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From Channelrhodopsins to Optogenetics ACCESS Perspective OPEN From channelrhodopsins to optogenetics ACCESS From channelrhodopsins to optogenetics We did not expect that research on the and identified the role of Ca2þ influx in forming a single protein complex (Braun molecular mechanism of algal phototaxis flagellar beat frequency changes (Halldal, & Hegemann, 1999). or archaeal light-driven ion transport 1957, Schmidt & Eckert, 1976). Then Oleg In parallel, biophysicists had character- might interest readers of a medical Sineshchekov from Moscow State Uni- ized the precise nature of light-regulated journal when we conceived and per- versity recorded electrical light responses ion transport across cellular membranes. formed our experiments a decade ago. On from Haematococcus pluvialis, an alga Some of these studies started with the other hand, it did not escape our known for the production of the anti- investigations on animal rhodopsin and attention that channelrhodopsin is helping oxidant Astaxanthine (Litvin et al, 1978). even suggested rhodopsin-mediated an ever-increasing number of researchers Oleg used a suction pipette technique light-induced calcium entry with rhodop- to address their specific questions. For applied at the time by Dennis Baylor for sin itself as the carrier for calcium (Cone, example, the channelrhodopsin approach recording photocurrents from bovine 1972). Several decades later, we know is used to study the molecular events photoreceptor rods and cones. But Oleg’s that animal-type rhodopsins are G pro- during the induction of synaptic plasticity publication gave no hints about the type tein-coupled receptors indirectly modu- or to map long-range connections from of photoreceptor involved. Kenneth W. lating ion channel activity via signalling one side of the brain to the other, and to Foster however, a physicist at Mount molecules. A big surprise was the map the spatial location of inputs on the Sinai School of Medicine re-analysed discovery of the first rhodopsin in a dendritic tree of individual neurons. The published action spectra for phototactic procaryote (Oesterhelt & Stoeckenius, current applications have been summar- movement of algae and postulated that 1971). This ‘bacteriorhodopsin’ is a ized in a number of recent reviews (Fenno light-driven proton pump and meanwhile et al, 2011; Yizhar et al, 2011; Zhang et al, the best-studied membrane protein. For 2011). Here, we give personal insight into » ...the photoreceptor and our considerations important are the the history of the discovery of channel- ion channel were intimately electrical studies on bacteriorhodopsin rhodopsin and a biophysical perspective linked, forming a single (BR) which started in the mid-1970s on this remarkable class of proteins that protein... (Bamberg, 1977; Herrmann & Rayfield, has been the main topic of our research « 1976), confirming and detailing the light- since the 1990s. activated proton pumping function of BR. the sensory photoreceptor is rhodopsin One of the big advantages of bacterior- (Foster & Smyth, 1980). Ken substan- hodopsin was its ready availability and Channelrhodopsin’s roots tiated his claim by restoring behavioural its unusual stability at room temperature. light responses in blind algae by com- Paradigms changed with the tremendous The discovery of channelrhodopsin is based plementation with retinal and retinal success of gene technology, when pro- on two quite different research fields, analogues (Foster et al, 1984). However, teins could be investigated without the studies on living algae and experiments the photoreceptor field did not really need of protein purification, simply by on reconstituted microbial rhodopsins. understand the importance of the claim expressing the protein in the cellular A number of researchers have char- and progress remained slow. Years system of choice. Even though a lot acterized the swimming behaviour and later, Peter Hegemann’s former graduate was already known about BR, the exact light responses of motile microalgae student Hartmann Harz recorded photo- voltage dependence of proton pumping over at least 140 years (Fig 1A). Early currents from Chlamydomonas by revi- was unclear. Therefore, Ernst Bamberg studies on green microalgae root back to talizing Oleg’s suction pipette technique and Georg Nagel decided to study BR in L.G. Treviranus (Treviranus, 1817) and for a Chlamydomonas cell wall-deficient the membrane of an animal cell, the behavioural responses were described mutant. He recorded action spectra, oocyte of Xenopus laevis (Fig 1B). This by A. Famintzin from St. Petersburg which led to the proposal that the gene transfer allowed the exact determi- University in 1878 (Famintzin, 1878). photocurrents were mediated by a rho- nation of the voltage dependence of light- During helical swimming of the green dopsin, the photoreceptor that also med- activated proton pumping in a wide alga Chlamydomonas, its orange eye iates phototaxis and phobic responses voltage range (Nagel et al, 1995). Later, signals to the flagella to alter the flagellar (Harz & Hegemann, 1991). The ultra-fast the ClÀ-pump halorhodopsin and the beating plane (Mast, 1916). Researchers appearance of the photoreceptor current phototaxis-mediating sensory rhodop- at Stanford University implicated Mg2þ suggested that the photoreceptor and sins were also studied successfully in and Ca2þ in the behavioural responses ion channel were intimately linked, oocytes (Schmies et al, 2001). ß 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. EMBO Mol Med (2013) 5, 173–176 173 Perspective www.embomolmed.org From channelrhodopsins to optogenetics Discovery of channelrhodopsins During this collaboration we also » ...demonstrated the expressed ChR2 in human kidney and functionality of ChR2 in After many years of hard work, the other mammalian cells, showed large the retina of blind mice, Hegemann group had not succeeded in light-induced membrane depolarization, purifying the photoreceptors biochemi- and suggested that ChR2 could also be hippocampal neurons, spine cally, due to the scarceness, instability, used in other cells to depolarize these of living chicken embryos, and heterogeneity of the proteins. A new cells with light (Nagel et al, 2003). PC12 cells, mouse brain slices approach needed to be initiated. In 2001, and transgenic worms... Suneel Kateriya in the Hegemann group « identified novel DNA sequences that Transfer to neuroscience, encoded for large microbial-type rhodop- take-off of optogenetics mice, hippocampal neurons, spine of sins in a cDNA data bank from Chlamy- living chicken embryos, PC12 cells, domonas. To explore their function, our Taking our suggestion into account, mouse brain slices and transgenic worms fruitful collaboration started when Georg several groups began to work with ChRs, (Bi et al, 2006; Boyden et al, 2005; Nagel expressed the two rhodopsins in primarily with a truncated version of Ishizuka et al, 2006; Li et al, 2005; Nagel Xenopus oocytes. We demonstrated that ChR2 that we had shown to be sufficient et al, 2005). These publications were both DNAs encode directly light-gated for light-gated cation conductance. The the beginning of the field that we now cation channels. We named these new seminal publications appeared in 2005 term optogenetics. In this emerging field, genes channelrhodopsin-1 (ChR1) and and 2006 and came from the laboratories researchers express light-activated pro- channelrhodopsin-2 (ChR2; Nagel et al, of Zhuo Pan, Karl Deisseroth, Stefan teins in well-defined cell subpopulations 2002, 2003; Fig 1C and D). These Herlitze, Hiromu Yawo and Alexander of a neuronal context and activate these experiments were the undisputable proof Gottschalk, who demonstrated the func- cells by using short light pulses. Opto- for a completely new class of rhodopsins. tionality of ChR2 in the retina of blind genetic studies started earlier, for example ABMin0 3 6 CW2 White light H17 C D K+ 2µA 1s Na+ Ca2+ Figure 1. The discovery of channelrhodopsins. A. Phototaxis of the Chlamydomonas wild type strain CW2 and the channelrhodopsin-defective mutant H17. B. Electrophysiological recording from oocytes (in the centre, with two electrodes, left and right) allows investigation of light-induced (via light guide, below oocyte) currents, e.g. mediated by rhodopsins. C. Light-induced currents mediated by channelrhodopsin-2 (two illuminations for 1 s, blue bars) at À100 mV. D. Model of channelrhodopsin opening, following light absorption and isomerization of covalently bound retinal. 174 ß 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. EMBO Mol Med (2013) 5, 173–176 www.embomolmed.org Perspective Peter Hegemann and Georg Nagel in Gero Miesenbo¨ck’s and Rich Kramer’s of unknown function, which is routinely opening path and that the kinetics of dark laboratories, when researchers imple- omitted for optogenetic purposes. The state recovery is many orders of magni- mented photosensitive actuators into light-absorbing chromophore retinal, a tudes slower. Besides the OH-cluster, host cells (Banghart et al, 2004; Zemel- vitamin A derivative, is embedded within two residues, C128 and D156 (DC-pair in man et al, 2002). These systems turned the hydrophobic center of the seven Fig 2) are of fundamental importance out to be either too complicated or the helices (Fig 2). The retinal is connected
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