Channelrhodopsins are a subfamily of opsin proteins that function as light-gated ion channels. They serve as sensory photoreceptors in unicellular green algae, controlling phototaxis, i.e. movement in response to light. Expressed in cells of other organisms, they enable the use of light to control intracellular acidity, calcium influx, electrical excitability, and other cellular processes. Three channelrhodopsins are currently known: Channelrhodopsin-1 (ChR1), Channelrhodopsin-2 (ChR2), and Volvox Channelrhodopsin (VChR1). All known Channelrhodopsins are nonspecific cation channels, conducting H+, Na+, K+, and Ca2+ ions.
Channelrhodopsins were first discovered to be a single-component light-activated cation channel from the green algae Chlamydomonas reinhardtii by Georg Nagel and Peter Hegemann in 2002. Channelrhodopsin-2 (ChR2), which was also isolated from Chlamydomonas reinhardtii, was similarly discovered by Peter Hegemann's group in 2001, and submitted directly to GenBank, before being characterized by Georg Nagel's group and discovered independently by John Spudich's group in 2002. In collaboration with Peter Hegemann, along with Ernst Bamberg and with Georg Nagel as first and corresponding author, it was demonstrated that channelrhodopsin-2 is also a directly light-gated ion channel like ChR1. In 2005, three groups sequentially established ChR2 as a tool for genetically targeted optical remote control (optogenetics) of neurons, neural circuits and behavior. At first, Karl Deisseroth's lab (in a paper published in August 2005) demonstrated that ChR2 could be deployed to control mammalian neurons in vitro, achieving temporal precision on the order of milliseconds (both, in terms of delay to spiking, as well as in terms of temporal jitter). This was a significant finding, since firstly, all opsins (microbial as well as vertebrate) require retinal as the light-sensing co-factor, and it was unclear, if central mammalian nerve cells would contain sufficient retinal levels - but surprisingly, they do. Secondly, it showed despite the small single-channel conductance, sufficient potency to drive mammalian neurons above action potential threshold. Thirdly, it demonstrated channelrhodopsin to be the first optogenetic tool, with which neural activity could be controlled with the temporal precision at which neurons operate (a few milliseconds); an earlier tool for photostimulation, cHARGe, demonstrated proof of principle in cultured neurons but was never usable  since it operated with a precision on the order of seconds, was highly variable, and did not allow control of individual action potentials. Five months later (December 2005), a second study was published by Peter Hegemann's and Stefan Herlitze's groups confirming the ability of ChR2 to control the activity of vertebrate neurons, at this time in the chick spinal cord. This study was also the first, where ChR2 was expressed alongside an optical silencer, vertebrate rhodopsin-4 in this case, demonstrating for the first time, that excitable cells could be activated and silenced using these two tools simultaneously, but illuminating the tissue at different wavelengths. In the same month, the groups of Alexander Gottschalk and Ernst Bamberg (with Georg Nagel taking the experimental lead) demonstrated that ChR2, if expressed in specific neurons or muscle cells, can evoke predictable behaviours, i.e. can control the nervous system of an intact animal, which in this case was the invertebrate C. elegans. This was the first study, using the remote control via ChR2 to steer the behaviour of an animal. And it was also the first study, that deployed ChR2 for an optogenetic experiment - i.e. that rendered genetically specified cell types subject to optical remote control, while the other two studies, did not specifically target ChR2 expression genetically. Although both aspects had been illustrated earlier that year by another group, the Miesenböck lab, deploying the indirectly light-gated ion channel P2X2, it was henceforth microbial opsins like channelrhodopsin that dominated the field of genetically targeted remote control of excitable cells, due to the power, speed, targetability, ease of use, and temporal precision of direct optical activation, not requiring any external chemical compound such as caged ligands.
To overcome its principle downsides - the small single-channel conductance (especially in steady-state), the fixation on one optimal excitation wavelength (~470 nm, blue) as well as the relatively long recovering time, not permitting controlled firing of neurons above 20–40 Hz - ChR2 has been optimized using genetic engineering: The first optimization involved the point mutation H134R (exchanging the amino acid Histidine in position 134 of the native protein for an Arginine), and published in the same paper, that established ChR2 as an optogenetic tool in C. elegans. Further improvements were mainly carried by the close collaboration between the groups of Peter Hegemann and Karl Deisseroth. They included the introduction of the point mutation C128S, which made the resulting ChR2-derivative a step-function tool, that stays in the open state once "switched on" by blue light, until it is switched off by yellow light - a modification that deteriorates temporal precision, but greatly increases light sensitivity (by two orders of magnitude). One year later (2010) the same authors introduced another mutation into the native molecule, E123T, yielding the ChR2-derivative ChETA, which does not only feature a higher single-channel conductance (in the desensitized/steady state), but also a much faster on- and off-kinetics, permitting the control of individual action potentials at frequencies of at least up to 200 Hz (in appropriate cell types). Even before these achievements, Roger Tsien's lab had also optimized ChR2 towards the same direction (higher steady-state conductance), by creating chimeras of ChR1 and ChR2 and mutating them at decisive amino acids, yielding the tools ChEF and ChIEF. Finally, the groups of Hegemann and Deisseroth discovered VChR1 in the multicellular algae Volvox carteri, and thus provided a tool - comparable to ChR2 - but with a red-shifted absorption spectrum, thus allowing excitation of two distinct cell populations at two distinct wavelengths.
Karl Deisseroth's group has also taken the lead in developing optimal viral vectors for genetic targeting of ChR2 and its derivatives, thereby pioneering many optogenetic applications in actual experiments, alone or in collaboration, including the genetically targeted remote control in rodents in vivo, the optogenetic induction of learning in rodents, the experimental treatment of Parkinson's disease in rats, the combination with imaging (all-optical systems) and the combination with fMRI (opto-fMRI). Other labs have pioneered essential applications of ChR2 in paradigms such as the mapping of long-range and local neural circuits, its expression from a transgenic locus - directly or in the Cre-lox conditional paradigm - as well as the two-photon excitation of ChR2, permitting the activation of individual cells.
Structurally, channelrhodopsins are retinylidene proteins. They are seven-transmembrane proteins like rhodopsin, and contain the light-isomerizable chromophore all-trans-retinal (an aldehyde derivative of vitamin A). The retinal chromophore is covalently linked to the rest of the protein via a protonated Schiff base. Whereas most 7-transmembrane proteins are G protein-coupled receptors that open other ion channels indirectly via second messengers (i.e. they are metabotropic), channelrhodopsins directly form ion channels (i.e. they are ionotropic). This makes cellular depolarization extremely fast, robust, and useful for bioengineering and neuroscience applications, including photostimulation.
ChR2 absorbs blue light with an absorption and action spectrum maximum at 480 nm. When the all-trans-retinal complex absorbs a photon, it induces a conformational change from all-trans to 13-cis-retinal. This conformational change introduces a further conformational change in the transmembrane protein, opening the pore to at least 6Å. Within a few milliseconds, the retinal relaxes back to the all-trans form, closing the pore and stopping the flow of ions.
The C-terminal end of Channelrhodopsin-2 extends into the intracellular space and can be replaced by fluorescent proteins without affecting channel function. This kind of fusion construct can be very useful to visualize the morphology of ChR2 expressing cells. Channel kinetics can be modified by point mutations close to the retinal binding pocket. For example, closing of the channel after optical activation can be substantially delayed by mutating a specific protein residue, C128. This modification results in a super-sensitive Channelrhodopsin that can be opened by a blue light pulse and closed by a green or yellow light pulse. Mutating the E123 residue accelerates channel kinetics, and the resulting ChR2 mutants have been used to spike neurons at up to 200 Hz. T159 mutants display increased photocurrents, and a combination of T159 and E123 (ET/TC) is both faster and more powerful than the original ChR2. In the future, directed molecular engineering might also be applied to develop channelrhodopsins with altered spectral sensitivity.
Channelrhodopsins can be readily expressed in excitable cells such as neurons using a variety of transfection techniques (viral transfection, electroporation, gene gun). The light absorbing pigment retinal is already present in most cells (of vertebrates) in the form of Vitamin A. This makes depolarization of excitable cells very straightforward, useful for many bioengineering and neuroscience applications such as photostimulation of neurons for probing of neural circuits. The blue-light sensitive ChR2 and the yellow light-activated chloride pump halorhodopsin together enable multiple-color optical activation and silencing of neural activity with millisecond precision. VChR1 form from the colonial alga Volvox carteri absorbs maximally at 535 nm and had been used to stimulate cells with yellow light (580 nm). The emerging field of controlling networks of genetically modified cells with light has been termed Optogenetics.
Using fluorescently labeled ChR2, light-stimulated axons and synapses can be identified in intact brain tissue. This is useful to study the molecular events during the induction of synaptic plasticity. ChR2 has also been used to map long-range connections from one side of the brain to the other, and to map the spatial location of specific inputs on the dendritic tree of individual neurons.
The behavior of transgenic animals expressing ChR2 in subpopulations of neurons can be remote-controlled by intense blue light. This has been demonstrated in nematodes, fruit flies, zebrafish, and in mice. Visual function in blind mice can be partially restored by expressing ChR2 in inner retinal cells. In the future, ChR2 might also find medical applications, e.g. in certain forms of retinal degeneration or for deep brain stimulation.
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