Perspective Tools for Optogenetics and Photopharmacology: From Design to Implementation

Optogenetics and photopharmacology are two perspective modern methodologies for control and monitoring of biological processes from an isolated cell to complex cell assemblies and organisms. Both methodologies use optically active components that being introduced into the cells of interest allow for optical control or monitoring of different cellular processes. In optogenetics, genetic materials are introduced into the cells to express light-sensitive proteins or protein constructs. In photopharmacology, photochromic compounds are delivered into a cell directly but not produced inside the cell from a genetic material. The development of both optogenetics and photopharmacology is inseparable from the design of improved tools (protein constructs or organic molecules) optimized for specific applications. Herein, we review the main tools that are used in modern optogenetics and photopharmaclogy and describe the types of cellular processes that can be controlled by these tools. Although a large number of different kinds of optogenetic tools exist, their performance can be evaluated with a limited number of metrics that have to be optimized for specific applications. We classify these metrics and describe the ways of their improvement.

[1]  K. Morokuma,et al.  A crossed molecular beam and ab initio study on the formation of 5- and 6-methyl-1,4-dihydronaphthalene (C11H12) via the reaction of meta-tolyl (C7H7) with 1,3-butadiene (C4H6). , 2015, Physical chemistry chemical physics : PCCP.

[2]  M. Heijde,et al.  The UVR8 UV-B Photoreceptor: Perception, Signaling and Response , 2013, The arabidopsis book.

[3]  Christopher A. Voigt,et al.  Spatiotemporal Control of Cell Signalling Using A Light-Switchable Protein Interaction , 2009, Nature.

[4]  Kunal K. Ghosh,et al.  Advances in light microscopy for neuroscience. , 2009, Annual review of neuroscience.

[5]  J. Spudich,et al.  Characterization of a Highly Efficient Blue-shifted Channelrhodopsin from the Marine Alga Platymonas subcordiformis* , 2013, The Journal of Biological Chemistry.

[6]  K. Deisseroth,et al.  High-efficiency channelrhodopsins for fast neuronal stimulation at low light levels , 2011, Proceedings of the National Academy of Sciences.

[7]  Hiroshi C. Watanabe,et al.  Color tuning in binding pocket models of the chlamydomonas-type channelrhodopsins. , 2011, The journal of physical chemistry. B.

[8]  Sangkyun Lee,et al.  Light-inducible receptor tyrosine kinases that regulate neurotrophin signalling , 2014, Nature Communications.

[9]  B. Epe,et al.  Oxidative DNA damage induced by visible light in mammalian cells: extent, inhibition by antioxidants and genotoxic effects. , 1998, Mutation research.

[10]  S. Gomes,et al.  A Rhodopsin-Guanylyl Cyclase Gene Fusion Functions in Visual Perception in a Fungus , 2014, Current Biology.

[11]  Chao Tang,et al.  A light-inducible organelle-targeting system for dynamically activating and inactivating signaling in budding yeast , 2013, Molecular biology of the cell.

[12]  K. Morokuma,et al.  Global investigation of potential energy surfaces for the pyrolysis of C(1)-C(3) hydrocarbons: toward the development of detailed kinetic models from first principles. , 2015, Physical chemistry chemical physics : PCCP.

[13]  Andreas Möglich,et al.  Engineering of a red-light–activated human cAMP/cGMP-specific phosphodiesterase , 2014, Proceedings of the National Academy of Sciences.

[14]  R. Dolmetsch,et al.  Induction of protein-protein interactions in live cells using light , 2009, Nature Biotechnology.

[15]  Feng Zhang,et al.  Channelrhodopsin-2 and optical control of excitable cells , 2006, Nature Methods.

[16]  Rebekka M. Wachter,et al.  Sensitivity of the yellow variant of green fluorescent protein to halides and nitrate , 1999, Current Biology.

[17]  Robert E Campbell,et al.  Red Fluorescent Protein pH Biosensor to Detect Concentrative Nucleoside Transport* , 2009, The Journal of Biological Chemistry.

[18]  Jens Timmer,et al.  Multi-chromatic control of mammalian gene expression and signaling , 2013, Nucleic acids research.

[19]  A S Verkman,et al.  Green fluorescent protein as a noninvasive intracellular pH indicator. , 1998, Biophysical journal.

[20]  N. Ferré,et al.  An artificial molecular switch that mimics the visual pigment and completes its photocycle in picoseconds , 2008, Proceedings of the National Academy of Sciences.

[21]  Xiaolan Yao,et al.  Rationally improving LOV domain–based photoswitches , 2010, Nature Methods.

[22]  A. Molchanov,et al.  A highly diastereoselective one-pot three-component 1,3-dipolar cycloaddition of cyclopropenes with azomethine ylides generated from 11H-indeno[1,2-b]-quinoxalin-11-ones , 2018 .

[23]  A. Lough,et al.  Bidirectional photocontrol of peptide conformation with a bridged azobenzene derivative. , 2012, Angewandte Chemie.

[24]  Karl Deisseroth,et al.  Optogenetic and chemogenetic strategies for sustained inhibition of pain , 2016, Scientific Reports.

[25]  V. Verkhusha,et al.  Engineering of bacterial phytochromes for near-infrared imaging, sensing, and light-control in mammals. , 2013, Chemical Society reviews.

[26]  Samouil L. Farhi,et al.  All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins , 2014, Nature Methods.

[27]  Dirk Trauner,et al.  Photochemical Restoration of Visual Responses in Blind Mice , 2012, Neuron.

[28]  Chuda Chittasupho Multivalent ligand: design principle for targeted therapeutic delivery approach. , 2012, Therapeutic delivery.

[29]  Austin J. Rice,et al.  Directed Evolution of a Bright Near-Infrared Fluorescent Rhodopsin Using a Synthetic Chromophore. , 2017, Cell chemical biology.

[30]  J. Christie,et al.  LOV to BLUF: flavoprotein contributions to the optogenetic toolkit. , 2012, Molecular plant.

[31]  O. Yizhar,et al.  Biophysical constraints of optogenetic inhibition at presynaptic terminals , 2016, Nature Neuroscience.

[32]  Feng Zhang,et al.  Multimodal fast optical interrogation of neural circuitry , 2007, Nature.

[33]  J. Spudich,et al.  Proteomonas sulcata ACR1: A Fast Anion Channelrhodopsin , 2016, Photochemistry and photobiology.

[34]  H. Adesnik,et al.  Optogenetic pharmacology for control of native neuronal signaling proteins , 2013, Nature Neuroscience.

[35]  Yasushi Okamura,et al.  Improving membrane voltage measurements using FRET with new fluorescent proteins , 2008, Nature Methods.

[36]  Michael Z. Lin,et al.  Characterization of engineered channelrhodopsin variants with improved properties and kinetics. , 2009, Biophysical journal.

[37]  R. Lucas,et al.  Reproducible and Sustained Regulation of Gαs Signalling Using a Metazoan Opsin as an Optogenetic Tool , 2012, PloS one.

[38]  K. Morokuma,et al.  Formation of 6-methyl-1,4-dihydronaphthalene in the reaction of the p-tolyl radical with 1,3-butadiene under single-collision conditions. , 2014, The journal of physical chemistry. A.

[39]  Il Yoon,et al.  Advance in Photosensitizers and Light Delivery for Photodynamic Therapy , 2013, Clinical endoscopy.

[40]  T. Knöpfel,et al.  Design and characterization of a DNA‐encoded, voltage‐sensitive fluorescent protein , 2001, The European journal of neuroscience.

[41]  S J Remington,et al.  Mechanism and Cellular Applications of a Green Fluorescent Protein-based Halide Sensor* , 2000, The Journal of Biological Chemistry.

[42]  Richard H. Kramer,et al.  Restoring visual function to the blind retina with a potent, safe and long-lasting photoswitch , 2017, Scientific Reports.

[43]  Karl Deisseroth,et al.  Color-tuned Channelrhodopsins for Multiwavelength Optogenetics , 2012, The Journal of Biological Chemistry.

[44]  Michael Z. Lin,et al.  Improving the photostability of bright monomeric orange and red fluorescent proteins , 2008, Nature Methods.

[45]  Fangli Zhao,et al.  ortho-Fluoroazobenzenes: visible light switches with very long-Lived Z isomers. , 2014, Chemistry.

[46]  Brian D Zoltowski,et al.  Blue light-induced dimerization of a bacterial LOV-HTH DNA-binding protein. , 2013, Biochemistry.

[47]  Klaus Gerwert,et al.  Early formation of the ion-conducting pore in channelrhodopsin-2. , 2015, Angewandte Chemie.

[48]  D. Bhattacharya,et al.  Eukaryotic algal phytochromes span the visible spectrum , 2014, Proceedings of the National Academy of Sciences.

[49]  Jens Timmer,et al.  A red/far-red light-responsive bi-stable toggle switch to control gene expression in mammalian cells , 2013, Nucleic acids research.

[50]  B. Zoltowski,et al.  Optimized second generation CRY2/CIB dimerizers and photoactivatable Cre recombinase , 2016, Nature chemical biology.

[51]  D. Raines,et al.  Azo-propofols: photochromic potentiators of GABA(A) receptors. , 2012, Angewandte Chemie.

[52]  E. Boyden,et al.  Multiple-Color Optical Activation, Silencing, and Desynchronization of Neural Activity, with Single-Spike Temporal Resolution , 2007, PloS one.

[53]  R. Tsien,et al.  Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein , 2004, Nature Biotechnology.

[54]  Ying Xu,et al.  Design and functional evaluation of an optically active μ-opioid receptor. , 2013, European journal of pharmacology.

[55]  Stanford Schor,et al.  Directed evolution of Gloeobacter violaceus rhodopsin spectral properties. , 2015, Journal of molecular biology.

[56]  M. Monici Cell and tissue autofluorescence research and diagnostic applications. , 2005, Biotechnology annual review.

[57]  G. Patterson,et al.  Use of the green fluorescent protein and its mutants in quantitative fluorescence microscopy. , 1997, Biophysical journal.

[58]  K. Deisseroth,et al.  Millisecond-timescale, genetically targeted optical control of neural activity , 2005, Nature Neuroscience.

[59]  Satoshi P. Tsunoda,et al.  Conversion of Channelrhodopsin into a Light-Gated Chloride Channel , 2014, Science.

[60]  Roger Y. Tsien,et al.  Crystal Structure of the Aequorea victoria Green Fluorescent Protein , 1996, Science.

[61]  Robert E Campbell,et al.  A Bright and Fast Red Fluorescent Protein Voltage Indicator That Reports Neuronal Activity in Organotypic Brain Slices , 2016, The Journal of Neuroscience.

[62]  Walther Akemann,et al.  Imaging neural circuit dynamics with a voltage-sensitive fluorescent protein. , 2012, Journal of neurophysiology.

[63]  J. Spudich,et al.  Gating mechanisms of a natural anion channelrhodopsin , 2015, Proceedings of the National Academy of Sciences.

[64]  Paul W. Sternberg,et al.  Archaerhodopsin Variants with Enhanced Voltage Sensitive Fluorescence in Mammalian and Caenorhabditis elegans Neurons , 2014, Nature Communications.

[65]  N. Ferré,et al.  Modeling, preparation, and characterization of a dipole moment switch driven by Z/E photoisomerization. , 2010, Journal of the American Chemical Society.

[66]  S. Hecht,et al.  o-Fluoroazobenzenes as readily synthesized photoswitches offering nearly quantitative two-way isomerization with visible light. , 2012, Journal of the American Chemical Society.

[67]  Alison G. Roberts,et al.  The photoreversible fluorescent protein iLOV outperforms GFP as a reporter of plant virus infection , 2008, Proceedings of the National Academy of Sciences.

[68]  E. Isacoff,et al.  Allosteric control of an ionotropic glutamate receptor with an optical switch , 2006, Nature chemical biology.

[69]  Martin Biel,et al.  Photopharmacological control of bipolar cells restores visual function in blind mice , 2017, The Journal of clinical investigation.

[70]  Takeharu Nagai,et al.  Optical control of the Ca2+ concentration in a live specimen with a genetically encoded Ca2+-releasing molecular tool. , 2014, ACS chemical biology.

[71]  Mark A. Brown,et al.  Predicting azo dye toxicity , 1993 .

[72]  Adam Santoro,et al.  Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity , 2015, Proceedings of the National Academy of Sciences.

[73]  George J. Augustine,et al.  A Genetically Encoded Ratiometric Indicator for Chloride Capturing Chloride Transients in Cultured Hippocampal Neurons , 2000, Neuron.

[74]  Michael W. Davidson,et al.  A bright monomeric green fluorescent protein derived from Branchiostoma lanceolatum , 2013, Nature Methods.

[75]  Fei Chen,et al.  A fully genetically-encoded protein architecture for optical control of peptide ligand concentration , 2014, Nature Communications.

[76]  Wiktor Szymanski,et al.  Photopharmacology: beyond proof of principle. , 2014, Journal of the American Chemical Society.

[77]  Brian Kuhlman,et al.  Designing photoswitchable peptides using the AsLOV2 domain. , 2012, Chemistry & biology.

[78]  K. Gardner,et al.  An optogenetic gene expression system with rapid activation and deactivation kinetics , 2013, Nature chemical biology.

[79]  A voltage-dependent fluorescent indicator for optogenetic applications, archaerhodopsin-3: Structure and optical properties from in silico modeling , 2017, F1000Research.

[80]  Lukas C. Kapitein,et al.  Optogenetic control of organelle transport and positioning , 2015, Nature.

[81]  Benedikt V. Ehinger,et al.  Melanopsin Variants as Intrinsic Optogenetic On and Off Switches for Transient versus Sustained Activation of G Protein Pathways , 2016, Current Biology.

[82]  Andrew A. Beharry,et al.  Azobenzene photoswitching without ultraviolet light. , 2011, Journal of the American Chemical Society.

[83]  P. Hegemann,et al.  Reaction dynamics of the chimeric channelrhodopsin C1C2 , 2017, Scientific Reports.

[84]  M. J. Mahon,et al.  pHluorin2: an enhanced, ratiometric, pH-sensitive green florescent protein. , 2011, Advances in bioscience and biotechnology.

[85]  S. Masuda Light detection and signal transduction in the BLUF photoreceptors. , 2013, Plant & cell physiology.

[86]  B. Cui,et al.  Optogenetic control of molecular motors and organelle distributions in cells. , 2015, Chemistry & biology.

[87]  M. R. Hoque,et al.  A Chimera Na+-Pump Rhodopsin as an Effective Optogenetic Silencer , 2016, PloS one.

[88]  Adam E Cohen,et al.  Temporal dynamics of microbial rhodopsin fluorescence reports absolute membrane voltage. , 2014, Biophysical journal.

[89]  Ralph Jimenez,et al.  Analysis of red-fluorescent proteins provides insight into dark-state conversion and photodegradation. , 2011, Biophysical journal.

[90]  R. Tsien,et al.  Fluorescent indicators for Ca2+based on green fluorescent proteins and calmodulin , 1997, Nature.

[91]  Takashi Maejima,et al.  Substitution of 5-HT1A Receptor Signaling by a Light-activated G Protein-coupled Receptor* , 2010, The Journal of Biological Chemistry.

[92]  Joel M. Kralj,et al.  Near-IR resonance Raman spectroscopy of archaerhodopsin 3: effects of transmembrane potential. , 2012, The journal of physical chemistry. B.

[93]  Dmitrii M. Nikolaev,et al.  A Comparative Study of Modern Homology Modeling Algorithms for Rhodopsin Structure Prediction , 2018, ACS omega.

[94]  Frances H. Arnold,et al.  Directed evolution of a far-red fluorescent rhodopsin , 2014, Proceedings of the National Academy of Sciences.

[95]  Can Yuan,et al.  Ca2+ signaling amplification by oligomerization of L-type Cav1.2 channels , 2012, Proceedings of the National Academy of Sciences.

[96]  E. Kosower,et al.  Glutathione. 13. Mechanism of thiol oxidation by diazenedicarboxylic acid derivatives. , 1976, Journal of the American Chemical Society.

[97]  V. Lorenz-Fonfria,et al.  Channelrhodopsin unchained: structure and mechanism of a light-gated cation channel. , 2014, Biochimica et biophysica acta.

[98]  Lief E. Fenno,et al.  Neocortical excitation/inhibition balance in information processing and social dysfunction , 2011, Nature.

[99]  J. Simon Wiegert,et al.  Silencing Neurons: Tools, Applications, and Experimental Constraints , 2017, Neuron.

[100]  H. Mutoh,et al.  Exploration of genetically encoded voltage indicators based on a chimeric voltage sensing domain , 2014, Front. Mol. Neurosci..

[101]  E. Peter,et al.  Mechanism of signal transduction of the LOV2-Jα photosensor from Avena sativa. , 2010, Nature communications.

[102]  Aristides B. Arrenberg,et al.  Optogenetic Control of Cardiac Function , 2010, Science.

[103]  S. Hayashi,et al.  A Blue-shifted Light-driven Proton Pump for Neural Silencing* , 2013, The Journal of Biological Chemistry.

[104]  G. Nagel,et al.  Optogenetic manipulation of cGMP in cells and animals by the tightly light-regulated guanylyl-cyclase opsin CyclOp , 2015, Nature Communications.

[105]  Josiah P. Zayner,et al.  TULIPs: Tunable, light-controlled interacting protein tags for cell biology , 2012, Nature Methods.

[106]  A. Gronenborn,et al.  Solution structure of a calmodulin-target peptide complex by multidimensional NMR. , 1994, Science.

[107]  M. Panov,et al.  5-Azido-2-aminopyridine, a new nitrene/nitrenium ion photoaffinity labeling agent that exhibits reversible intersystem crossing between singlet and triplet nitrenes. , 2013, Journal of the American Chemical Society.

[108]  Walther Akemann,et al.  Effect of voltage sensitive fluorescent proteins on neuronal excitability. , 2009, Biophysical journal.

[109]  Hui-wang Ai,et al.  Monitoring redox dynamics in living cells with a redox-sensitive red fluorescent protein. , 2015, Analytical chemistry.

[110]  E. Bamberg,et al.  Structural guidance of the photocycle of channelrhodopsin-2 by an interhelical hydrogen bond. , 2010, Biochemistry.

[111]  Helen H Yang,et al.  Genetically Encoded Voltage Indicators: Opportunities and Challenges , 2016, The Journal of Neuroscience.

[112]  Jin Zhong Li,et al.  Enhanced Archaerhodopsin Fluorescent Protein Voltage Indicators , 2013, PloS one.

[113]  B. Cui,et al.  Light-Mediated Kinetic Control Reveals the Temporal Effect of the Raf/MEK/ERK Pathway in PC12 Cell Neurite Outgrowth , 2014, PloS one.

[114]  Hongkui Zeng,et al.  Genetically Targeted All-Optical Electrophysiology with a Transgenic Cre-Dependent Optopatch Mouse , 2016, The Journal of Neuroscience.

[115]  A. Losi,et al.  Modulation of the photocycle of a LOV domain photoreceptor by the hydrogen-bonding network. , 2011, Journal of the American Chemical Society.

[116]  Gooitzen M van Dam,et al.  Emerging Targets in Photopharmacology. , 2016, Angewandte Chemie.

[117]  Egor Marin,et al.  Structural insights into ion conduction by channelrhodopsin 2 , 2017, Science.

[118]  Bradley J. Baker,et al.  Developing Fast Fluorescent Protein Voltage Sensors by Optimizing FRET Interactions , 2015, PloS one.

[119]  G. Nagel,et al.  Channelrhodopsin-2–XXL, a powerful optogenetic tool for low-light applications , 2014, Proceedings of the National Academy of Sciences.

[120]  Mark J. Schnitzer,et al.  Imaging neural spiking in brain tissue using FRET-opsin protein voltage sensors , 2014, Nature Communications.

[121]  J. Rogers,et al.  Optodynamic simulation of β-adrenergic receptor signalling , 2015, Nature Communications.

[122]  Ehud Y Isacoff,et al.  A Genetically Encoded Optical Probe of Membrane Voltage , 1997, Neuron.

[123]  L. Kriegsfeld,et al.  Review: regulatory mechanisms of gonadotropin-inhibitory hormone (GnIH) synthesis and release in photoperiodic animals , 2013, Front. Neurosci..

[124]  Gaudenz Danuser,et al.  LOVTRAP, An Optogenetic System for Photo-induced Protein Dissociation , 2016, Nature Methods.

[125]  A S Verkman,et al.  Green fluorescent protein‐based halide indicators with improved chloride and iodide affinities , 2001, FEBS letters.

[126]  Carole Williams,et al.  Tethered blockers as molecular ‘tape measures’ for a voltage-gated K+ channel , 2000, Nature Structural Biology.

[127]  H. Chiel,et al.  Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[128]  Michael A. Henninger,et al.  High-Performance Genetically Targetable Optical Neural Silencing via Light-Driven Proton Pumps , 2010 .

[129]  Takeshi Suzuki,et al.  Functional transplant of photoactivated adenylyl cyclase (PAC) into Aplysia sensory neurons , 2007, Neuroscience Research.

[130]  Mikhail N. Ryazantsev,et al.  New Experimental Models of Retinal Degeneration for Screening Molecular Photochromic Ion Channel Blockers , 2018, Acta naturae.

[131]  Kazuya Saito,et al.  Acceleration of the Z to E photoisomerization of penta-2,4-dieniminium by hydrogen out-of-plane motion: theoretical study on a model system of retinal protonated Schiff base. , 2009, Physical chemistry chemical physics : PCCP.

[132]  Raag D. Airan,et al.  Temporally precise in vivo control of intracellular signalling , 2009, Nature.

[133]  Jessica A. Cardin,et al.  Noninvasive optical inhibition with a red-shifted microbial rhodopsin , 2014, Nature Neuroscience.

[134]  T. Schwartz,et al.  Enhanced fluorescence resonance energy transfer between spectral variants of green fluorescent protein through zinc-site engineering. , 2001, Biochemistry.

[135]  Roland Lindh,et al.  The ultrafast photoisomerizations of rhodopsin and bathorhodopsin are modulated by bond length alternation and HOOP driven electronic effects. , 2011, Journal of the American Chemical Society.

[136]  Nathan C. Klapoetke,et al.  A High-Light Sensitivity Optical Neural Silencer: Development and Application to Optogenetic Control of Non-Human Primate Cortex , 2010, Front. Syst. Neurosci..

[137]  D. Kleinfeld,et al.  ReaChR: A red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation , 2013, Nature Neuroscience.

[138]  Takashi Maejima,et al.  Vertebrate Cone Opsins Enable Sustained and Highly Sensitive Rapid Control of Gi/o Signaling in Anxiety Circuitry , 2014, Neuron.

[139]  Masahiro Irie,et al.  Diarylethenes for Memories and Switches. , 2000, Chemical reviews.

[140]  Adam E. Cohen,et al.  Electrical Spiking in Escherichia coli Probed with a Fluorescent Voltage-Indicating Protein , 2011, Science.

[141]  S. Zbaida The mechanism of microsomal azoreduction: predictions based on electronic aspects of structure-activity relationships. , 1995, Drug metabolism reviews.

[142]  Brian Kuhlman,et al.  Engineering an improved light-induced dimer (iLID) for controlling the localization and activity of signaling proteins , 2014, Proceedings of the National Academy of Sciences.

[143]  Stefan R. Pulver,et al.  Independent Optical Excitation of Distinct Neural Populations , 2014, Nature Methods.

[144]  Matias D Zurbriggen,et al.  Red Light-Regulated Reversible Nuclear Localization of Proteins in Mammalian Cells and Zebrafish. , 2015, ACS synthetic biology.

[145]  A. Bird,et al.  FUNDUS AUTOFLUORESCENCE IMAGING: Review and Perspectives , 2008, Retina.

[146]  Walther Akemann,et al.  Engineering and Characterization of an Enhanced Fluorescent Protein Voltage Sensor , 2007, PLoS ONE.

[147]  Neela K. Codadu,et al.  The Contribution of Raised Intraneuronal Chloride to Epileptic Network Activity , 2015, The Journal of Neuroscience.

[148]  K. Deisseroth,et al.  Bi-stable neural state switches , 2009, Nature Neuroscience.

[149]  Edward S Boyden,et al.  A gene-fusion strategy for stoichiometric and co-localized expression of light-gated membrane proteins , 2011, Nature Methods.

[150]  B. Feringa,et al.  Azobenzene photoswitches for Staudinger-Bertozzi ligation. , 2013, Angewandte Chemie.

[151]  T. Halazonetis,et al.  Ultraviolet-B-mediated induction of protein–protein interactions in mammalian cells , 2013, Nature Communications.

[152]  John C. Williams,et al.  Computational Optogenetics: Empirically-Derived Voltage- and Light-Sensitive Channelrhodopsin-2 Model , 2013, PLoS Comput. Biol..

[153]  Karl Deisseroth,et al.  Structure-Guided Transformation of Channelrhodopsin into a Light-Activated Chloride Channel , 2014, Science.

[154]  V. Magidson,et al.  Circumventing photodamage in live-cell microscopy. , 2013, Methods in cell biology.

[155]  Mikhail N. Ryazantsev,et al.  Computational Photobiology and Beyond , 2010 .

[156]  M. Ehlers,et al.  Rapid blue light induction of protein interactions in living cells , 2010, Nature Methods.

[157]  K. Svoboda,et al.  Principles of Two-Photon Excitation Microscopy and Its Applications to Neuroscience , 2006, Neuron.

[158]  Peter Hegemann,et al.  Ion selectivity and competition in channelrhodopsins. , 2013, Biophysical journal.

[159]  Arno Germond,et al.  Design and development of genetically encoded fluorescent sensors to monitor intracellular chemical and physical parameters , 2016, Biophysical Reviews.

[160]  Z. Ren,et al.  How Does Photoreceptor UVR8 Perceive a UV‐B Signal? , 2015, Photochemistry and photobiology.

[161]  K. Deisseroth,et al.  Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri , 2008, Nature Neuroscience.

[162]  K. Deisseroth,et al.  Molecular and Cellular Approaches for Diversifying and Extending Optogenetics , 2010, Cell.

[163]  Matias D. Zurbriggen,et al.  Synthesis of phycocyanobilin in mammalian cells. , 2013, Chemical communications.

[164]  Bradley J. Baker,et al.  Pado, a fluorescent protein with proton channel activity can optically monitor membrane potential, intracellular pH, and map gap junctions , 2016, Scientific Reports.

[165]  J. Lehn,et al.  Multiplexing optical systems: Multicolor‐bifluorescent‐biredox photochromic mixtures , 1997 .

[166]  Katsuki Nakamura,et al.  Evolution of Mammalian Opn5 as a Specialized UV-absorbing Pigment by a Single Amino Acid Mutation* , 2014, The Journal of Biological Chemistry.

[167]  E. Bamberg,et al.  Light Activation of Channelrhodopsin-2 in Excitable Cells of Caenorhabditis elegans Triggers Rapid Behavioral Responses , 2005, Current Biology.

[168]  Dougal Maclaurin,et al.  Mechanism of voltage-sensitive fluorescence in a microbial rhodopsin , 2013, Proceedings of the National Academy of Sciences.

[169]  Lief E. Fenno,et al.  Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins , 2011, Nature Methods.

[170]  J. Clarke,et al.  Reversible Optogenetic Control of Subcellular Protein Localization in a Live Vertebrate Embryo , 2016, Developmental cell.

[171]  S. Nonell,et al.  Fastest molecular photochromic switches based on nanosecond isomerizing benzothiazolium azophenolic salts , 2014 .

[172]  S. Lukyanov,et al.  Genetically encoded fluorescent indicator for intracellular hydrogen peroxide , 2006, Nature Methods.

[173]  Justin D. Vrana,et al.  An optimized optogenetic clustering tool for probing protein interaction and function , 2014, Nature Communications.

[174]  D. Trauner,et al.  A roadmap to success in photopharmacology. , 2015, Accounts of Chemical Research.

[175]  E. Bamberg,et al.  Ultra light-sensitive and fast neuronal activation with the Ca2+-permeable channelrhodopsin CatCh , 2011, Nature Neuroscience.

[176]  C. Renner,et al.  Redox Potential of Azobenzene as an Amino Acid Residue in Peptides , 2007, Chembiochem : a European journal of chemical biology.

[177]  B. Kuhlman,et al.  A genetically-encoded photoactivatable Rac controls the motility of living cells , 2009, Nature.

[178]  Michael Z. Lin,et al.  High-fidelity optical reporting of neuronal electrical activity with an ultrafast fluorescent voltage sensor , 2014, Nature Neuroscience.

[179]  Allan R. Jones,et al.  A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing , 2012, Nature Neuroscience.

[180]  B. Roth DREADDs for Neuroscientists , 2016, Neuron.

[181]  R. Tsien,et al.  Circular permutation and receptor insertion within green fluorescent proteins. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[182]  Mohamady El-Gaby,et al.  Archaerhodopsin Selectively and Reversibly Silences Synaptic Transmission through Altered pH , 2016, Cell reports.

[183]  Winslow R. Briggs,et al.  The Photocycle of a Flavin-binding Domain of the Blue Light Photoreceptor Phototropin* , 2001, The Journal of Biological Chemistry.

[184]  Lopamudra Giri,et al.  Optically triggering spatiotemporally confined GPCR activity in a cell and programming neurite initiation and extension , 2013, Proceedings of the National Academy of Sciences.

[185]  E. Bamberg,et al.  Crystal structure of a light-driven sodium pump , 2015, Nature Structural &Molecular Biology.

[186]  M. R. Hoque,et al.  Structural basis for Na+ transport mechanism by a light-driven Na+ pump , 2015, Nature.

[187]  K. Deisseroth,et al.  Ultrafast optogenetic control , 2010, Nature Neuroscience.

[188]  Mathew Tantama,et al.  Optogenetic reporters: Fluorescent protein-based genetically encoded indicators of signaling and metabolism in the brain. , 2012, Progress in brain research.

[189]  Bradley J. Baker,et al.  Genetically encoded fluorescent voltage sensors using the voltage-sensing domain of Nematostella and Danio phosphatases exhibit fast kinetics , 2012, Journal of Neuroscience Methods.

[190]  Amy B Tyszkiewicz,et al.  Activation of protein splicing with light in yeast , 2008, Nature Methods.

[191]  Dietmar Schmitz,et al.  Optogenetic Tools for Subcellular Applications in Neuroscience , 2017, Neuron.

[192]  James E. Fitzgerald,et al.  Photon shot noise limits on optical detection of neuronal spikes and estimation of spike timing. , 2013, Biophysical journal.

[193]  K. Morokuma,et al.  Color Tuning in rhodopsins: the origin of the spectral shift between the chloride-bound and anion-free forms of halorhodopsin. , 2012, Journal of the American Chemical Society.

[194]  M. N. Ryazantsev,et al.  Wavepacket Motion via a Conical Intersection in the Photochemistry of Aqueous Transition-Metal Dianions , 2011 .

[195]  P. Hegemann,et al.  Bimodal Activation of Different Neuron Classes with the Spectrally Red-Shifted Channelrhodopsin Chimera C1V1 in Caenorhabditis elegans , 2012, PloS one.

[196]  Michael B. Hoppa,et al.  Control and Plasticity of the Presynaptic Action Potential Waveform at Small CNS Nerve Terminals , 2014, Neuron.

[197]  D. Maclaurin,et al.  Optical recording of action potentials in mammalian neurons using a microbial rhodopsin , 2011, Nature Methods.

[198]  K. Deisseroth,et al.  eNpHR: a Natronomonas halorhodopsin enhanced for optogenetic applications , 2008, Brain cell biology.

[199]  Vincent A. Pieribone,et al.  Single Action Potentials and Subthreshold Electrical Events Imaged in Neurons with a Fluorescent Protein Voltage Probe , 2012, Neuron.

[200]  V. Tropepe,et al.  Photoswitching azo compounds in vivo with red light. , 2013, Journal of the American Chemical Society.

[201]  Sang J. Chung,et al.  Intrinsic Tryptophan Fluorescence in the Detection and Analysis of Proteins: A Focus on Förster Resonance Energy Transfer Techniques , 2014, International journal of molecular sciences.

[202]  Masakatsu Watanabe,et al.  Fast manipulation of cellular cAMP level by light in vivo , 2007, Nature Methods.

[203]  Rebecca A. Ayers,et al.  Design and signaling mechanism of light‐regulated histidine kinases , 2009, Journal of molecular biology.

[204]  A. Losi,et al.  Old Chromophores, New Photoactivation Paradigms, Trendy Applications: Flavins in Blue Light‐Sensing Photoreceptors † , 2011, Photochemistry and photobiology.

[205]  Kenji Matsuda,et al.  Photochromism of diarylethene molecules and crystals: memories, switches, and actuators. , 2014, Chemical reviews.

[206]  Peter Hegemann,et al.  Biophysics of Channelrhodopsin. , 2015, Annual review of biophysics.

[207]  J. Christie Phototropin blue-light receptors. , 2007, Annual review of plant biology.