Editorial Cite This: Chem. Rev. 2018, 118, 10627−10628
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Introduction: Optogenetics and Photopharmacology
Chem. Rev. 2018.118:10627-10628. Downloaded from pubs.acs.org by 79.110.28.24 on 11/14/18. For personal use only.
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are abundant in most organisms and do not need to be externally supplied. In contrast to fluorophores, photoswitches that form spontaneously from a protein backbone have not yet been identified or engineered, although the bilin-binding phytochrome-related proteins have been successfully employed as fluorescent tags. Although optogenetic systems have already been developed to a high level of sophistication, many challenges and opportunities for molecular engineering remain. It would, for instance, be desirable to improve the permeability and selectivity of certain ions passing a membrane channel or optimize the ON and OFF kinetics of photoreceptors. The action spectrum of the receptors should be adapted to spectral regions that are orthogonal to other wavelengths or beneficial to tissue penetration. Furthermore, their expression levels need to be increased or adjusted to ensure that they are positioned subcellularly at the desired locations or in selected tissues avoiding malfunction or toxicity. This issue of Chemical Reviews presents a range of articles that provide new insights in the structure and function of genetically encoded photoreceptors and discusses new applications of these fascinating molecules. Light-driven chloride pumps that can counteract the function of channelrhodopsins are covered by Engelhard et al., who describe the structural and functional characteristics of halorhodopsins. Into the same protein family falls a recently identified light-driven sodium pump, the potentially interesting properties of which are discussed by Kandori, Inoue, and Tsunoda. In another article, Losi, Gardner, and Möglich focus on blue-light receptors, emphasizing the many modalities that these proteins provide for the optical control of cellular functions, in particular with respect to applications in neuroscience. They also highlight a dual function of these flavin-based photoreceptors, which are not only able to modulate fused enzyme activities but can also serve as fluorescent probes useful to superresolution microscopy. In contrast to optogenetics, photopharmacology relies on entirely synthetic chromophores that need to be externally supplied. These can be covalently attached to modified receptors to bear a bioconjugation motif, or they can bind noncovalently like photoswitchable drugs. Structurally, they can belong to any type of synthetic switch that is compatible with the presence of oxygen and light in a cellular environment; in many applications these compounds are derivatives of azobenzenes, as laid out in detail in Trauner’s review. This article focuses on in vivo applications of photopharmacology, where pharmacokinetics and pharmacodynamics, metabolism, and clearance become important issues. One fascinating topic is the applicability of optogenetics and photopharmacology to human medicine. Isacoff and Kramer discuss the employment of these systems for restoring vision to blind animals with the ultimate goal to treat humans suffering
n recent years, several molecular techniques have revolutionized the way we interrogate, elucidate, and engineer biological systems. Fluorescent tagging and single molecule imaging have provided fundamental new insights into cellular form and function. CRISPR/Cas has allowed for the manipulation of DNA with unprecedented precision and has significantly increased the power of genetic engineering. Optogenetics, which relies on photoreceptors introduced at the genetic level, has enabled the control of biological networks with the unsurpassed temporal and spatial resolution of light. Its ability to regulate cellular functions, such as excitability, mobility, proliferation, and secretion, has transformed many areas of biological research, such as neurobiology or muscle physiology. Optogenetics has opened new perspectives in synthetic biology and promises to make a significant impact on human precision medicine. Optogenetics started with the discovery of channelrhodopsins, light-gated cation channels. When used together with structurally related outward (and inward) directed ion pumps, electrically excitable cells in tissue culture and living animals can be activated (depolarized) or silenced (hyperpolarized) by light with unprecedented spatiotemporal resolution. Optogenetics allows the manipulation by light under electrode-free conditions in a minimally invasive manner. Because of the genetically encoded application, virus-induced transduction can be performed with extremely high cell specificity in tissue and in living animals allowing completely new approaches for the analysis of neural networks. Out of the many variations, channelrhodopsin-2 (ChR2) is distinguished by its optimal structural and functional properties. It allows application of practically the entire setup of biochemical and biophysical methods. A presentation of the capabilities of ChRs versus ion pumps will highlight the various advantageous properties of one or the other system. The success of the channelrhodopsins, which are now routinely employed by hundreds if not thousands of laboratories, is overwhelming. A presentation of ChR applications has to be limited to selected examples such as studies on cell culture, neural tissue, muscle physiology, and remote control of animal behavior by scanning the brain of living animals with appropriate light sources. Building on ChRs, a wide range of optogenetic systems have been introduced that provide light sensitivity to different cell types. Besides employment of retinal (vitamin-A aldehyde) as chromophore (ChRs), now tetrapyrrole-based photoreceptors, using biliverdin or phycocyanobilin, or flavin-binding systems, employing, e.g., flavin mononucleotide, have entered the stage of optogentics applications. Their prosthetic groups undergo reversible double bond isomerization (bilin chromophores), single bond formation with a cysteine side chain of the enveloping protein, or reorganization of a hydrogen-bond network upon illumination (both latter mechanisms are accomplished by flavin chromophores) to activate the receptor proteins and effectors of downstream signaling pathways. Importantly, these chromophores or their biological precursors © 2018 American Chemical Society
Special Issue: Optogenetics and Photopharmacology Published: November 14, 2018 10627
DOI: 10.1021/acs.chemrev.8b00483 Chem. Rev. 2018, 118, 10627−10628
Chemical Reviews
Editorial
from retinitis pigmentosa or late stage macular degeneration. After briefly outlining (opto)genetic-based therapy strategies and alternative approaches involving stem cells, these authors focus on chemically synthesized photoswitches that generate action potentials and are able to restore visually guided behavior in blind animals. The development of optogenetics and photopharmacology and the eventual success of these approaches in the clinic will critically depend on a detailed understanding of the proteins, prosthetic groups, and switches involved and their interactions with highly complex cellular and organismic environments. These are eminently “chemical” problems. As such, we believe that Chemical Reviews is an excellent forum for articles that survey the state of the art and outline future challenges in this field. We hope that this thematic issue it will appeal to its adherents but also to those more generally interested in molecular switches, molecular machines, photoreception, protein engineering, bioconjugation, and genetic engineering.
for Biochemistry at the University of Düsseldorf. He was a guest professor at the Huazhong Agricultural University in Wuhan and was awarded in 2017 Professor ad Honorem at the University of Parma, Italy. He is a long-standing member of the American Society of Photobiology (ASP) where he was elected for two terms as a member of the society’s council. He has since served many years as Associate Editor to the society’s journal Photochemistry and Photobiology and is also an editorial board member of the Journal of Biological Chemistry. He is emeritus since 2016 and continues his research as a guest professor at the University of Leipzig. Dirk Trauner was born and raised in Linz, Austria, studied biology and chemistry at the University of Vienna, and received his undergraduate degree in chemistry from the Free University, Berlin. He then pursued a Ph.D. in chemistry under the direction of Prof. Johann Mulzer, with whom he moved to the University of Frankfurt and then back to Vienna. Following a mandatory stint in the Austrian Army, he became a postdoctoral fellow with Prof. Samuel J. Danishefsky at the Memorial Sloan-Kettering Cancer Center. After two years in New York City, Dr. Trauner joined the Department of Chemistry at the University of California, Berkeley, where he rose through the ranks to become an associate professor of chemistry and a member of the Lawrence Berkeley National Laboratory. In the summer of 2008, he moved to the University of Munich, where he served as a professor of chemical biology and chemical genetics. In March of 2017, he returned to the United States to become the Janice Cutler Chair of Chemistry at New York University. He also holds a position as an adjunct professor of neuroscience at the NYU Langone Medical School. The broad objective of Prof. Trauner’s research is to demonstrate the awesome power of chemical synthesis and to use it toward the establishment of synthetic biological pathways.
Ernst Bamberg*
Max-Planck-Institute for Biophysics
Wolfgang Gärtner
Institute of Analytical Chemistry, University Leipzig
Dirk Trauner
Department of Chemistry, New York University
AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected] ORCID
Wolfgang Gärtner: 0000-0002-6898-7011 Dirk Trauner: 0000-0002-6782-6056 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. Biographies Ernst Bamberg studied physical chemistry at the University of Basel (Ph.D., 1971). He then moved to the University of Konstanz, where he got his Habilitation (1977). In 1979, he was awarded a Heisenberg Fellowship, and in 1983 he accepted the offer to lead an independent research group at the Max Planck Institute of Biophysics in Frankfurt. He became professor adjunct at the University of Frankfurt in 1987 and a full professor of biophysical chemistry and director of the Department of Biophysical Chemistry at the Max Planck Institute of Biophysics in 1993. Since 2016, his status has been emeritus. In 2017, he became a visiting professor at the Moscow Institute of Physics and Technology (MIPT). Dr. Bamberg’s main interest is membrane biophysics, especially light-stimulated membrane proteins with a focus on optogenetics. Since 2011, he has been a member of the Leopoldina, the German National Academy of Sciences. Dr. Bamberg is the recipient of several national and international prizes. Wolfgang Gärtner studied chemistry at the Universities of Göttingen and Wü rzburg, Germany, and graduated in 1982. After two postdoctoral sojourns at the Max-Planck-Institute for Biochemistry in Martinsried (Germany) and the Biocenter of the University of Basel (Switzerland), he was a research assistant at the University of Freiburg (Germany) before he joined the Max-Planck-Institute for Chemical Energy Conversion (at that time MPI for Radiation Chemistry) as a group leader in 1991. He habilitated at the University of Duisburg in Bio-Organic Chemistry and became Professor Adjunct 10628
DOI: 10.1021/acs.chemrev.8b00483 Chem. Rev. 2018, 118, 10627−10628
