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Genetically encoded voltage indicator

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protein biosensors and actuators, once it passes the initial threshold of practicality, there will be more attempts to reshape the tool for its usage in different target applications, each with a different emphasis and requirement for a subset of performance metrics. For example, authors of JEDI-2P stated that the negative-going (bright-to-dim) sensor is good for detecting subthreshold depolarizations and hyperpolarizations but positive-going (dim-to-bright) sensors might be better for spike detection. We may argue that it takes effort to engineer (screen) a perfect sensor, but often the more compelling reason is that simply there is not a unanimous definition of such perfection. For example, scientist might prefer sensors of different emission and excitation colors to be spectrally compatible with other
3493: 774:. It has subcellular spatial resolution and temporal resolution as low as 0.2 milliseconds, about an order of magnitude faster than calcium imaging. This allows for spike detection fidelity comparable to electrode-based electrophysiology but without the invasiveness. Researchers have used it to probe neural communications of an intact brain (of 86:
GEVI can have many configuration designs in order to realize voltage sensing function. An essential feature of GEVI structure is that it must situate on the cell membrane. Conceptually, the structure of a GEVI should permit the function of sensing the voltage difference and reporting it by change in
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Despite that the idea of optical measurement of neuronal activity was proposed in the late 1960s, the first successful GEVI that was convenient enough to put into actual use was not developed until technologies of genetic engineering had become mature in the late 1990s. The first GEVI, coined FlaSh,
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For GEVI development, its future direction is highly coupled with the target applications. With newer generations of GEVIs overcome the poor performance of the first generation ones, we will see more routes open up for GEVIs to be used in more challenging and versatile applications. Like many other
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Piatkevich, Kiryl D.; Jung, Erica E.; Straub, Christoph; Linghu, Changyang; Park, Demian; Suk, Ho-Jun; Hochbaum, Daniel R.; Goodwin, Daniel; Pnevmatikakis, Eftychios; Pak, Nikita; Kawashima, Takashi; Yang, Chao-Tsung; Rhoades, Jeffrey L.; Shemesh, Or; Asano, Shoh; Yoon, Young-Gyu; Freifeld, Limor;
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Piatkevich, Kiryl D.; Jung, Erica E.; Straub, Christoph; Linghu, Changyang; Park, Demian; Suk, Ho-Jun; Hochbaum, Daniel R.; Goodwin, Daniel; Pnevmatikakis, Eftychios; Pak, Nikita; Kawashima, Takashi; Yang, Chao-Tsung; Rhoades, Jeffrey L.; Shemesh, Or; Asano, Shoh; Yoon, Young-Gyu; Freifeld, Limor;
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By structure, GEVIs can be classified into four categories based on the current findings: (1) GEVIs contain a fluorescent protein FRET pair, e.g. VSFP1, (2) Single opsin GEVIs, e.g. Arch, (3) Opsin-FP FRET pair GEVIs, e.g. MacQ-mCitrine, (4) single FP with special types of voltage sensing domains,
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Piatkevich, Kiryl D.; Bensussen, Seth; Tseng, Hua-an; Shroff, Sanaya N.; Lopez-Huerta, Violeta Gisselle; Park, Demian; Jung, Erica E.; Shemesh, Or A.; Straub, Christoph; Gritton, Howard J.; Romano, Michael F.; Costa, Emma; Sabatini, Bernardo L.; Fu, Zhanyan; Boyden, Edward S.; Han, Xue (October
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survey of the organism. Some GEVIs might have similar components, but with different positioning of them. For example, ASAP1 and ArcLight both use a VSD and one FP, but the FP of ASAP1 is on the outside of the cell whereas that of ArcLight is on the inside, and the two FPs of VSFP-Butterfly are
67:). Unlike fluorescent proteins, the discovery of new GEVIs were seldom inspired by the nature, for it is hard to find an organism which naturally has the ability to change its fluorescence based on voltage. Therefore, new GEVIs are mostly the products of genetic and protein engineering. 3017:
Liu, Zhuohe; Lu, Xiaoyu; Villette, Vincent; Gou, Yueyang; Colbert, Kevin L.; Lai, Shujuan; Guan, Sihui; Land, Michelle A.; Lee, Jihwan; Assefa, Tensae; Zollinger, Daniel R.; Korympidou, Maria M.; Vlasits, Anna L.; Pang, Michelle M.; Su, Sharon (2022-08-18).
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fluorescence. Usually, the voltage-sensing domain (VSD) of a GEVI spans across the membrane, and is connected to the fluorescent protein(s). However, it is not necessary that sensing and reporting should happen in different structures, e.g. Archons.
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Villette, V; Chavarha, M; Dimov, IK; Bradley, J; Pradhan, L; Mathieu, B; Evans, SW; Chamberland, S; Shi, D; Yang, R; Kim, BB; Ayon, A; Jalil, A; St-Pierre, F; Schnitzer, MJ; Bi, G; Toth, K; Ding, J; Dieudonné, S; Lin, MZ (12 December 2019).
754:), plasma membrane localization, adaptability of deep-tissue imaging, etc. For now, no existing GEVI meets all the desired properties, so searching for a perfect GEVI is still a quite competitive research area. 1288:
Saulnier, Jessica L.; Riegler, Clemens; Engert, Florian; Hughes, Thom; Drobizhev, Mikhail; Szabo, Balint; Ahrens, Misha B.; Flavell, Steven W.; Sabatini, Bernardo L.; Boyden, Edward S. (April 2018).
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Saulnier, Jessica L.; Riegler, Clemens; Engert, Florian; Hughes, Thom; Drobizhev, Mikhail; Szabo, Balint; Ahrens, Misha B.; Flavell, Steven W.; Sabatini, Bernardo L.; Boyden, Edward S. (April 2018).
2985:"We fused paQuasAr3 with a trafficking motif from the soma-localized KV2.1 potassium channel, which led to largely soma-localized expression (Fig. 2a, b). We called this construct paQuasAr3-s." 746:
A GEVI can be evaluated by its many characteristics. These traits can be classified into two categories: performance and compatibility. The performance properties include brightness,
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Zhang, Joe Z.; Termglinchan, Vittavat; Shao, Ning-Yi; Itzhaki, Ilanit; Liu, Chun; Ma, Ning; Tian, Lei; Wang, Vicky Y.; Chang, Alex C. Y.; Guo, Hongchao; Kitani, Tomoya (2019-05-02).
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Different types of GEVIs are being developed in many biological or physiological research areas. It is thought to be superior to conventional voltage detecting methods like
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Chamberland, S; Yang, HH; Pan, MM; Evans, SW; Guan, S; Chavarha, M; Yang, Y; Salesse, C; Wu, H; Wu, JC; Clandinin, TR; Toth, K; Lin, MZ; St-Pierre, F (27 July 2017).
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signals from cultured cells, live animals, and ultimately human brain. Examples of notable GEVIs include ArcLight, ASAP1, ASAP3, Archons, SomArchon, and Ace2N-mNeon.
78:. The former method contributes to the most of new GEVI variants, but recent researches using directed evolution have shown promising results in GEVI optimization. 807:. Recently, to compensate for the low signal-to-noise ratio (SNR) due to the poor brightness of GEVI, several denoising methods have been applied to increase SNR. 3261: 1661:
Baker BJ, Lee H, Pieribone VA, et al. (2007). "Three fluorescent protein voltage sensors exhibit low plasma membrane expression in mammalian cells".
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Kralj JM, Hochbaum DR, Douglass AD, et al. (2011). "Electrical spiking in Escherichia coli probed with a fluorescent voltage-indicating protein".
1347:"Directed Evolution of Key Residues in Fluorescent Protein Inverses the Polarity of Voltage Sensitivity in the Genetically Encoded Indicator ArcLight" 3457: 1498:
Sakai R, Repunte-Canonigo V, Raj CD, et al. (2001). "Design and characterization of a DNA-encoded, voltage-sensitive fluorescent protein".
3383: 1970:"Genetically encoded fluorescent voltage sensors using the voltage-sensing domain of Nematostella and Danio phosphatases exhibit fast kinetics" 3309:"A Human iPSC Double-Reporter System Enables Purification of Cardiac Lineage Subpopulations with Distinct Function and Drug Response Profiles" 2611:"Pado, a fluorescent protein with proton channel activity can optically monitor membrane potential, intracellular pH, and map gap junctions" 1500: 1767:
Tsutsui H, Karasawa S, Okamura Y, et al. (2008). "Improving membrane voltage measurements using FRET with new fluorescent proteins".
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Murata Y, Iwasaki H, Sasaki M, et al. (2005). "Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor".
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Knöpfel T, Gallero-Salas Y, Song C (2015). "Genetically encoded voltage indicators for large scale cortical imaging come of age".
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Akemann W, Mutoh H, Perron A, et al. (2012). "Imaging neural circuit dynamics with a voltage-sensitive fluorescent protein".
1974: 1663: 3000: 823: 97: 3529: 2720:"A Bright and Fast Red Fluorescent Protein Voltage Indicator That Reports Neuronal Activity in Organotypic Brain Slices" 2021:"Single action potentials and subthreshold electrical events imaged in neurons with a fluorescent protein voltage probe" 850:"Single action potentials and subthreshold electrical events imaged in neurons with a fluorescent protein voltage probe" 2438:"Archaerhodopsin variants with enhanced voltage-sensitive fluorescence in mammalian and Caenorhabditis elegans neurons" 3081: 2724: 1818: 1708:"Engineering of a genetically encodable fluorescent voltage sensor exploiting fast Ci-VSP voltage-sensing movements" 3534: 3376: 2184: 2282: 1351: 750:, sensitivity, kinetics (speed), linearity of response, etc., while the compatibility properties cover toxicity ( 60: 2828:"Fast two-photon imaging of subcellular voltage dynamics in neuronal tissue with genetically encoded indicators" 904:"High-fidelity optical reporting of neuronal electrical activity with an ultrafast fluorescent voltage sensor" 3496: 3524: 1868: 1188:
Cohen LB, Keynes RD, Hille B (1968). "Light scattering and birefringence changes during nerve activity".
3519: 3478: 3369: 2994: 2442: 2333: 771: 763: 2278:"Improved detection of electrical activity with a voltage probe based on a voltage-sensing phosphatase" 2950: 2891: 2879:"Biophysical Characterization of Genetically Encoded Voltage Sensor ASAP1: Dynamic Range Improvement" 2782: 2623: 2512: 2450: 2341: 2232: 2136: 1926: 1721: 1615: 1556: 1456: 1199: 1142: 1077: 804: 2883: 2770:"Improving a genetically encoded voltage indicator by modifying the cytoplasmic charge composition" 2224: 1548: 908: 791: 3020:"Sustained deep-tissue voltage recording using a fast indicator evolved for two-photon microscopy" 2774: 2615: 2499:"High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor" 1950: 1794: 1688: 1524: 1480: 1290:"A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters" 1223: 1131:"High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor" 1008:"A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters" 620: 334: 93: 75: 31: 2558:"Single-molecule fluorimetry and gating currents inspire an improved optical voltage indicator" 3426: 3348: 3330: 3289: 3237: 3201: 3150: 3107: 3057: 3039: 2976: 2917: 2859: 2808: 2750: 2700: 2649: 2591: 2538: 2503: 2476: 2418: 2367: 2309: 2258: 2200: 2164: 2103: 2052: 2001: 1942: 1917: 1894: 1844: 1786: 1749: 1680: 1643: 1582: 1516: 1472: 1427: 1377: 1327: 1309: 1269: 1215: 1170: 1129:
Gong, Y; Huang, C; Li, JZ; Grewe, BF; Zhang, Y; Eismann, S; Schnitzer, MJ (11 December 2015).
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separated by the VSD, while the two FPs of Mermaid are relatively close to each other.
3431: 3421: 2387:"All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins" 767: 2123:"A fluorescent, genetically-encoded voltage probe capable of resolving action potentials" 2072:"Optical recording of action potentials in mammalian neurons using a microbial rhodopsin" 848:
Jin, L; Han, Z; Platisa, J; Wooltorton, JR; Cohen, LB; Pieribone, VA (6 September 2012).
2954: 2895: 2786: 2627: 2516: 2454: 2345: 2236: 2140: 1930: 1725: 1619: 1560: 1460: 1203: 1146: 1081: 3343: 3308: 3284: 3256: 3196: 3174: 3169: 3131: 3102: 3076: 3052: 3019: 2971: 2936: 2912: 2878: 2854: 2827: 2803: 2769: 2745: 2719: 2695: 2673: 2668: 2644: 2610: 2586: 2557: 2533: 2498: 2471: 2437: 2413: 2391: 2386: 2362: 2328: 2304: 2277: 2253: 2219: 2159: 2122: 2098: 2076: 2071: 2047: 2020: 1996: 1969: 1889: 1863: 1839: 1813: 1769: 1744: 1707: 1638: 1601: 1577: 1543: 1422: 1396: 1372: 1346: 1322: 1289: 1165: 1130: 1106: 1065: 1040: 1007: 982: 957: 929: 903: 876: 849: 747: 71: 2669:"Subcellular Imaging of Voltage and Calcium Signals Reveals Neural Processing In Vivo" 1568: 1264: 1245: 958:"Ultrafast Two-Photon Imaging of a High-Gain Voltage Indicator in Awake Behaving Mice" 3513: 3416: 1512: 1397:"The evolving capabilities of rhodopsin-based genetically encoded voltage indicators" 751: 265: 1798: 1602:"Engineering and characterization of an enhanced fluorescent protein voltage sensor" 1528: 3392: 3093: 2736: 1987: 1954: 1880: 1830: 1692: 1676: 1484: 1227: 43: 39: 1544:"A genetically targetable fluorescent probe of channel gating with rapid kinetics" 2329:"Imaging neural spiking in brain tissue using FRET-opsin protein voltage sensors" 2295: 2149: 2038: 1734: 1628: 1363: 866: 64: 3325: 3233: 3187: 3145: 3126: 3035: 2794: 2686: 2244: 1413: 973: 2962: 2903: 1305: 1089: 1023: 776: 3334: 3043: 2220:"Improving FRET Dynamic Range with Bright Green and Red Fluorescent Proteins" 1313: 1097: 1031: 2524: 1938: 1155: 3352: 3293: 3241: 3205: 3154: 3111: 3061: 2980: 2921: 2863: 2812: 2754: 2704: 2653: 2595: 2542: 2480: 2422: 2371: 2313: 2262: 2204: 2168: 2107: 2056: 2005: 1946: 1898: 1848: 1790: 1753: 1684: 1647: 1586: 1520: 1476: 1431: 1381: 1331: 1174: 1115: 1049: 991: 938: 885: 3274: 3170:"Genetically targeted optical electrophysiology in intact neural circuits" 2196: 1273: 1219: 2127: 1712: 1606: 781: 101: 2844: 2576: 1468: 2462: 2404: 2353: 2089: 1782: 35: 27: 3077:"Genetically Encoded Voltage Indicators: Opportunities and Challenges" 2635: 1211: 950: 948: 920: 100:(Ci-VSP or Ci-VSD (domain)), which was discovered in 2005 from the 2562: 3257:"Genetically Encoded Voltage Indicators in Circulation Research" 3127:"Neuronal Computations Made Visible with Subcellular Resolution" 2989:"QuasAr2(K171R)-TS-citrine-TS-TS-TS-ER2, which we call QuasAr3." 3365: 3361: 2987:"We called QuasAr3(V59A) 'photoactivated QuasAr3' (paQuasAr3)." 1066:"Population imaging of neural activity in awake behaving mice" 1246:"A genetically encoded optical probe of membrane voltage" 2070:
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Barnett L, Platisa J, Popovic M, et al. (2012).
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Cao G, Platisa J, Pieribone VA, et al. (2013).
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Opin. Chem. Biol. 2525:10.1126/science.aab0810 1939:10.1126/science.1204763 1402:Curr. Opin. Chem. Biol. 1294:Nature Chemical Biology 1156:10.1126/science.aab0810 1012:Nature Chemical Biology 530:FRET doner: mNeonGreen 527:Modified Ace rhodopsin 772:voltage sensitive dyes 729: 154:Rat Kv2.1 (K channel) 3479:Voltage-sensitive dye 3400:Optogenetic actuators 3275:10.3390/ijms160921626 3030:(18): 3408–3425.e29. 2197:10.1152/jn.00452.2012 805:optogenetic actuators 1975:J. Neurosci. Methods 1664:J. Neurosci. Methods 968:(7): 1590–1608.e23. 828:Openoptogenetics.org 48:electrophysiological 42:. It is a promising 3530:Protein engineering 3441:Optogenetic sensors 2955:2019Natur.569..413A 2896:2017BpJ...113.2178L 2845:10.7554/eLife.25690 2787:2017NatSR...7.8286L 2628:2016NatSR...623865K 2577:10.7554/eLife.10482 2517:2015Sci...350.1361G 2511:(6266): 1361–1366. 2455:2014NatCo...5.4894F 2346:2014NatCo...5.3674G 2283:J. Physiol. (Lond.) 2237:2013BpJ...104..683L 2141:2012PLoSO...743454B 1931:2011Sci...333..345K 1726:2008PLoSO...3.2514L 1620:2007PLoSO...2..440D 1561:2002BpJ....82..509A 1555:(1 Pt 1): 509–516. 1469:10.1038/nature03650 1461:2005Natur.435.1239M 1455:(7046): 1239–1243. 1352:ACS Chem. Neurosci. 1204:1968Natur.218..438C 1147:2015Sci...350.1361G 1082:2019Natur.574..413P 137:Shaker (K channel) 110: 3472:Related techniques 3268:(9): 21626–21642. 2463:10.1038/ncomms5894 2405:10.1038/nmeth.3000 2354:10.1038/ncomms4674 2090:10.1038/nmeth.1782 1783:10.1038/nmeth.1235 279:Red-shifted VSFP's 211:Kv1.4 (K channel) 160:pair: CFP and YFP 108: 94:Ciona intestinalis 76:directed evolution 32:membrane potential 3535:Electrophysiology 3507: 3506: 3427:Bacteriorhodopsin 3319:(5): 802–811.e5. 3262:Int. J. Mol. Sci. 3088:(39): 9977–9989. 2949:(7756): 413–417. 2890:(10): 2178–2181. 2636:10.1038/srep23865 2290:(18): 4427–4437. 1925:(6040): 345–348. 1875:(12): 1268–1277. 1825:(21): 5582–5593. 1507:(12): 2314–2318. 1501:Eur. J. Neurosci. 1198:(5140): 438–441. 1076:(7778): 413–417. 798:Future directions 728: 727: 468:QuasAr1, QuasAr2 360:Archaerhodopsin 3 40:fluorescent level 3542: 3495: 3494: 3411:Anion-conducting 3407:Channelrhodopsin 3386: 3379: 3372: 3363: 3357: 3356: 3346: 3328: 3304: 3298: 3297: 3287: 3277: 3252: 3246: 3245: 3216: 3210: 3209: 3199: 3165: 3159: 3158: 3148: 3122: 3116: 3115: 3105: 3072: 3066: 3065: 3055: 3014: 3005: 3004: 2998: 2990: 2974: 2932: 2926: 2925: 2915: 2874: 2868: 2867: 2857: 2847: 2823: 2817: 2816: 2806: 2765: 2759: 2758: 2748: 2731:(8): 2458–2472. 2715: 2709: 2708: 2698: 2664: 2658: 2657: 2647: 2606: 2600: 2599: 2589: 2579: 2553: 2547: 2546: 2536: 2494: 2485: 2484: 2474: 2433: 2427: 2426: 2416: 2382: 2376: 2375: 2365: 2324: 2318: 2317: 2307: 2273: 2267: 2266: 2256: 2231:(2): 1005–1012. 2215: 2209: 2208: 2191:(8): 2323–2337. 2185:J. Neurophysiol. 2179: 2173: 2172: 2162: 2152: 2118: 2112: 2111: 2101: 2067: 2061: 2060: 2050: 2016: 2010: 2009: 1999: 1965: 1959: 1958: 1912: 1903: 1902: 1892: 1859: 1853: 1852: 1842: 1809: 1803: 1802: 1764: 1758: 1757: 1747: 1737: 1703: 1697: 1696: 1658: 1652: 1651: 1641: 1631: 1597: 1591: 1590: 1580: 1539: 1533: 1532: 1495: 1489: 1488: 1442: 1436: 1435: 1425: 1392: 1386: 1385: 1375: 1342: 1336: 1335: 1325: 1284: 1278: 1277: 1267: 1241: 1232: 1231: 1212:10.1038/218438a0 1185: 1179: 1178: 1168: 1158: 1141:(6266): 1361–6. 1126: 1120: 1119: 1109: 1060: 1054: 1053: 1043: 1002: 996: 995: 985: 952: 943: 942: 932: 899: 890: 889: 879: 869: 845: 839: 838: 836: 834: 820: 737: 718:Modified Gg-VSD 701:Modified Gg-VSD 661:(pa)QuasAr3(-s) 650:Modified Gg-VSD 633:Modified Gg-VSD 580:Modified Gg-VSD 508:Modified Gg-VSD 111: 3550: 3549: 3545: 3544: 3543: 3541: 3540: 3539: 3510: 3509: 3508: 3503: 3483: 3467: 3436: 3432:Proteorhodopsin 3422:Archaerhodopsin 3395: 3390: 3360: 3306: 3305: 3301: 3254: 3253: 3249: 3218: 3217: 3213: 3167: 3166: 3162: 3124: 3123: 3119: 3074: 3073: 3069: 3016: 3015: 3008: 2991: 2988: 2986: 2984: 2934: 2933: 2929: 2876: 2875: 2871: 2825: 2824: 2820: 2767: 2766: 2762: 2717: 2716: 2712: 2666: 2665: 2661: 2608: 2607: 2603: 2555: 2554: 2550: 2496: 2495: 2488: 2435: 2434: 2430: 2384: 2383: 2379: 2326: 2325: 2321: 2275: 2274: 2270: 2217: 2216: 2212: 2181: 2180: 2176: 2120: 2119: 2115: 2069: 2068: 2064: 2018: 2017: 2013: 1967: 1966: 1962: 1914: 1913: 1906: 1861: 1860: 1856: 1811: 1810: 1806: 1766: 1765: 1761: 1705: 1704: 1700: 1660: 1659: 1655: 1599: 1598: 1594: 1541: 1540: 1536: 1497: 1496: 1492: 1444: 1443: 1439: 1395:Gong Y (2015). 1394: 1393: 1389: 1344: 1343: 1339: 1286: 1285: 1281: 1243: 1242: 1235: 1187: 1186: 1182: 1128: 1127: 1123: 1062: 1061: 1057: 1004: 1003: 999: 954: 953: 946: 921:10.1038/nn.3709 901: 900: 893: 847: 846: 842: 832: 830: 822: 821: 817: 813: 800: 768:calcium imaging 764:electrode-based 760: 744: 742:Characteristics 731: 389:VSFP-Butterfly 320:Nv-VSD, Dr-VSD 314:Zahra, Zahra 2 174:Rat Na channel 84: 72:rational design 56: 30:that can sense 17: 12: 11: 5: 3548: 3546: 3538: 3537: 3532: 3527: 3522: 3512: 3511: 3505: 3504: 3502: 3501: 3488: 3485: 3484: 3482: 3481: 3475: 3473: 3469: 3468: 3466: 3465: 3460: 3455: 3450: 3444: 3442: 3438: 3437: 3435: 3434: 3429: 3424: 3419: 3414: 3403: 3401: 3397: 3396: 3391: 3389: 3388: 3381: 3374: 3366: 3359: 3358: 3313:Cell Stem Cell 3299: 3247: 3211: 3182:(4): 904–913. 3160: 3117: 3067: 3006: 2927: 2869: 2818: 2760: 2710: 2681:(1): 245–257. 2659: 2601: 2548: 2486: 2428: 2399:(8): 825–833. 2377: 2319: 2268: 2210: 2174: 2113: 2062: 2033:(5): 779–785. 2011: 1982:(2): 190–196. 1960: 1904: 1854: 1804: 1777:(8): 683–685. 1759: 1698: 1653: 1592: 1534: 1490: 1437: 1387: 1358:(3): 513–523. 1337: 1300:(4): 352–360. 1279: 1258:(4): 735–741. 1233: 1180: 1121: 1055: 1018:(4): 352–360. 997: 944: 915:(6): 884–889. 909:Nat. Neurosci. 891: 840: 814: 812: 809: 799: 796: 759: 756: 748:photostability 743: 740: 739: 738: 726: 725: 722: 719: 716: 713: 709: 708: 705: 702: 699: 696: 692: 691: 688: 685: 682: 679: 675: 674: 671: 668: 665: 662: 658: 657: 654: 651: 648: 645: 641: 640: 637: 634: 631: 628: 624: 623: 618: 615: 612: 609: 605: 604: 601: 598: 595: 592: 588: 587: 584: 581: 578: 575: 571: 570: 567: 564: 561: 558: 554: 553: 550: 547: 544: 541: 537: 536: 531: 528: 525: 522: 516: 515: 512: 509: 506: 503: 499: 498: 495: 492: 489: 486: 482: 481: 478: 475: 472: 469: 465: 464: 461: 458: 455: 452: 446: 445: 442: 436: 433: 430: 426: 425: 422: 416: 413: 410: 406: 405: 402: 396: 393: 390: 386: 385: 382: 379: 376: 373: 369: 368: 365: 362: 357: 354: 350: 349: 346: 343: 340: 337: 331: 330: 327: 321: 318: 315: 311: 310: 307: 304: 301: 298: 294: 293: 290: 287: 284: 281: 275: 274: 271: 268: 263: 260: 256: 255: 252: 246: 243: 240: 236: 235: 232: 229: 226: 223: 219: 218: 215: 212: 209: 206: 202: 201: 198: 192: 189: 186: 182: 181: 178: 175: 172: 169: 165: 164: 161: 155: 152: 149: 145: 144: 141: 138: 135: 132: 128: 127: 124: 121: 118: 115: 83: 80: 55: 52: 15: 13: 10: 9: 6: 4: 3: 2: 3547: 3536: 3533: 3531: 3528: 3526: 3525:Biotechnology 3523: 3521: 3518: 3517: 3515: 3500: 3499: 3490: 3489: 3486: 3480: 3477: 3476: 3474: 3470: 3464: 3461: 3459: 3456: 3454: 3451: 3449: 3446: 3445: 3443: 3439: 3433: 3430: 3428: 3425: 3423: 3420: 3418: 3417:Halorhodopsin 3415: 3412: 3408: 3405: 3404: 3402: 3398: 3394: 3387: 3382: 3380: 3375: 3373: 3368: 3367: 3364: 3354: 3350: 3345: 3340: 3336: 3332: 3327: 3322: 3318: 3314: 3310: 3303: 3300: 3295: 3291: 3286: 3281: 3276: 3271: 3267: 3264: 3263: 3258: 3251: 3248: 3243: 3239: 3235: 3231: 3227: 3224: 3223: 3215: 3212: 3207: 3203: 3198: 3193: 3189: 3185: 3181: 3177: 3176: 3171: 3164: 3161: 3156: 3152: 3147: 3142: 3138: 3134: 3133: 3128: 3121: 3118: 3113: 3109: 3104: 3099: 3095: 3091: 3087: 3084: 3083: 3078: 3071: 3068: 3063: 3059: 3054: 3049: 3045: 3041: 3037: 3033: 3029: 3025: 3021: 3013: 3011: 3007: 3002: 2996: 2982: 2978: 2973: 2968: 2964: 2960: 2956: 2952: 2948: 2944: 2943: 2938: 2931: 2928: 2923: 2919: 2914: 2909: 2905: 2901: 2897: 2893: 2889: 2886: 2885: 2880: 2873: 2870: 2865: 2861: 2856: 2851: 2846: 2841: 2837: 2833: 2829: 2822: 2819: 2814: 2810: 2805: 2800: 2796: 2792: 2788: 2784: 2780: 2777: 2776: 2771: 2764: 2761: 2756: 2752: 2747: 2742: 2738: 2734: 2730: 2727: 2726: 2721: 2714: 2711: 2706: 2702: 2697: 2692: 2688: 2684: 2680: 2676: 2675: 2670: 2663: 2660: 2655: 2651: 2646: 2641: 2637: 2633: 2629: 2625: 2621: 2618: 2617: 2612: 2605: 2602: 2597: 2593: 2588: 2583: 2578: 2573: 2569: 2565: 2564: 2559: 2552: 2549: 2544: 2540: 2535: 2530: 2526: 2522: 2518: 2514: 2510: 2506: 2505: 2500: 2493: 2491: 2487: 2482: 2478: 2473: 2468: 2464: 2460: 2456: 2452: 2448: 2445: 2444: 2439: 2432: 2429: 2424: 2420: 2415: 2410: 2406: 2402: 2398: 2394: 2393: 2388: 2381: 2378: 2373: 2369: 2364: 2359: 2355: 2351: 2347: 2343: 2339: 2336: 2335: 2330: 2323: 2320: 2315: 2311: 2306: 2301: 2297: 2293: 2289: 2285: 2284: 2279: 2272: 2269: 2264: 2260: 2255: 2250: 2246: 2242: 2238: 2234: 2230: 2227: 2226: 2221: 2214: 2211: 2206: 2202: 2198: 2194: 2190: 2187: 2186: 2178: 2175: 2170: 2166: 2161: 2156: 2151: 2146: 2142: 2138: 2135:(9): e43454. 2134: 2130: 2129: 2124: 2117: 2114: 2109: 2105: 2100: 2095: 2091: 2087: 2083: 2079: 2078: 2073: 2066: 2063: 2058: 2054: 2049: 2044: 2040: 2036: 2032: 2028: 2027: 2022: 2015: 2012: 2007: 2003: 1998: 1993: 1989: 1985: 1981: 1977: 1976: 1971: 1964: 1961: 1956: 1952: 1948: 1944: 1940: 1936: 1932: 1928: 1924: 1920: 1919: 1911: 1909: 1905: 1900: 1896: 1891: 1886: 1882: 1878: 1874: 1871: 1870: 1865: 1858: 1855: 1850: 1846: 1841: 1836: 1832: 1828: 1824: 1821: 1820: 1815: 1808: 1805: 1800: 1796: 1792: 1788: 1784: 1780: 1776: 1772: 1771: 1763: 1760: 1755: 1751: 1746: 1741: 1736: 1731: 1727: 1723: 1719: 1715: 1714: 1709: 1702: 1699: 1694: 1690: 1686: 1682: 1678: 1674: 1670: 1666: 1665: 1657: 1654: 1649: 1645: 1640: 1635: 1630: 1625: 1621: 1617: 1613: 1609: 1608: 1603: 1596: 1593: 1588: 1584: 1579: 1574: 1570: 1566: 1562: 1558: 1554: 1551: 1550: 1545: 1538: 1535: 1530: 1526: 1522: 1518: 1514: 1510: 1506: 1503: 1502: 1494: 1491: 1486: 1482: 1478: 1474: 1470: 1466: 1462: 1458: 1454: 1450: 1449: 1441: 1438: 1433: 1429: 1424: 1419: 1415: 1411: 1407: 1404: 1403: 1398: 1391: 1388: 1383: 1379: 1374: 1369: 1365: 1361: 1357: 1354: 1353: 1348: 1341: 1338: 1333: 1329: 1324: 1319: 1315: 1311: 1307: 1303: 1299: 1295: 1291: 1283: 1280: 1275: 1271: 1266: 1261: 1257: 1253: 1252: 1247: 1240: 1238: 1234: 1229: 1225: 1221: 1217: 1213: 1209: 1205: 1201: 1197: 1193: 1192: 1184: 1181: 1176: 1172: 1167: 1162: 1157: 1152: 1148: 1144: 1140: 1136: 1132: 1125: 1122: 1117: 1113: 1108: 1103: 1099: 1095: 1091: 1087: 1083: 1079: 1075: 1071: 1067: 1059: 1056: 1051: 1047: 1042: 1037: 1033: 1029: 1025: 1021: 1017: 1013: 1009: 1001: 998: 993: 989: 984: 979: 975: 971: 967: 963: 959: 951: 949: 945: 940: 936: 931: 926: 922: 918: 914: 911: 910: 905: 898: 896: 892: 887: 883: 878: 873: 868: 863: 860:(5): 779–85. 859: 855: 851: 844: 841: 829: 825: 819: 816: 810: 808: 806: 797: 795: 793: 792:cardiomyocyte 789: 788: 783: 779: 778: 773: 769: 765: 757: 755: 753: 752:phototoxicity 749: 741: 735: 734: 730: 723: 720: 717: 714: 711: 710: 706: 703: 700: 697: 694: 693: 689: 686: 683: 680: 678:Voltron(-ST) 677: 676: 672: 670:Same as left 669: 666: 663: 660: 659: 655: 652: 649: 646: 643: 642: 638: 635: 632: 629: 626: 625: 622: 619: 616: 613: 610: 607: 606: 602: 599: 596: 593: 590: 589: 585: 582: 579: 576: 573: 572: 568: 565: 562: 559: 556: 555: 551: 548: 545: 542: 540:ArcLightning 539: 538: 535: 532: 529: 526: 523: 521: 518: 517: 513: 510: 507: 504: 501: 500: 496: 494:Same as left 493: 490: 487: 484: 483: 479: 477:Same as left 476: 473: 470: 467: 466: 462: 459: 456: 453: 451: 448: 447: 443: 440: 437: 434: 431: 428: 427: 423: 420: 417: 414: 411: 408: 407: 403: 400: 397: 394: 391: 388: 387: 383: 380: 377: 374: 371: 370: 366: 364:Same as left 363: 361: 358: 355: 352: 351: 347: 344: 341: 338: 336: 333: 332: 328: 325: 322: 319: 316: 313: 312: 308: 306:Same as left 305: 302: 299: 296: 295: 291: 288: 285: 282: 280: 277: 276: 272: 269: 267: 266:Dipicrylamine 264: 261: 258: 257: 253: 250: 247: 244: 241: 238: 237: 233: 230: 227: 224: 221: 220: 216: 213: 210: 207: 204: 203: 199: 196: 193: 190: 187: 184: 183: 179: 176: 173: 170: 167: 166: 162: 159: 156: 153: 150: 147: 146: 142: 139: 136: 133: 130: 129: 125: 122: 119: 116: 113: 112: 106: 103: 99: 96: 95: 88: 81: 79: 77: 73: 68: 66: 62: 53: 51: 49: 45: 41: 37: 33: 29: 25: 21: 3520:Neuroscience 3497: 3452: 3393:Optogenetics 3316: 3312: 3302: 3265: 3260: 3250: 3225: 3220: 3214: 3179: 3173: 3163: 3139:(1): 18–20. 3136: 3130: 3120: 3085: 3082:J. Neurosci. 3080: 3070: 3027: 3023: 2995:cite journal 2946: 2940: 2930: 2887: 2882: 2872: 2835: 2831: 2821: 2778: 2773: 2763: 2728: 2725:J. Neurosci. 2723: 2713: 2678: 2672: 2662: 2619: 2614: 2604: 2567: 2561: 2551: 2508: 2502: 2446: 2443:Nat. Commun. 2441: 2431: 2396: 2392:Nat. Methods 2390: 2380: 2337: 2334:Nat. Commun. 2332: 2322: 2287: 2281: 2271: 2228: 2223: 2213: 2188: 2183: 2177: 2132: 2126: 2116: 2084:(1): 90–95. 2081: 2077:Nat. Methods 2075: 2065: 2030: 2024: 2014: 1979: 1973: 1963: 1922: 1916: 1872: 1867: 1857: 1822: 1819:J. Neurosci. 1817: 1807: 1774: 1770:Nat. Methods 1768: 1762: 1720:(6): e2514. 1717: 1711: 1701: 1671:(1): 32–38. 1668: 1662: 1656: 1611: 1605: 1595: 1552: 1547: 1537: 1504: 1499: 1493: 1452: 1446: 1440: 1405: 1400: 1390: 1355: 1350: 1340: 1297: 1293: 1282: 1255: 1249: 1195: 1189: 1183: 1138: 1134: 1124: 1073: 1069: 1058: 1015: 1011: 1000: 965: 961: 912: 907: 857: 853: 843: 831:. Retrieved 827: 818: 801: 785: 775: 761: 745: 733: 533: 519: 449: 278: 92: 89: 85: 69: 57: 23: 19: 18: 2884:Biophys. J. 2781:(1): 8286. 2225:Biophys. J. 1869:Chem. Biol. 1614:(5): e440. 1549:Biophys. J. 372:ElectricPk 44:optogenetic 3514:Categories 2570:: e10482. 811:References 777:Drosophila 608:Bongwoori 126:Precursor 123:Reporting 3458:Glutamate 3335:1934-5909 3228:: 75–83. 3044:0092-8674 2775:Sci. Rep. 2622:: 23865. 2616:Sci. Rep. 1408:: 84–89. 1314:1552-4469 1098:1476-4687 1032:1552-4469 552:ArcLight 534:Mac GEVIs 520:Ace GEVIs 450:Mac GEVIs 429:Mermaid2 82:Structure 3353:30880024 3294:26370981 3242:26115448 3206:23932121 3155:27368098 3112:27683896 3062:35985322 2981:31043747 2922:29108650 2864:28749338 2813:28811673 2755:26911693 2705:27264607 2654:27040905 2596:26599732 2543:26586188 2481:25222271 2449:: 4894. 2423:24952910 2372:24755708 2340:: 3674. 2314:23836686 2263:22961245 2205:22815406 2169:22970127 2128:PLoS One 2108:22120467 2057:22958819 2006:22634212 1947:21764748 1899:20064437 1849:18495892 1799:30661869 1791:18622396 1754:18575613 1713:PLoS One 1685:17126911 1648:17487283 1607:PLoS One 1587:11751337 1529:10969720 1521:11454036 1477:15902207 1432:26143170 1382:28045247 1332:29483642 1175:26586188 1116:31597963 1050:29483642 992:31835034 939:24755780 886:22958819 782:bacteria 712:JEDI-2P 673:QuasAr2 621:ArcLight 603:VSFP3.1 444:Mermaid 424:VSFP2.3 409:VSFP-CR 404:VSFP2's 384:VSFP3.1 335:ArcLight 329:VSFP2's 292:VSFP3.1 254:VSFP2's 239:Mermaid 234:VSFP2's 222:VSFP3.1 185:VSFP2's 120:Sensing 3498:Commons 3463:Vesicle 3453:Voltage 3448:Calcium 3344:6499654 3285:4613271 3197:3874294 3103:5039263 3053:9563101 2972:6613938 2951:Bibcode 2913:5700382 2892:Bibcode 2855:5584994 2804:5557843 2783:Bibcode 2746:4764664 2696:5606228 2645:4878010 2624:Bibcode 2587:4658195 2534:4904846 2513:Bibcode 2504:Science 2472:4166526 2451:Bibcode 2414:4117813 2363:4247277 2342:Bibcode 2305:3784191 2254:3461113 2233:Bibcode 2160:3435330 2137:Bibcode 2099:3248630 2048:3439164 1997:3398169 1955:2195943 1927:Bibcode 1918:Science 1890:2818747 1840:2714581 1745:2429971 1722:Bibcode 1693:8540453 1639:1857823 1616:Bibcode 1578:1302490 1557:Bibcode 1485:4427755 1457:Bibcode 1423:4571180 1373:5355904 1323:5866759 1274:9354320 1228:4288546 1220:5649693 1200:Bibcode 1166:4904846 1143:Bibcode 1135:Science 1107:6858559 1078:Bibcode 1064:2019). 1041:5866759 983:6941988 930:4494739 877:3439164 787:E. coli 724:ASAP2s 707:ASAP2s 644:ASAP-Y 627:ASAP2s 614:Ci-VSD 597:Ci-VSD 591:FlicR1 574:ASAP2f 546:Ci-VSD 485:Archer 435:Ci-VSD 415:Ci-VSD 395:Ci-VSD 378:Ci-VSD 342:Ci-VSD 286:Ci-VSD 245:Ci-VSD 228:Ci-VSD 191:Ci-VSD 102:genomic 54:History 36:voltage 28:protein 26:) is a 16:Protein 3351:  3341:  3333:  3292:  3282:  3240:  3204:  3194:  3153:  3110:  3100:  3060:  3050:  3042:  2979:  2969:  2942:Nature 2920:  2910:  2862:  2852:  2811:  2801:  2753:  2743:  2703:  2693:  2652:  2642:  2594:  2584:  2541:  2531:  2479:  2469:  2421:  2411:  2370:  2360:  2312:  2302:  2261:  2251:  2203:  2167:  2157:  2106:  2096:  2055:  2045:  2026:Neuron 2004:  1994:  1953:  1945:  1897:  1887:  1847:  1837:  1797:  1789:  1752:  1742:  1691:  1683:  1646:  1636:  1585:  1575:  1527:  1519:  1483:  1475:  1448:Nature 1430:  1420:  1380:  1370:  1330:  1320:  1312:  1272:  1251:Neuron 1226:  1218:  1191:Nature 1173:  1163:  1114:  1104:  1096:  1070:Nature 1048:  1038:  1030:  990:  980:  937:  927:  884:  874:  854:Neuron 695:ASAP3 656:ASAP1 639:ASAP1 586:ASAP1 502:ASAP1 297:PROPS 217:FlaSh 205:Flare 200:VSFP1 168:SPARC 148:VSFP1 131:FlaSh 65:Shaker 2832:eLife 2563:eLife 1951:S2CID 1795:S2CID 1689:S2CID 1525:S2CID 1481:S2CID 1224:S2CID 833:8 May 770:, or 715:2022 698:2019 681:2019 664:2019 647:2017 630:2017 611:2017 594:2016 577:2016 560:2016 557:Pado 543:2015 524:2015 505:2014 497:Arch 488:2014 480:Arch 471:2014 454:2014 432:2013 412:2013 392:2012 375:2012 356:2012 353:Arch 339:2012 317:2012 300:2011 283:2009 262:2008 259:hVOS 242:2008 225:2008 208:2007 188:2007 171:2002 151:2001 134:1997 117:Year 114:GEVI 3349:PMID 3331:ISSN 3290:PMID 3238:PMID 3202:PMID 3175:Cell 3151:PMID 3132:Cell 3108:PMID 3058:PMID 3040:ISSN 3024:Cell 3001:link 2977:PMID 2918:PMID 2860:PMID 2809:PMID 2751:PMID 2701:PMID 2674:Cell 2650:PMID 2592:PMID 2539:PMID 2477:PMID 2419:PMID 2368:PMID 2310:PMID 2259:PMID 2201:PMID 2165:PMID 2104:PMID 2053:PMID 2002:PMID 1943:PMID 1895:PMID 1845:PMID 1787:PMID 1750:PMID 1681:PMID 1644:PMID 1583:PMID 1517:PMID 1473:PMID 1428:PMID 1378:PMID 1328:PMID 1310:ISSN 1270:PMID 1216:PMID 1171:PMID 1112:PMID 1094:ISSN 1046:PMID 1028:ISSN 988:PMID 962:Cell 935:PMID 882:PMID 835:2017 439:FRET 419:FRET 399:FRET 324:FRET 270:GFP 249:FRET 231:CFP 214:YFP 195:FRET 177:GFP 158:FRET 140:GFP 74:and 24:GEVI 22:(or 3339:PMC 3321:doi 3280:PMC 3270:doi 3230:doi 3192:PMC 3184:doi 3180:154 3141:doi 3137:166 3098:PMC 3090:doi 3048:PMC 3032:doi 3028:185 2967:PMC 2959:doi 2947:569 2908:PMC 2900:doi 2888:113 2850:PMC 2840:doi 2799:PMC 2791:doi 2741:PMC 2733:doi 2691:PMC 2683:doi 2679:166 2640:PMC 2632:doi 2582:PMC 2572:doi 2529:PMC 2521:doi 2509:350 2467:PMC 2459:doi 2409:PMC 2401:doi 2358:PMC 2350:doi 2300:PMC 2292:doi 2288:591 2249:PMC 2241:doi 2229:104 2193:doi 2189:108 2155:PMC 2145:doi 2094:PMC 2086:doi 2043:PMC 2035:doi 1992:PMC 1984:doi 1980:208 1935:doi 1923:333 1885:PMC 1877:doi 1835:PMC 1827:doi 1779:doi 1740:PMC 1730:doi 1673:doi 1669:161 1634:PMC 1624:doi 1573:PMC 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Index

protein
membrane potential
voltage
fluorescent level
optogenetic
electrophysiological
green fluorescent protein
Shaker
rational design
directed evolution
Ciona intestinalis
voltage sensitive phosphatase
genomic
FRET
FRET
FRET
Dipicrylamine
FRET
ArcLight
Archaerhodopsin 3
FRET
FRET
FRET
ArcLight

photostability
phototoxicity
electrode-based
calcium imaging
voltage sensitive dyes

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