011) 681691.

545. V.L. Kolossov, M.T. Leslie, A. Chatterjee, B.M. Sheehan, P.J. Kenis, H.R. Gaskins, Forster resonance energy transfer-based sensor targeting endoplasmicreticulum reveals highly oxidative environment, Exp Biol Med (Maywood), 237 (2012) 652-662

546. J R Lohman, S J Remington, Development of a family of redox-sensitive green fluorescent protein indicators for use in relatively oxidizing subcellular environments, Biochemistry, 47 (2008) 8678-8688

547. В Enyedi, M Zana, A Donko, M Geiszt, Spatial and Temporal Analysis of NADPH Oxidase-Generated Hydrogen Peroxide Signals by Novel Fluorescent Reporter Proteins, Antioxid Redox Signal, (2012)

548. W Wang, H Fang, L Groom, A Cheng, W Zhang, J Liu, X Wang, K Li, P Han, M Zheng, J Yin, M P Mattson, J P Kao, E G Lakatta, S S Sheu, K Ouyang, J Chen, RT Dirksen, H Cheng, Superoxide flashes in single mitochondria, Cell, 134 (2008) 279-290

549. FL Muller, A critical evaluation of cpYFP as a probe for superoxide, Free Radic Biol Med, 47 (2009) 1779-1780

550. M Schwarzlander, M P Murphy, M R Duchen, D C Logan, M D Fricker, A P Halestrap, F L Muller, R Rizzuto, T P Dick, A J Meyer, L J Sweetlove, Mitochondrial 'flashes' a radical concept repHined, Trends Cell Biol, 22 (2012) 503508

551. E Quatresous, C Legrand, S Pouvreau, Mitochondria-targeted cpYFP pH or superoxide sensor?, J Gen Physiol, 140 (2012) 567-570

552. K N Markvicheva, D S Bilan, N M Mishina, A Y Gorokhovatsky, L M Vinokurov, S Lukyanov, V V Belousov, A genetically encoded sensor for H202 with expanded dynamic range, Bioorg Med Chem, 19 (2011) 1079-1084

553. KN Markvicheva, EA Bogdanova, DB Staroverov, S Lukyanov, VV Belousov, Imaging of intracellular hydrogen peroxide production with HyPer upon stimulation of HeLa cells with epidermal growth factor, Methods Мої Biol, 476 (2008) 79-86

554. A. Espinosa, A. Garcia, S. Hartel, C. Hidalgo, E. Jaimovich, NADPH oxidase and hydrogen peroxide mediate insulin-induced calcium increase in skeletal muscle cells, J Biol Chem, 284 (2009) 2568-2575.

555. J. Jiang, A. Maeda, J. Ji, C.J. Baty, S.C. Watkins, J.S. Greenberger, V.E. Kagan, Are mitochondrial reactive oxygen species required for autophagy?, Biochem Biophys Res Commun, 412 (2011) 55-60.

556. N.M. Mishina, I. Bogeski, D A. Bolotin, M. Hoth, B.A. Niemeyer, C. Schultz, E.V. Zagaynova, S. Lukyanov, V.V. Belousov, Can We See PIP(3) and Hydrogen Peroxide with a Single Probe?, Antioxid Redox Signal, (2012).

557. N R. Love, Y. Chen, S. Ishibashi, P. Kritsiligkou, R. Lea, Y. Koh, J.L. Gallop, K. Dorey, E. Amaya, Amputation-induced reactive oxygen species are required for successful Xenopus tadpole tail regeneration, Nat Cell Biol, 15 (2013) 222-228.

558. S. Bieker, L. Riester, M. Stahl, J. Franzaring, U. Zentgraf, Senescence-specific alteration of hydrogen peroxide levels in Arabidopsis thaliana and oilseed rape spring variety Brassica napus L. cv. Mozart, J Integr Plant Biol, 54 (2012) 540-554.

559. S.C. Albrecht, A G. Barata, J. Grosshans, A.A. Teleman, T P. Dick, In vivo mapping of hydrogen peroxide and oxidized glutathione reveals chemical and regional specificity of redox homeostasis, Cell Metab, 14 (2012) 819-829.

560. D. Knoefler, M. Thamsen, M. Koniczek, N.J. Niemuth, A.K. Diederich, U. Jakob, Quantitative in vivo redox sensors uncover oxidative stress as an early event in life, Mol Cell, 47 (2012) 767-776.

561. D. Shcherbo, E M. Merzlyak, T V. Chepurnykh, A.F. Fradkov, G.V. Ermakova, E.A. Solovieva, K.A. Lukyanov, E.A. Bogdanova, A.G. Zaraisky, S. Lukyanov, D.M.

562. Chudakov, Bright far-red fluorescent protein for whole-body imaging, Nat Methods, 4 (2007) 741-746.

563. G.S. Filonov, K.D. Piatkevich, L.M. Ting, J. Zhang, K. Kim, V.V. Verkhusha, Bright and stable near-infrared fluorescent protein for in vivo imaging, Nat Biotechnol, 29 (2011) 757-761.

564. X. Shu, A. Royant, M.Z. Lin, T A. Aguilera, V. Lev-Ram, P.A. Steinbach, R.Y. Tsien, Mammalian expression of infrared fluorescent proteins engineered from a bacterial phytochrome, Science, 324 (2009) 804-807.