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• W2104579888 abstract "The capture and utilization of light is an exquisitely evolved process. The single-component microbial opsins, although more limited than multicomponent cascades in processing, display unparalleled compactness and speed. Recent advances in understanding microbial opsins have been driven by molecular engineering for optogenetics and by comparative genomics. Here we provide a Primer on these light-activated ion channels and pumps, describe a group of opsins bridging prior categories, and explore the convergence of molecular engineering and genomic discovery for the utilization and understanding of these remarkable molecular machines. The capture and utilization of light is an exquisitely evolved process. The single-component microbial opsins, although more limited than multicomponent cascades in processing, display unparalleled compactness and speed. Recent advances in understanding microbial opsins have been driven by molecular engineering for optogenetics and by comparative genomics. Here we provide a Primer on these light-activated ion channels and pumps, describe a group of opsins bridging prior categories, and explore the convergence of molecular engineering and genomic discovery for the utilization and understanding of these remarkable molecular machines. Diverse and elegant mechanisms have evolved to enable organisms to harvest light for a variety of survival functions, including energy generation and the identification of suitable environments. A major class of light-sensitive protein consists of 7-transmembrane (TM) rhodopsins that can be found across all kingdoms of life and serve a diverse range of functions (Figure 1). Many prokaryotes employ these proteins to control proton gradients and to maintain membrane potential and ionic homeostasis, and many motile microorganisms have evolved opsin-based photoreceptors to modulate flagellar beating or flagellar motor rotation and thereby direct phototaxis toward environments with optimal light intensities for photosynthesis. Owing to their structural simplicity (both light-sensing and effector domains are encoded within a single gene) and fast kinetics, microbial opsins can be treated as precise and modular photosensitization components for introduction into non-light-sensitive cells to enable rapid optical control of specific cellular processes. In recent years, the development of cellular perturbation tools based on these and other light-sensitive proteins has resulted in a technology called optogenetics (Deisseroth, 2011Deisseroth K. Optogenetics.Nat. Methods. 2011; 8: 26-29Crossref PubMed Scopus (1329) Google Scholar, Deisseroth et al., 2006Deisseroth K. Feng G. Majewska A.K. Miesenböck G. Ting A. Schnitzer M.J. Next-generation optical technologies for illuminating genetically targeted brain circuits.J. Neurosci. 2006; 26: 10380-10386Crossref PubMed Scopus (565) Google Scholar), which refers to the integration of genetic and optical control to achieve gain or loss of function of precisely defined events within specified cells of living tissue. Details of practical application for neuroscience have been recently summarized elsewhere (Yizhar et al., 2011aYizhar O. Fenno L.E. Davidson T.J. Mogri M. Deisseroth K. Optogenetics in neural systems.Neuron. 2011; 71: 9-34Abstract Full Text Full Text PDF PubMed Scopus (1337) Google Scholar, Zhang et al., 2010Zhang F. Gradinaru V. Adamantidis A.R. Durand R. Airan R.D. de Lecea L. Deisseroth K. Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures.Nat. Protoc. 2010; 5: 439-456Crossref PubMed Scopus (548) Google Scholar). The experimental potential of optogenetics has triggered a surge of genome prospecting and molecular engineering to expand the repertoire of tools and generate new classes of functionality, all of which have catalyzed further mechanistic studies of microbial proteins such as channelrhodopsins (ChRs). Here we provide a Primer on the structural and functional diversity of the microbial opsins, introduce an array of new sequences that inform mechanistic understanding of function, and explore resulting inferences into the principles of operation of this widespread and remarkably evolved class of proteins. Each opsin protein requires the incorporation of retinal, a vitamin A-related organic photon-absorbing cofactor, to enable light sensitivity; this opsin-retinal complex is referred to as rhodopsin. The retinal molecule is covalently fixed in the binding pocket within the 7-TM helices and forms a protonated retinal Schiff base (RSBH+; Figure 2A ) with a conserved lysine residue located on TM helix seven (TM7). The ionic environment of the RSBH+, heavily influenced by the residues lining the binding pocket, dictates the spectral characteristics of each individual protein; upon absorption of a photon, the retinal chromophore isomerizes and triggers a series of structural changes leading to ion transport, channel opening, or interaction with signaling transducer proteins (discussed below). Opsin genes are divided into two distinct superfamilies: microbial opsins (type I) and animal opsins (type II) (Spudich et al., 2000Spudich J.L. Yang C.S. Jung K.H. Spudich E.N. Retinylidene proteins: structures and functions from archaea to humans.Annu. Rev. Cell Dev. Biol. 2000; 16: 365-392Crossref PubMed Scopus (503) Google Scholar). Although both opsin families encode 7-TM structures (Luecke et al., 1999Luecke H. Schobert B. Richter H.T. Cartailler J.P. Lanyi J.K. Structure of bacteriorhodopsin at 1.55 A resolution.J. Mol. Biol. 1999; 291: 899-911Crossref PubMed Scopus (1301) Google Scholar, Palczewski et al., 2000Palczewski K. Kumasaka T. Hori T. Behnke C.A. Motoshima H. Fox B.A. Le Trong I. Teller D.C. Okada T. Stenkamp R.E. et al.Crystal structure of rhodopsin: A G protein-coupled receptor.Science. 2000; 289: 739-745Crossref PubMed Scopus (5023) Google Scholar), sequence homology between the two families is practically nonexistent; homology within families, however, is high (25%–80% sequence similarity; Man et al., 2003Man D. Wang W. Sabehi G. Aravind L. Post A.F. Massana R. Spudich E.N. Spudich J.L. Béjà O. Diversification and spectral tuning in marine proteorhodopsins.EMBO J. 2003; 22: 1725-1731Crossref PubMed Scopus (241) Google Scholar). Type I opsin genes are found in prokaryotes, algae, and fungi and control diverse functions including phototaxis, energy storage, development, and retinal biosynthesis (Spudich, 2006Spudich J.L. The multitalented microbial sensory rhodopsins.Trends Microbiol. 2006; 14: 480-487Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar). Type I opsins utilize the all-trans isomer of retinal, which isomerizes to the 13-cis configuration upon photon absorption (Figure 2A, top). The activated retinal molecule in type I rhodopsins remains associated with its opsin protein partner and thermally reverts to the all-trans state while maintaining a covalent bond to its protein partner (Haupts et al., 1997Haupts U. Tittor J. Bamberg E. Oesterhelt D. General concept for ion translocation by halobacterial retinal proteins: the isomerization/switch/transfer (IST) model.Biochemistry. 1997; 36: 2-7Crossref PubMed Scopus (126) Google Scholar). This reversible reaction occurs rapidly and is critical for allowing microbial rhodopsins to modulate neuronal activity at high frequencies when used as optogenetic tools (Boyden et al., 2005Boyden E.S. Zhang F. Bamberg E. Nagel G. Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity.Nat. Neurosci. 2005; 8: 1263-1268Crossref PubMed Scopus (3373) Google Scholar, Zhang et al., 2006Zhang F. Wang L.P. Boyden E.S. Deisseroth K. Channelrhodopsin-2 and optical control of excitable cells.Nat. Methods. 2006; 3: 785-792Crossref PubMed Scopus (552) Google Scholar, Zhang et al., 2007aZhang F. Aravanis A.M. Adamantidis A. de Lecea L. Deisseroth K. Circuit-breakers: optical technologies for probing neural signals and systems.Nat. Rev. Neurosci. 2007; 8: 577-581Crossref PubMed Scopus (505) Google Scholar, Ishizuka et al., 2006Ishizuka T. Kakuda M. Araki R. Yawo H. Kinetic evaluation of photosensitivity in genetically engineered neurons expressing green algae light-gated channels.Neurosci. Res. 2006; 54: 85-94Crossref PubMed Scopus (298) Google Scholar); fortuitously, mammalian brains, and indeed the vertebrate tissues thus far examined, contain sufficient levels of retinal so that additional retinal does not need to be supplemented to achieve optical control (Zhang et al., 2006Zhang F. Wang L.P. Boyden E.S. Deisseroth K. Channelrhodopsin-2 and optical control of excitable cells.Nat. Methods. 2006; 3: 785-792Crossref PubMed Scopus (552) Google Scholar). In contrast, type II opsin genes are present only in higher eukaryotes and are mainly responsible for vision (Sakmar, 2002Sakmar T.P. Structure of rhodopsin and the superfamily of seven-helical receptors: the same and not the same.Curr. Opin. Cell Biol. 2002; 14: 189-195Crossref PubMed Scopus (101) Google Scholar). A small fraction of type II opsins also play roles in circadian rhythm and pigment regulation (Sakmar, 2002Sakmar T.P. Structure of rhodopsin and the superfamily of seven-helical receptors: the same and not the same.Curr. Opin. Cell Biol. 2002; 14: 189-195Crossref PubMed Scopus (101) Google Scholar, Shichida and Yamashita, 2003Shichida Y. Yamashita T. Diversity of visual pigments from the viewpoint of G protein activation—comparison with other G protein-coupled receptors.Photochem. Photobiol. Sci. 2003; 2: 1237-1246Crossref PubMed Scopus (20) Google Scholar). Type II opsins primarily function as G protein-coupled receptors (GPCRs) and appear to all use the 11-cis isomer of retinal (or derivatives) for photon absorption (Figure 2A, bottom). Upon illumination, 11-cis retinal isomerizes into the all-trans configuration and initiates protein-protein interactions (not ion flux) that trigger the visual phototransduction second messenger cascade. Unlike the situation in type I rhodopsins, here the retinal dissociates from its opsin partner after isomerization into the all-trans configuration, and a new 11-cis retinal must be recruited. Due to these chromophore turnover reactions and the requirement for interaction with downstream biochemical signal transduction partners, type II opsins effect cellular changes with slower kinetics compared to type I opsins. The power of using microbial opsins to modulate neuronal electrical activity has also stimulated strong interest in using light to control biochemical events in cells. Although not the focus here, it is worth noting that structure-function work in type II vertebrate opsins from many laboratories (such as Kim et al., 2005Kim J.M. Hwa J. Garriga P. Reeves P.J. RajBhandary U.L. Khorana H.G. Light-driven activation of beta 2-adrenergic receptor signaling by a chimeric rhodopsin containing the beta 2-adrenergic receptor cytoplasmic loops.Biochemistry. 2005; 44: 2284-2292Crossref PubMed Scopus (129) Google Scholar) inspired the design of synthetic opsins for controlling specific biochemical events in freely moving mammals. By replacing the intracellular loops of bovine rhodopsin with the intracellular loops from GPCRs, an expanding family of synthetic rhodopsins called optoXRs has enabled optical control of Gs, Gq, or Gi signaling in neuronal settings (Airan et al., 2009Airan R.D. Thompson K.R. Fenno L.E. Bernstein H. Deisseroth K. Temporally precise in vivo control of intracellular signalling.Nature. 2009; 458: 1025-1029Crossref PubMed Scopus (536) Google Scholar, Oh et al., 2010Oh E. Maejima T. Liu C. Deneris E. Herlitze S. Substitution of 5-HT1A receptor signaling by a light-activated G protein-coupled receptor.J. Biol. Chem. 2010; 285: 30825-30836Crossref PubMed Scopus (107) Google Scholar). It is also noteworthy that several groups have expanded control of intracellular signaling by engineering non-opsin-based light-regulated proteins to modulate general second messengers such as cAMP and cGMP (Schröder-Lang et al., 2007Schröder-Lang S. Schwärzel M. Seifert R. Strünker T. Kateriya S. Looser J. Watanabe M. Kaupp U.B. Hegemann P. Nagel G. Fast manipulation of cellular cAMP level by light in vivo.Nat. Methods. 2007; 4: 39-42Crossref PubMed Scopus (200) Google Scholar). For example, the photoactivated adenylyl cyclases (PACs) can be so employed and use the ubiquitous FAD as a cofactor for photoactivation, although early efforts using PACs from Euglena gracilis were hampered by a combination of high levels of basal activity in the dark, poor protein solubility, and large (∼3 kbp) transgene size (Schröder-Lang et al., 2007Schröder-Lang S. Schwärzel M. Seifert R. Strünker T. Kateriya S. Looser J. Watanabe M. Kaupp U.B. Hegemann P. Nagel G. Fast manipulation of cellular cAMP level by light in vivo.Nat. Methods. 2007; 4: 39-42Crossref PubMed Scopus (200) Google Scholar). More recently, a smaller PAC derivative with lower dark activity from the soil bacterium Beggiatoa has been shown in neurons and Drosophila to alter membrane currents and influence behavior (Stierl et al., 2011Stierl M. Stumpf P. Udwari D. Gueta R. Hagedorn R. Losi A. Gärtner W. Petereit L. Efetova M. Schwarzel M. et al.Light modulation of cellular cAMP by a small bacterial photoactivated adenylyl cyclase, bPAC, of the soil bacterium Beggiatoa.J. Biol. Chem. 2011; 286: 1181-1188Crossref PubMed Scopus (274) Google Scholar). Yet the microbial opsins remain remarkable for both (1) unitary encoding of light sensation and final effector capability by a single compact gene and (2) virtually zero dark activity, along with millisecond-scale response to well-tolerated wavelengths and intensities of light. These core properties have provided a foundation for, and motivated, further investigation and engineering. Bacteriorhodopsin (BR) was first described as a single-component TM protein capable of translocating protons from the intracellular to the extracellular space (Oesterhelt and Stoeckenius, 1971Oesterhelt D. Stoeckenius W. Rhodopsin-like protein from the purple membrane of Halobacterium halobium.Nat. New Biol. 1971; 233: 149-152Crossref PubMed Scopus (1642) Google Scholar). Haloarchaea express BR at high levels under low-oxygen conditions to maintain a proton gradient across the cellular membrane to drive ATP synthesis and maintain cellular energetics in the absence of respiration (Michel and Oesterhelt, 1976Michel H. Oesterhelt D. Light-induced changes of the pH gradient and the membrane potential in H. halobium.FEBS Lett. 1976; 65: 175-178Crossref PubMed Scopus (106) Google Scholar, Racker and Stoeckenius, 1974Racker E. Stoeckenius W. Reconstitution of purple membrane vesicles catalyzing light-driven proton uptake and adenosine triphosphate formation.J. Biol. Chem. 1974; 249: 662-663Abstract Full Text PDF PubMed Google Scholar). During the proton translocation process, BR undergoes a cascade of photointermediate states, and each state can be identified by a distinct spectral signature (Lanyi, 2004Lanyi J.K. Bacteriorhodopsin.Annu. Rev. Physiol. 2004; 66: 665-688Crossref PubMed Scopus (493) Google Scholar). Photon absorption by BR first initiates the isomerization of the bound retinal from the all-trans to the 13-cis configuration (Figures 2A and 2B), thereby triggering a series of proton-transfer reactions that constitute the proton translocation mechanism (Figure 2C). This proton transport process, like chloride transport in halorhodopsins, is elegantly evolved to be (necessarily) spatially discontinuous to prevent passive back-diffusion of the ion down the gradient. Internal proton translocation begins when retinal isomerization triggers a conformational change in the protein and shifts the dipole of the RSBH+. This dipole shift raises the pKa of the RSB, thereby resulting in the release of the proton to its nearby acceptor D85 (Figure 2D), and proton movement triggers additional changes in the protein. In the BR pump, the proton is released to the extracellular milieu via a proton release site defined by two surface glutamates. The RSB then indirectly absorbs a second proton from the cytoplasm, such that the photocycle can repeat with absorption of another photon. In sensory rhodopsins (SRs) the internal proton transfer and subsequent structural changes trigger conformational changes in the transducer molecule (Htr) interacting with the rhodopsin. Certain aspects of the internal proton translocation process are conserved across many type I opsins; for example, locations of the carboxylate Schiff base proton acceptor and donor on the third TM helix are conserved across type I proton pumps. BR-type proton-pumping opsins have been found across other kingdoms of life; for example, proteorhodopsins (PRs) have been found in marine proteobacteria with photocycles similar to that of BR (Váró et al., 2003Váró G. Brown L.S. Lakatos M. Lanyi J.K. Characterization of the photochemical reaction cycle of proteorhodopsin.Biophys. J. 2003; 84: 1202-1207Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). Because marine PRs share a high degree of sequence similarity across species and have action spectra that are tuned according to the ocean depth and latitude of their origin, several groups have explored genomic approaches to understand opsin spectral tuning (Man et al., 2003Man D. Wang W. Sabehi G. Aravind L. Post A.F. Massana R. Spudich E.N. Spudich J.L. Béjà O. Diversification and spectral tuning in marine proteorhodopsins.EMBO J. 2003; 22: 1725-1731Crossref PubMed Scopus (241) Google Scholar). Interestingly, absorption variance between blue and green wavelengths can depend on a single amino acid residue (Béjà et al., 2001Béjà O. Spudich E.N. Spudich J.L. Leclerc M. DeLong E.F. Proteorhodopsin phototrophy in the ocean.Nature. 2001; 411: 786-789Crossref PubMed Scopus (636) Google Scholar, Man et al., 2003Man D. Wang W. Sabehi G. Aravind L. Post A.F. Massana R. Spudich E.N. Spudich J.L. Béjà O. Diversification and spectral tuning in marine proteorhodopsins.EMBO J. 2003; 22: 1725-1731Crossref PubMed Scopus (241) Google Scholar), but attempts to transfer mutations conferring spectral tuning from PR to other microbial opsins have met with limited success (Yoshitsugu et al., 2009Yoshitsugu M. Yamada J. Kandori H. Color-changing mutation in the E-F loop of proteorhodopsin.Biochemistry. 2009; 48: 4324-4330Crossref PubMed Scopus (19) Google Scholar). More extensive high-resolution crystal structures and molecular dynamics/molecular modeling of PRs, fungal opsins, and BRs may provide an opportunity to deepen understanding and extend functionality. A BR-type proton pump called Archaerhodopsin-3 (initially identified by Ihara et al., 1999Ihara K. Umemura T. Katagiri I. Kitajima-Ihara T. Sugiyama Y. Kimura Y. Mukohata Y. Evolution of the archaeal rhodopsins: evolution rate changes by gene duplication and functional differentiation.J. Mol. Biol. 1999; 285: 163-174Crossref PubMed Scopus (139) Google Scholar) has been shown to allow detection of voltage transients in neurons through generation of a voltage-dependent optical signal (Kralj et al., 2011Kralj J.M. Douglass A.D. Hochbaum D.R. Maclaurin D. Cohen A.E. Optical recording of action potentials in mammalian neurons using a microbial rhodopsin.Nat. Methods. 2011; (Published online November 27, 2011)https://doi.org/10.1038/nmeth.1782Crossref PubMed Scopus (344) Google Scholar); although it remains to be seen whether this functionality will be of utility in vivo, this class of experiment represents a potentially interesting value for the microbial opsins in neuroscience. The same protein (Archaerhodopsin-3) is also capable of generating hyperpolarizing currents that can be used to inhibit neural activity (Chow et al., 2010Chow B.Y. Han X. Dobry A.S. Qian X. Chuong A.S. Li M. Henninger M.A. Belfort G.M. Lin Y. Monahan P.E. Boyden E.S. High-performance genetically targetable optical neural silencing by light-driven proton pumps.Nature. 2010; 463: 98-102Crossref PubMed Scopus (880) Google Scholar), as with other BR-type proton pumps (and indeed BR itself, optimized for mammalian expression; Gradinaru et al., 2010Gradinaru V. Zhang F. Ramakrishnan C. Mattis J. Prakash R. Diester I. Goshen I. Thompson K.R. Deisseroth K. Molecular and cellular approaches for diversifying and extending optogenetics.Cell. 2010; 141: 154-165Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar); however, the efflux of protons elicited by all of these proton pumps under typical steady-illumination experimental conditions will result in decreased extracellular pH. A distinct class of outward current-generating archaeal opsins known as halorhodopsins (HRs) (Matsuno-Yagi and Mukohata, 1977Matsuno-Yagi A. Mukohata Y. Two possible roles of bacteriorhodopsin; a comparative study of strains of Halobacterium halobium differing in pigmentation.Biochem. Biophys. Res. Commun. 1977; 78: 237-243Crossref PubMed Scopus (255) Google Scholar) instead use chloride as the charge carrier. HRs control gradients across the cell membrane by transporting chloride ions from the extracellular medium into the cell (Bamberg et al., 1984Bamberg E. Hegemann P. Oesterhelt D. Reconstitution of halorhodopsin in black lipid membranes.Prog. Clin. Biol. Res. 1984; 164: 73-79PubMed Google Scholar, Schobert and Lanyi, 1982Schobert B. Lanyi J.K. Halorhodopsin is a light-driven chloride pump.J. Biol. Chem. 1982; 257: 10306-10313Abstract Full Text PDF PubMed Google Scholar). The primary photocycle, although qualitatively similar to that of BR, does not show RSBH+ deprotonation (Essen, 2002Essen L.O. Halorhodopsin: light-driven ion pumping made simple?.Curr. Opin. Struct. Biol. 2002; 12: 516-522Crossref PubMed Scopus (96) Google Scholar, Oesterhelt et al., 1985Oesterhelt D. Hegemann P. Tittor J. The photocycle of the chloride pump halorhodopsin. II: Quantum yields and a kinetic model.EMBO J. 1985; 4: 2351-2356Crossref PubMed Scopus (89) Google Scholar) due to a single amino acid substitution of the Asp acceptor with Thr. Therefore after the light-induced retinal isomerization and RSBH+ dipole switch, the proton cannot be released due to the absence of an appropriate acceptor. Instead, a Cl− ion already present in the HR protein is transported from the external side of the RSBH+ chromophore to the internal side (Figure 2D) and is subsequently released into the intracellular space (Kolbe et al., 2000Kolbe M. Besir H. Essen L.O. Oesterhelt D. Structure of the light-driven chloride pump halorhodopsin at 1.8 A resolution.Science. 2000; 288: 1390-1396Crossref PubMed Scopus (478) Google Scholar). An experimental screen (Zhang et al., 2007bZhang F. Wang L.P. Brauner M. Liewald J.F. Kay K. Watzke N. Wood P.G. Bamberg E. Nagel G. Gottschalk A. Deisseroth K. Multimodal fast optical interrogation of neural circuitry.Nature. 2007; 446: 633-639Crossref PubMed Scopus (1366) Google Scholar) revealed that the best known HR (from Halobacterium salinarum) failed to maintain stable photocurrents when expressed heterologously, whereas the HR from the less halophilic Egyptian Natronomonas pharaonis (NpHR) (initially identified by Lanyi et al., 1990Lanyi J.K. Duschl A. Hatfield G.W. May K. Oesterhelt D. The primary structure of a halorhodopsin from Natronobacterium pharaonis. Structural, functional and evolutionary implications for bacterial rhodopsins and halorhodopsins.J. Biol. Chem. 1990; 265: 1253-1260Abstract Full Text PDF PubMed Google Scholar, Scharf and Engelhard, 1994Scharf B. Engelhard M. Blue halorhodopsin from Natronobacterium pharaonis: wavelength regulation by anions.Biochemistry. 1994; 33: 6387-6393Crossref PubMed Scopus (95) Google Scholar) was capable of blocking animal (C. elegans) behavior by hyperpolarizing neurons with electrogenic inward Cl− currents. Pump desensitization is modest, allowing stable, step-like currents over many tens of minutes in response to steady yellow light, but due to the stoichiometry of only one transported ion per photocycle (true for all light-driven pumps), robust expression and fast photocycles are required. Increased heterologous membrane expression can be achieved with addition of trafficking signals from mammalian membrane proteins (Gradinaru et al., 2008Gradinaru V. Thompson K.R. Deisseroth K. eNpHR: a Natronomonas halorhodopsin enhanced for optogenetic applications.Brain Cell Biol. 2008; 36: 129-139Crossref PubMed Scopus (381) Google Scholar), and ultimately this version allowed the first optogenetic inhibition of behavior in mammals (Witten et al., 2010Witten I.B. Lin S.C. Brodsky M. Prakash R. Diester I. Anikeeva P. Gradinaru V. Ramakrishnan C. Deisseroth K. Cholinergic interneurons control local circuit activity and cocaine conditioning.Science. 2010; 330: 1677-1681Crossref PubMed Scopus (365) Google Scholar; reviewed in Yizhar et al., 2011aYizhar O. Fenno L.E. Davidson T.J. Mogri M. Deisseroth K. Optogenetics in neural systems.Neuron. 2011; 71: 9-34Abstract Full Text Full Text PDF PubMed Scopus (1337) Google Scholar). Moreover, by significantly increasing the number of HR molecules on the neuronal membrane, NpHR (in this case, eNpHR3.0)-expressing neurons can even be inhibited by 680 nm far-red light, which is far from the action spectrum peak (Gradinaru et al., 2010Gradinaru V. Zhang F. Ramakrishnan C. Mattis J. Prakash R. Diester I. Goshen I. Thompson K.R. Deisseroth K. Molecular and cellular approaches for diversifying and extending optogenetics.Cell. 2010; 141: 154-165Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar). Additional retinal-binding proteins have been identified from Halobacterium salinarum as behaviorally relevant photosensors (Hildebrand and Dencher, 1975Hildebrand E. Dencher N. Two photosystems controlling behavioural responses of Halobacterium halobium.Nature. 1975; 257: 46-48Crossref PubMed Scopus (124) Google Scholar, Takahashi et al., 1985Takahashi T. Mochizuki Y. Kamo N. Kobatake Y. Evidence that the long-lifetime photointermediate of s-rhodopsin is a receptor for negative phototaxis in Halobacterium halobium.Biochem. Biophys. Res. Commun. 1985; 127: 99-105Crossref PubMed Scopus (51) Google Scholar), such as sensory rhodopsins SRI (Bogomolni and Spudich, 1982Bogomolni R.A. Spudich J.L. Identification of a third rhodopsin-like pigment in phototactic Halobacterium halobium.Proc. Natl. Acad. Sci. USA. 1982; 79: 6250-6254Crossref PubMed Scopus (238) Google Scholar, Hildebrand and Dencher, 1975Hildebrand E. Dencher N. Two photosystems controlling behavioural responses of Halobacterium halobium.Nature. 1975; 257: 46-48Crossref PubMed Scopus (124) Google Scholar, Takahashi et al., 1985Takahashi T. Mochizuki Y. Kamo N. Kobatake Y. Evidence that the long-lifetime photointermediate of s-rhodopsin is a receptor for negative phototaxis in Halobacterium halobium.Biochem. Biophys. Res. Commun. 1985; 127: 99-105Crossref PubMed Scopus (51) Google Scholar) and SRII, initially termed phoborhodopsin (Tomioka et al., 1986Tomioka H. Takahashi T. Kamo N. Kobatake Y. Flash spectrophotometric identification of a fourth rhodopsin-like pigment in Halobacterium halobium.Biochem. Biophys. Res. Commun. 1986; 139: 389-395Crossref PubMed Scopus (79) Google Scholar) or P480 (Marwan and Oesterhelt, 1987Marwan W. Oesterhelt D. Signal formation in the halobacterial photophobic response mediated by a fourth retinal protein (P480).J. Mol. Biol. 1987; 195: 333-342Crossref PubMed Scopus (79) Google Scholar). The photocycle of SRs is similar to that of BR with analogous internal proton movements (Spudich, 1998Spudich J.L. Variations on a molecular switch: transport and sensory signalling by archaeal rhodopsins.Mol. Microbiol. 1998; 28: 1051-1058Crossref PubMed Scopus (117) Google Scholar, Spudich and Bogomolni, 1984Spudich J.L. Bogomolni R.A. Mechanism of colour discrimination by a bacterial sensory rhodopsin.Nature. 1984; 312: 509-513Crossref PubMed Scopus (250) Google Scholar), except that light-initiated conformational changes of the opsin are used to activate a closely associated transducer molecule Htr (Figure 1D) (Büldt et al., 1998Büldt G. Heberle J. Dencher N.A. Sass H.J. Structure, dynamics, and function of bacteriorhodopsin.J. Protein Chem. 1998; 17: 536-538PubMed Google Scholar, Chen and Spudich, 2002Chen X. Spudich J.L. Demonstration of 2:2 stoichiometry in the functional SRI-HtrI signaling complex in Halobacterium membranes by gene fusion analysis.Biochemistry. 2002; 41: 3891-3896Crossref PubMed Scopus (42) Google Scholar). When activated, Htr initiates a phosphorylation cascade that controls the directionality of the flagellar motor and directs phototaxis toward green and yellow light (SRI, peak absorption 587 nm) and away from blue light (SRII, peak absorption 487 nm) (Spudich, 2006Spudich J.L. The multitalented microbial sensory rhodopsins.Trends Microbiol. 2006; 14: 480-487Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, Spudich and Bogomolni, 1984Spudich J.L. Bogomolni R.A. Mechanism of colour discrimination by a bacterial sensory rhodopsin.Nature. 1984; 312: 509-513Crossref PubMed Scopus (250) Google Scholar). Given that prokaryotic kinase cascades are fundamentally different from eukaryotic second messengers (Scharf, 2010Scharf B.E. Summary of useful methods for two-component system research.Curr. Opin. Microbiol. 2010; 13: 246-252Crossref PubMed Scopus (31) Google Scholar), opportunities to translate SR function to heterologous systems may be more complicated than with the ion pumps; such an effort could require reconstitution of the entire signal transduction cascade. ChRs are 7-TM proteins capable of conducting passive nonselective cation flow across the cellular membrane upon illumination and, in algae, also mediate intracellular signaling via a long C-terminal extension (Figure 1); for optogenetic applications, only the 7-TM ChR fragments are used, but" @default.
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• W2104579888 title "The Microbial Opsin Family of Optogenetic Tools" @default.
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