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词条 Genetically encoded voltage indicator
释义

  1. History

  2. Structure

  3. Characteristics

  4. Applications and advantages

  5. References

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, ASAP1,[2] ASAP2s,[3] and Ace2N-mNeon.

History

Despite that the idea of optical measurement of neuronal activity was proposed in the late 1960s,[4] 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,[5] 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 seldomly 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.[6]

Structure

GEVI can have many configuration designs in order to realize voltage sensing function.[7] 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. Arch.

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 opsion 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.[8] 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
name|A|↑YearSensingReportingPrecursor
FlaSh[5]1997Shaker (K+ channel)GFP -
VSFP1[9]2001Rat Kv2.1 (K+ channel)FRET pair: CFP and YFP -
SPARC[10]2002Rat Na+ channelGFP -
VSFP2's[11]2007Ci-VSDFRET pair: CFP (Cerulean) and YFP (Citrine)VSFP1
Flare[12]2007Kv1.4 (K+ channel)YFPFlaSh
VSFP3.1[13]2008Ci-VSDCFPVSFP2's
Mermaid[14]2008Ci-VSDFRET pair: Marine GFP (mUKG) and OFP (mKOκ)VSFP2's
hVOS[15]2008DipicrylamineGFP -
Red-shifted VSFP's[16]2009Ci-VSDRFP/YFP (Citrine, mOrange2, TagRFP, or mKate2)VSFP3.1
PROPS[17]2011Modified green-absorbing proteorhodopsin (GPR)Same as left -
Zahra, Zahra 2[18]2012Nv-VSD, Dr-VSDFRET pair: CFP (Cerulean) and YFP (Citrine)VSFP2's
ArcLight[19]2012Ci-VSDModified super ecliptic pHluorin -
Arch[20]2012Archaerhodopsin 3Same as left -
ElectricPk[21]2012Ci-VSDCircularly permuted EGFPVSFP3.1
VSFP-Butterfly[22]2012Ci-VSDFRET pair: YFP (mCitrine) and RFP (mKate2)VSFP2's
VSFP-CR[23]2013Ci-VSDFRET pair: GFP (Clover) and RFP(mRuby2)VSFP2.3
Mermaid2[24]2013Ci-VSDFRET pair: CFP (seCFP2) and YFPMermaid
Mac GEVIs[25]2014Mac rhodopsin (FRET acceptor)FRET doner: mCitrine, or mOrange2
QuasAr1, QuasAr2[26]2014Modified Archaerhodopsin 3Same as leftArch
Archer[27]2014Modified Archaerhodopsin 3Same as leftArch
ASAP1[2]2014Modified Gg-VSDCircularly permuted GFP -
Ace GEVIs[28]2015Modified Ace rhodopsinFRET doner: mNeonGreenMac GEVIs
ArcLightning[29]2015Ci-VSDModified super ecliptic pHluorinArcLight
Pado[30]2016Voltage-gated proton channelSuper ecliptic pHluorin -
ASAP2f[31]2016Modified Gg-VSDCircularly permuted GFPASAP1
FlicR1[32]2016Ci-VSDCircularly permuted RFP (mApple)VSFP3.1
Bongwoori[33]2017Ci-VSDModified super ecliptic pHluorinArcLight
ASAP2s[3]2017Modified Gg-VSDCircularly permuted GFPASAP1
ASAP-Y[34]2017Modified Gg-VSDCircularly permuted GFPASAP1
  1. {{note label|name|A|↑|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.[35] 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 seen being used 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 can show neuron signals with subcellular spatial resolution.[36] It has fast temporal resolution (sub-millisecond[28]), matching or surpassing that of the electrode recordings, and about one magnitude faster than calcium imaging. Researchers have used it to probe neural communications of an intact brain (of Drosophila[37] or mouse[38]), electrical spiking of bacteria (E. coli[17]), and human stem-cell derived cardiomyocyte.[39]

References

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