Biology:Genetically encoded voltage indicator

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Short description: Protein

Genetically encoded voltage indicator (or GEVI) is a protein that can sense membrane potential in a cell and relate the change in voltage to a form of output, often fluorescent level.[1] It is a promising optogenetic recording tool that enables exporting electrophysiological signals from cultured cells, live animals, and ultimately human brain. Examples of notable GEVIs include ArcLight,[2] ASAP1,[3] ASAP3,[4] Archons,[5] SomArchon,[6] and Ace2N-mNeon.[7]

History

Despite that the idea of optical measurement of neuronal activity was proposed in the late 1960s,[8] 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,[9] was constructed by fusing a modified green fluorescent protein with a voltage-sensitive K+ channel (Shaker). 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.

Two methods can be utilized to find novel GEVIs: rational design and directed evolution. The former method contributes to the most of new GEVI variants, but recent researches using directed evolution have shown promising results in GEVI optimization.[10][11]

Structure

GEVI can have many configuration designs in order to realize voltage sensing function.[12] 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 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.

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, e.g. ASAP1. A majority of GEVIs are based on the Ciona intestinalis voltage sensitive phosphatase (Ci-VSP or Ci-VSD (domain)), which was discovered in 2005 from the genomic survey of the organism.[13] 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 separated by the VSD, while the two FPs of Mermaid are relatively close to each other.

Table of GEVIs and their structure
GEVI[A] Year Sensing Reporting Precursor
FlaSh[9] 1997 Shaker (K+ channel) GFP -
VSFP1[14] 2001 Rat Kv2.1 (K+ channel) FRET pair: CFP and YFP -
SPARC[15] 2002 Rat Na+ channel GFP -
VSFP2's[16] 2007 Ci-VSD FRET pair: CFP (Cerulean) and YFP (Citrine) VSFP1
Flare[17] 2007 Kv1.4 (K+ channel) YFP FlaSh
VSFP3.1[18] 2008 Ci-VSD CFP VSFP2's
Mermaid[19] 2008 Ci-VSD FRET pair: Marine GFP (mUKG) and OFP (mKOκ) VSFP2's
hVOS[20] 2008 Dipicrylamine GFP -
Red-shifted VSFP's[21] 2009 Ci-VSD RFP/YFP (Citrine, mOrange2, TagRFP, or mKate2) VSFP3.1
PROPS[22] 2011 Modified green-absorbing proteorhodopsin (GPR) Same as left -
Zahra, Zahra 2[23] 2012 Nv-VSD, Dr-VSD FRET pair: CFP (Cerulean) and YFP (Citrine) VSFP2's
ArcLight[24] 2012 Ci-VSD Modified super ecliptic pHluorin -
Arch[25] 2012 Archaerhodopsin 3 Same as left -
ElectricPk[26] 2012 Ci-VSD Circularly permuted EGFP VSFP3.1
VSFP-Butterfly[27] 2012 Ci-VSD FRET pair: YFP (mCitrine) and RFP (mKate2) VSFP2's
VSFP-CR[28] 2013 Ci-VSD FRET pair: GFP (Clover) and RFP(mRuby2) VSFP2.3
Mermaid2[29] 2013 Ci-VSD FRET pair: CFP (seCFP2) and YFP Mermaid
Mac GEVIs[30] 2014 Mac rhodopsin (FRET acceptor) FRET doner: mCitrine, or mOrange2 -
QuasAr1, QuasAr2[31] 2014 Modified Archaerhodopsin 3 Same as left Arch
Archer[32] 2014 Modified Archaerhodopsin 3 Same as left Arch
ASAP1[3] 2014 Modified Gg-VSD Circularly permuted GFP -
Ace GEVIs[33] 2015 Modified Ace rhodopsin FRET doner: mNeonGreen Mac GEVIs
ArcLightning[34] 2015 Ci-VSD Modified super ecliptic pHluorin ArcLight
Pado[35] 2016 Voltage-gated proton channel Super ecliptic pHluorin -
ASAP2f[36] 2016 Modified Gg-VSD Circularly permuted GFP ASAP1
FlicR1[37] 2016 Ci-VSD Circularly permuted RFP (mApple) VSFP3.1
Bongwoori[38] 2017 Ci-VSD Modified super ecliptic pHluorin ArcLight
ASAP2s[39] 2017 Modified Gg-VSD Circularly permuted GFP ASAP1
ASAP-Y[40] 2017 Modified Gg-VSD Circularly permuted GFP ASAP1
(pa)QuasAr3(-s)[41] 2019 Modified Archaerhodopsin 3 Same as left QuasAr2
Voltron(-ST) 2019 Modified Ace rhodopsin (Ace2) FRET doner: Janelia Fluor (chemical) -
ASAP3[4] 2019 Modified Gg-VSD Circularly permuted GFP ASAP2s
JEDI-2P[42] 2022 Modified Gg-VSD Circularly permuted GFP ASAP2s
  1. ↑Names in italic denote GEVIs not named.

Characteristics

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, photostability, sensitivity, kinetics (speed), linearity of response, etc., while the compatibility properties cover toxicity (phototoxicity), plasma membrane localization, adaptability of deep-tissue imaging, etc.[43] For now, no existing GEVI meets all the desired properties, so searching for a perfect GEVI is still a quite competitive research area.

Applications and advantages

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 electrode-based electrophysiological recordings, calcium imaging, or voltage sensitive dyes. It has subcellular spatial resolution[44] 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.[33] Researchers have used it to probe neural communications of an intact brain (of Drosophila[45] or mouse[46]), electrical spiking of bacteria (E. coli[22]), and human stem-cell derived cardiomyocyte.[47][48]

Future directions

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 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, JEDI-2P, the latest generation of GEIV, is a fast, sensitive, bright, and photostable two-photon-compatible sensor which is considered to be almost perfect for many challenging deep-tissue imaging applications.[42] However, 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.[42] 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 optogenetic actuators. 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.

References

  1. ↑ "Genetically-Encoded Voltage Indicators". https://www.openoptogenetics.org/index.php?title=Genetically-Encoded_Voltage_Indicators. 
  2. ↑ Jin, L; Han, Z; Platisa, J; Wooltorton, JR; Cohen, LB; Pieribone, VA (6 September 2012). "Single action potentials and subthreshold electrical events imaged in neurons with a fluorescent protein voltage probe.". Neuron 75 (5): 779–85. doi:10.1016/j.neuron.2012.06.040. PMID 22958819. 
  3. ↑ 3.0 3.1 "High-fidelity optical reporting of neuronal electrical activity with an ultrafast fluorescent voltage sensor". Nat. Neurosci. 17 (6): 884–889. 2014. doi:10.1038/nn.3709. PMID 24755780. 
  4. ↑ 4.0 4.1 Villette, V; Chavarha, M; Dimov, IK; Bradley, J; Pradhan, L; Mathieu, B; Evans, SW; Chamberland, S et al. (12 December 2019). "Ultrafast Two-Photon Imaging of a High-Gain Voltage Indicator in Awake Behaving Mice.". Cell 179 (7): 1590–1608.e23. doi:10.1016/j.cell.2019.11.004. PMID 31835034. 
  5. ↑ Piatkevich, Kiryl D.; Jung, Erica E.; Straub, Christoph; Linghu, Changyang; Park, Demian; Suk, Ho-Jun; Hochbaum, Daniel R.; Goodwin, Daniel et al. (April 2018). "A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters" (in en). Nature Chemical Biology 14 (4): 352–360. doi:10.1038/s41589-018-0004-9. ISSN 1552-4469. PMID 29483642. 
  6. ↑ Piatkevich, Kiryl D.; Bensussen, Seth; Tseng, Hua-an; Shroff, Sanaya N.; Lopez-Huerta, Violeta Gisselle; Park, Demian; Jung, Erica E.; Shemesh, Or A. et al. (October 2019). "Population imaging of neural activity in awake behaving mice" (in en). Nature 574 (7778): 413–417. doi:10.1038/s41586-019-1641-1. ISSN 1476-4687. PMID 31597963. Bibcode: 2019Natur.574..413P. 
  7. ↑ Gong, Y; Huang, C; Li, JZ; Grewe, BF; Zhang, Y; Eismann, S; Schnitzer, MJ (11 December 2015). "High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor.". Science 350 (6266): 1361–6. doi:10.1126/science.aab0810. PMID 26586188. Bibcode: 2015Sci...350.1361G. 
  8. ↑ "Light scattering and birefringence changes during nerve activity". Nature 218 (5140): 438–441. 1968. doi:10.1038/218438a0. PMID 5649693. Bibcode: 1968Natur.218..438C. 
  9. ↑ 9.0 9.1 "A genetically encoded optical probe of membrane voltage". Neuron 19 (4): 735–741. 1997. doi:10.1016/S0896-6273(00)80955-1. PMID 9354320. 
  10. ↑ Piatkevich, Kiryl D.; Jung, Erica E.; Straub, Christoph; Linghu, Changyang; Park, Demian; Suk, Ho-Jun; Hochbaum, Daniel R.; Goodwin, Daniel et al. (April 2018). "A robotic multidimensional directed evolution approach applied to fluorescent voltage reporters" (in en). Nature Chemical Biology 14 (4): 352–360. doi:10.1038/s41589-018-0004-9. ISSN 1552-4469. PMID 29483642. 
  11. ↑ "Directed Evolution of Key Residues in Fluorescent Protein Inverses the Polarity of Voltage Sensitivity in the Genetically Encoded Indicator ArcLight". ACS Chem. Neurosci. 8 (3): 513–523. 2017. doi:10.1021/acschemneuro.6b00234. PMID 28045247. 
  12. ↑ "The evolving capabilities of rhodopsin-based genetically encoded voltage indicators". Curr. Opin. Chem. Biol. 27: 84–89. 2015. doi:10.1016/j.cbpa.2015.05.006. PMID 26143170. 
  13. ↑ "Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor". Nature 435 (7046): 1239–1243. 2005. doi:10.1038/nature03650. PMID 15902207. Bibcode: 2005Natur.435.1239M. 
  14. ↑ "Design and characterization of a DNA-encoded, voltage-sensitive fluorescent protein". Eur. J. Neurosci. 13 (12): 2314–2318. 2001. doi:10.1046/j.0953-816x.2001.01617.x. PMID 11454036. 
  15. ↑ "A genetically targetable fluorescent probe of channel gating with rapid kinetics". Biophys. J. 82 (1 Pt 1): 509–516. 2002. doi:10.1016/S0006-3495(02)75415-5. PMID 11751337. Bibcode: 2002BpJ....82..509A. 
  16. ↑ "Engineering and characterization of an enhanced fluorescent protein voltage sensor". PLoS One 2 (5): e440. 2007. doi:10.1371/journal.pone.0000440. PMID 17487283. Bibcode: 2007PLoSO...2..440D. 
  17. ↑ "Three fluorescent protein voltage sensors exhibit low plasma membrane expression in mammalian cells". J. Neurosci. Methods 161 (1): 32–38. 2007. doi:10.1016/j.jneumeth.2006.10.005. PMID 17126911. 
  18. ↑ "Engineering of a genetically encodable fluorescent voltage sensor exploiting fast Ci-VSP voltage-sensing movements". PLoS One 3 (6): e2514. 2008. doi:10.1371/journal.pone.0002514. PMID 18575613. Bibcode: 2008PLoSO...3.2514L. 
  19. ↑ "Improving membrane voltage measurements using FRET with new fluorescent proteins". Nat. Methods 5 (8): 683–685. 2008. doi:10.1038/nmeth.1235. PMID 18622396. 
  20. ↑ "Rational optimization and imaging in vivo of a genetically encoded optical voltage reporter". J. Neurosci. 28 (21): 5582–5593. 2008. doi:10.1523/JNEUROSCI.0055-08.2008. PMID 18495892. 
  21. ↑ "Red-shifted voltage-sensitive fluorescent proteins". Chem. Biol. 16 (12): 1268–1277. 2009. doi:10.1016/j.chembiol.2009.11.014. PMID 20064437. 
  22. ↑ 22.0 22.1 "Electrical spiking in Escherichia coli probed with a fluorescent voltage-indicating protein". Science 333 (6040): 345–348. 2011. doi:10.1126/science.1204763. PMID 21764748. Bibcode: 2011Sci...333..345K. 
  23. ↑ "Genetically encoded fluorescent voltage sensors using the voltage-sensing domain of Nematostella and Danio phosphatases exhibit fast kinetics". J. Neurosci. Methods 208 (2): 190–196. 2012. doi:10.1016/j.jneumeth.2012.05.016. PMID 22634212. 
  24. ↑ "Single action potentials and subthreshold electrical events imaged in neurons with a fluorescent protein voltage probe". Neuron 75 (5): 779–785. 2012. doi:10.1016/j.neuron.2012.06.040. PMID 22958819. 
  25. ↑ "Optical recording of action potentials in mammalian neurons using a microbial rhodopsin". Nat. Methods 9 (1): 90–95. 2011. doi:10.1038/nmeth.1782. PMID 22120467. 
  26. ↑ "A fluorescent, genetically-encoded voltage probe capable of resolving action potentials". PLoS One 7 (9): e43454. 2012. doi:10.1371/journal.pone.0043454. PMID 22970127. Bibcode: 2012PLoSO...743454B. 
  27. ↑ "Imaging neural circuit dynamics with a voltage-sensitive fluorescent protein". J. Neurophysiol. 108 (8): 2323–2337. 2012. doi:10.1152/jn.00452.2012. PMID 22815406. 
  28. ↑ "Improving FRET Dynamic Range with Bright Green and Red Fluorescent Proteins". Biophys. J. 104 (2): 1005–1012. 2013. doi:10.1016/j.bpj.2012.11.3773. PMID 22961245. Bibcode: 2013BpJ...104..683L. 
  29. ↑ "Improved detection of electrical activity with a voltage probe based on a voltage-sensing phosphatase". J. Physiol. (Lond.) 591 (18): 4427–4437. 2013. doi:10.1113/jphysiol.2013.257048. PMID 23836686. 
  30. ↑ "Imaging neural spiking in brain tissue using FRET-opsin protein voltage sensors". Nat. Commun. 5: 3674. 2014. doi:10.1038/ncomms4674. PMID 24755708. Bibcode: 2014NatCo...5.3674G. 
  31. ↑ "All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins". Nat. Methods 11 (8): 825–833. 2014. doi:10.1038/nmeth.3000. PMID 24952910. 
  32. ↑ "Archaerhodopsin variants with enhanced voltage-sensitive fluorescence in mammalian and Caenorhabditis elegans neurons". Nat. Commun. 5: 4894. 2014. doi:10.1038/ncomms5894. PMID 25222271. Bibcode: 2014NatCo...5.4894F. 
  33. ↑ 33.0 33.1 "High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor". Science 350 (6266): 1361–1366. 2015. doi:10.1126/science.aab0810. PMID 26586188. Bibcode: 2015Sci...350.1361G. 
  34. ↑ "Single-molecule fluorimetry and gating currents inspire an improved optical voltage indicator". eLife 4: e10482. 2015. doi:10.7554/eLife.10482. PMID 26599732. 
  35. ↑ "Pado, a fluorescent protein with proton channel activity can optically monitor membrane potential, intracellular pH, and map gap junctions". Sci. Rep. 6: 23865. 2016. doi:10.1038/srep23865. PMID 27040905. Bibcode: 2016NatSR...623865K. 
  36. ↑ "Subcellular Imaging of Voltage and Calcium Signals Reveals Neural Processing In Vivo". Cell 166 (1): 245–257. 2016. doi:10.1016/j.cell.2016.05.031. PMID 27264607. 
  37. ↑ "A Bright and Fast Red Fluorescent Protein Voltage Indicator That Reports Neuronal Activity in Organotypic Brain Slices". J. Neurosci. 36 (8): 2458–2472. 2016. doi:10.1523/JNEUROSCI.3484-15.2016. PMID 26911693. 
  38. ↑ "Improving a genetically encoded voltage indicator by modifying the cytoplasmic charge composition". Sci. Rep. 7 (1): 8286. 2017. doi:10.1038/s41598-017-08731-2. PMID 28811673. Bibcode: 2017NatSR...7.8286L. 
  39. ↑ Chamberland, S; Yang, HH; Pan, MM; Evans, SW; Guan, S; Chavarha, M; Yang, Y; Salesse, C et al. (27 July 2017). "Fast two-photon imaging of subcellular voltage dynamics in neuronal tissue with genetically encoded indicators.". eLife 6. doi:10.7554/eLife.25690. PMID 28749338. 
  40. ↑ "Biophysical Characterization of Genetically Encoded Voltage Sensor ASAP1: Dynamic Range Improvement". Biophys. J. 113 (10): 2178–2181. 2017. doi:10.1016/j.bpj.2017.10.018. PMID 29108650. Bibcode: 2017BpJ...113.2178L. 
  41. ↑ "Voltage imaging and optogenetics reveal behaviour-dependent changes in hippocampal dynamics". Nature 569 (7756): 413–417. 2019. doi:10.1038/s41586-019-1166-7. PMID 31043747. Bibcode: 2019Natur.569..413A.
    "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."
    "We called QuasAr3(V59A) ‘photoactivated QuasAr3’ (paQuasAr3)."
    "QuasAr2(K171R)-TS-citrine-TS-TS-TS-ER2, which we call QuasAr3."     
  42. ↑ 42.0 42.1 42.2 Liu, Zhuohe; Lu, Xiaoyu; Villette, Vincent; Gou, Yueyang; Colbert, Kevin L.; Lai, Shujuan; Guan, Sihui; Land, Michelle A. et al. (2022-08-18). "Sustained deep-tissue voltage recording using a fast indicator evolved for two-photon microscopy" (in English). Cell 185 (18): 3408–3425.e29. doi:10.1016/j.cell.2022.07.013. ISSN 0092-8674. PMID 35985322. 
  43. ↑ "Genetically Encoded Voltage Indicators: Opportunities and Challenges". J. Neurosci. 36 (39): 9977–9989. 2016. doi:10.1523/JNEUROSCI.1095-16.2016. PMID 27683896. 
  44. ↑ "Neuronal Computations Made Visible with Subcellular Resolution". Cell 166 (1): 18–20. 2016. doi:10.1016/j.cell.2016.06.022. PMID 27368098. 
  45. ↑ "Genetically targeted optical electrophysiology in intact neural circuits". Cell 154 (4): 904–913. 2013. doi:10.1016/j.cell.2013.07.027. PMID 23932121. 
  46. ↑ "Genetically encoded voltage indicators for large scale cortical imaging come of age". Curr. Opin. Chem. Biol. 27: 75–83. 2015. doi:10.1016/j.cbpa.2015.06.006. PMID 26115448. 
  47. ↑ "Genetically Encoded Voltage Indicators in Circulation Research". Int. J. Mol. Sci. 16 (9): 21626–21642. 2015. doi:10.3390/ijms160921626. PMID 26370981. 
  48. ↑ Zhang, Joe Z.; Termglinchan, Vittavat; Shao, Ning-Yi; Itzhaki, Ilanit; Liu, Chun; Ma, Ning; Tian, Lei; Wang, Vicky Y. et al. (2019-05-02). "A Human iPSC Double-Reporter System Enables Purification of Cardiac Lineage Subpopulations with Distinct Function and Drug Response Profiles" (in en). Cell Stem Cell 24 (5): 802–811.e5. doi:10.1016/j.stem.2019.02.015. ISSN 1934-5909. PMID 30880024. 



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