Flipping the Photoswitch: Ion Channels Under Light Control

  • Catherine K. McKenzie
  • Inmaculada Sanchez-Romero
  • Harald JanovjakEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 869)


Nature has incorporated small photochromic molecules, colloquially termed ‘photoswitches’, in photoreceptor proteins to sense optical cues in phototaxis and vision. While Nature’s ability to employ light-responsive functionalities has long been recognized, it was not until recently that scientists designed, synthesized and applied synthetic photochromes to manipulate many of which open rapidly and locally in their native cell types, biological processes with the temporal and spatial resolution of light. Ion channels in particular have come to the forefront of proteins that can be put under the designer control of synthetic photochromes. Photochromic ion channel controllers are comprised of three classes, photochromic soluble ligands (PCLs), photochromic tethered ligands (PTLs) and photochromic crosslinkers (PXs), and in each class ion channel functionality is controlled through reversible changes in photochrome structure. By acting as light-dependent ion channel agonists, antagonist or modulators, photochromic controllers effectively converted a wide range of ion channels, including voltage-gated ion channels, ‘leak channels’, tri-, tetra- and pentameric ligand-gated ion channels, and temperature-sensitive ion channels, into man-made photoreceptors. Control by photochromes can be reversible, unlike in the case of ‘caged’ compounds, and non-invasive with high spatial precision, unlike pharmacology and electrical manipulation. Here, we introduce design principles of emerging photochromic molecules that act on ion channels and discuss the impact that these molecules are beginning to have on ion channel biophysics and neuronal physiology.


Optochemical genetics Optogenetics Photopharmacology Optical control Photochrome Azobenzene Tethered ligand 


  1. Aldoshin SM (1990) Spiropyrans: structural features and photochemical properties. Russ Chem Rev 59:663–684CrossRefGoogle Scholar
  2. Banghart M, Borges K, Isacoff E, Trauner D, Kramer RH (2004) Light-activated ion channels for remote control of neuronal firing. Nat Neurosci 7(12):1381–1386PubMedCentralCrossRefPubMedGoogle Scholar
  3. Banghart MR, Mourot A, Fortin DL, Yao JZ, Kramer RH, Trauner D (2009) Photochromic blockers of voltage-gated potassium channels. Angew Chem Int Ed Engl 48(48):9097–9101. doi:10.1002/anie.200904504PubMedCentralCrossRefPubMedGoogle Scholar
  4. Bartels E, Wassermann NH, Erlanger BF (1971) Photochromic activators of the acetylcholine receptor. Proc Natl Acad Sci U S A 68(8):1820–1823PubMedCentralCrossRefPubMedGoogle Scholar
  5. Beharry AA, Woolley GA (2011) Azobenzene photoswitches for biomolecules. Chem Soc Rev 40(8):4422–4437. doi:10.1039/c1cs15023eCrossRefPubMedGoogle Scholar
  6. Berkovic G, Krongauz V, Weiss V (2000) Spiropyrans and spirooxazines for memories and switches. Chem Rev 100(5):1741–1754CrossRefPubMedGoogle Scholar
  7. Bieth J, Vratsanos SM, Wassermann N, Erlanger BF (1969) Photoregulation of biological activity by photocromic reagents. II. Inhibitors of acetylcholinesterase. Proc Natl Acad Sci U S A 64(3):1103–1106PubMedCentralCrossRefPubMedGoogle Scholar
  8. Binshtok AM, Bean BP, Woolf CJ (2007) Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449(7162):607–610. doi:10.1038/nature06191CrossRefPubMedGoogle Scholar
  9. Browne LE, Nunes JP, Sim JA, Chudasama V, Bragg L, Caddick S, Alan North R (2014) Optical control of trimeric P2X receptors and acid-sensing ion channels. Proc Natl Acad Sci U S A 111(1):521–526. doi:10.1073/pnas.1318582111PubMedCentralCrossRefPubMedGoogle Scholar
  10. Caporale N, Kolstad KD, Lee T, Tochitsky I, Dalkara D, Trauner D, Kramer R, Dan Y, Isacoff EY, Flannery JG (2011) LiGluR restores visual responses in rodent models of inherited blindness. Mol Ther 19(7):1212–1219. doi:10.1038/mt.2011.103PubMedCentralCrossRefPubMedGoogle Scholar
  11. Chabala LD, Lester HA (1986) Activation of acetylcholine receptor channels by covalently bound agonists in cultured rat myoballs. J Physiol 379:83–108PubMedCentralCrossRefPubMedGoogle Scholar
  12. Chabala LD, Gurney AM, Lester HA (1985) Photoactivation and dissociation of agonist molecules at the nicotinic acetylcholine receptor in voltage-clamped rat myoballs. Biophys J 48(2):241–246. doi:10.1016/S0006-3495(85)83777-2PubMedCentralCrossRefPubMedGoogle Scholar
  13. Chambers JJ, Banghart MR, Trauner D, Kramer RH (2006) Light-induced depolarization of neurons using a modified Shaker K(+) channel and a molecular photoswitch. J Neurophysiol 96(5):2792–2796CrossRefPubMedGoogle Scholar
  14. Chen X, Islamova NI, Robles RV, Lees WJ (2011) Photochromic properties of a water-soluble methyl carboxylic acid indolylfulgimide. Photochem Photobiol Sci 10(6):1023–1029. doi:10.1039/c1pp05016hPubMedCentralCrossRefPubMedGoogle Scholar
  15. Cordes T, Heinz B, Regner N, Hoppmann C, Schrader TE, Summerer W, Ruck-Braun K, Zinth W (2007) Photochemical Z–>E isomerization of a hemithioindigo/hemistilbene omega-amino acid. Chemphyschem 8(11):1713–1721CrossRefPubMedGoogle Scholar
  16. Deal WJ, Erlanger BF, Nachmansohn D (1969) Photoregulation of biological activity by photochromic reagents. 3. Photoregulation of bioelectricity by acetylcholine receptor inhibitors. Proc Natl Acad Sci U S A 64(4):1230–1234PubMedCentralCrossRefPubMedGoogle Scholar
  17. Dynamic Studies in Biology: phototriggers, Photoswitches and Caged Biomolecules (2005) Wiley-VCH. ISBN 3-527-30783-4Google Scholar
  18. Eggers K, Fyles TM, Montoya-Pelaez PJ (2001) Synthesis and characterization of photoswitchable lipids containing hemithioindigo chromophores. J Org Chem 66(9):2966–2977CrossRefPubMedGoogle Scholar
  19. Fasold H, Klappenberger J, Meyer C, Remold H (1971) Bifunctional reagents for the crosslinking of proteins. Angew Chem Int Ed Engl 10(11):795–801CrossRefPubMedGoogle Scholar
  20. Fehrentz T, Kuttruff CA, Huber FM, Kienzler MA, Mayer P, Trauner D (2012) Exploring the pharmacology and action spectra of photochromic open-channel blockers. Chembiochem 13(12):1746–1749. doi:10.1002/cbic.201200216CrossRefPubMedGoogle Scholar
  21. Fortin DL, Dunn TW, Fedorchak A, Allen D, Montpetit R, Banghart MR, Trauner D, Adelman JP, Kramer RH (2011) Optogenetic photochemical control of designer K + channels in mammalian neurons. J Neurophysiol 106(1):488–496. doi:jn.00251.2011 [pii]10.1152/jn.00251.2011PubMedCentralCrossRefPubMedGoogle Scholar
  22. Fritzsche J (1867) Note sur les carbures d’hydrogène solides, tirés du gaudron de houille. Compt Rend Acad Sci 69:1035–1037Google Scholar
  23. Fujimoto K, Kajino M, Sakaguchi I, Inouye M (2012) Photoswitchable, DNA-binding helical peptides assembled with two independently designed sequences for photoregulation and DNA recognition. Chemistry 18(32):9834–9840. doi:10.1002/chem.201201431CrossRefPubMedGoogle Scholar
  24. Herre S, Steinle W, Rück-Braun K (2005) Synthesis of photoswitchable hemithioindigo-based w-amino acids and application in Boc-based peptide assembly. Synthesis 19:3297–3300Google Scholar
  25. Hirshberg Y (1950) Photochromie dans la serie de la bianthrone. Compt Rend Acad Sci 231(18):903–904Google Scholar
  26. Irie M (2000) Diarylethenes for memories and switches. Chem Rev 100(5):1685–1716CrossRefPubMedGoogle Scholar
  27. Izquierdo-Serra M, Trauner D, Llobet A, Gorostiza P (2013) Optical control of calcium-regulated exocytosis. Biochim Biophys Acta 1830(3):2853–2860. doi:10.1016/j.bbagen.2012.11.003CrossRefPubMedGoogle Scholar
  28. Janovjak H, Szobota S, Wyart C, Trauner D, Isacoff EY (2010) A light-gated, potassium-selective glutamate receptor for the optical inhibition of neuronal firing. Nat Neurosci 13(8):1027–1032PubMedCentralCrossRefPubMedGoogle Scholar
  29. Janovjak H, Sandoz G, Isacoff EY (2011) A modern ionotropic glutamate receptor with a K(+) selectivity signature sequence. Nat Commun 2:232. doi:10.1038/ncomms1231CrossRefPubMedGoogle Scholar
  30. Ji TH (1983) Bifunctional reagents. Methods Enzymol 91:580–609CrossRefPubMedGoogle Scholar
  31. Kienzler MA, Reiner A, Trautman E, Yoo S, Trauner D, Isacoff EY (2013) A red-shifted, fast-relaxing azobenzene photoswitch for visible light control of an ionotropic glutamate receptor. J Am Chem Soc 135(47):17683–17686. doi:10.1021/ja408104wPubMedCentralCrossRefPubMedGoogle Scholar
  32. Kokel D, Cheung CY, Mills R, Coutinho-Budd J, Huang L, Setola V, Sprague J, Jin S, Jin YN, Huang XP, Bruni G, Woolf CJ, Roth BL, Hamblin MR, Zylka MJ, Milan DJ, Peterson RT (2013) Photochemical activation of TRPA1 channels in neurons and animals. Nat Chem Biol 9(4):257–263Google Scholar
  33. Kumita JR, Smart OS, Woolley GA (2000) Photo-control of helix content in a short peptide. Proc Natl Acad Sci U S A 97(8):3803–3808PubMedCentralCrossRefPubMedGoogle Scholar
  34. Lemoine D, Habermacher C, Martz A, Mery PF, Bouquier N, Diverchy F, Taly A, Rassendren F, Specht A, Grutter T (2013) Optical control of an ion channel gate. Proc Natl Acad Sci U S A 110(51):20813–20818. doi:10.1073/pnas.1318715110PubMedCentralCrossRefPubMedGoogle Scholar
  35. Lester HA, Krouse ME, Nass MM, Wassermann NH, Erlanger BF (1979) Light-activated drug confirms a mechanism of ion channel blockade. Nature 280(5722):509–510CrossRefPubMedGoogle Scholar
  36. Lester HA, Krouse ME, Nass MM, Wassermann NH, Erlanger BF (1980) A covalently bound photoisomerizable agonist: comparison with reversibly bound agonists at Electrophorus electroplaques. J Gen Physiol 75(2):207–232PubMedCentralCrossRefPubMedGoogle Scholar
  37. Levitz J, Pantoja C, Gaub B, Janovjak H, Reiner A, Hoagland A, Schoppik D, Kane B, Stawski P, Schier AF, Trauner D, Isacoff EY (2013) Optical control of metabotropic glutamate receptors. Nat Neurosci 16(4):507–516. doi:10.1038/nn.3346PubMedCentralCrossRefPubMedGoogle Scholar
  38. Li D, Herault K, Isacoff EY, Oheim M, Ropert N (2012) Optogenetic activation of LiGluR-expressing astrocytes evokes anion channel-mediated glutamate release. J Physiol 590 (4):855–873. doi:10.1113/jphysiol.2011.219345PubMedCentralCrossRefPubMedGoogle Scholar
  39. Mao S, Benninger RK, Yan Y, Petchprayoon C, Jackson D, Easley CJ, Piston DW, Marriott G (2008) Optical lock-in detection of FRET using synthetic and genetically encoded optical switches. Biophys J 94(11):4515–4524. doi:10.1529/biophysj.107.124859PubMedCentralCrossRefPubMedGoogle Scholar
  40. Marriott G, Mao S, Sakata T, Ran J, Jackson DK, Petchprayoon C, Gomez TJ, Warp E, Tulyathan O, Aaron HL, Isacoff EY, Yan Y (2008) Optical lock-in detection imaging microscopy for contrast-enhanced imaging in living cells. Proc Natl Acad Sci U S A 105(46):17789–17794PubMedCentralCrossRefPubMedGoogle Scholar
  41. Mayer ML (2011) Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation. Curr Opin Neurobiol 21(2):283–290. doi:10.1016/j.conb.2011.02.001PubMedCentralCrossRefPubMedGoogle Scholar
  42. Mostoslavskii MA, Kravchenko MD (1970) Absorption spectra of 3-oxo-2,3-dihydrothionaphthene and its derivatives. Chem Heterocycl Comp 4:45–47CrossRefGoogle Scholar
  43. Mourot A, Kienzler MA, Banghart MR, Fehrentz T, Huber FM, Stein M, Kramer RH, Trauner D (2011) Tuning photochromic ion channel blockers. ACS Chem Neurosci 2(9):536–543. doi:10.1021/cn200037pPubMedCentralCrossRefPubMedGoogle Scholar
  44. Mourot A, Fehrentz T, Feuvre Y L, Smith CM, Herold C, Dalkara D, Nagy F, Trauner D, Kramer RH (2012) Rapid optical control of nociception with an ion-channel photoswitch. Nat Methods 9(4):396–402. doi:10.1038/nmeth.1897PubMedCentralCrossRefPubMedGoogle Scholar
  45. Nargeot J, Lester HA, Birdsall NJ, Stockton J, Wassermann NH, Erlanger BF (1982) A photoisomerizable muscarinic antagonist. Studies of binding and of conductance relaxations in frog heart. J Gen Physiol 79(4):657–678CrossRefPubMedGoogle Scholar
  46. Numano R, Szobota S, Lau AY, Gorostiza P, Volgraf M, Roux B, Trauner D, Isacoff EY (2009) Nanosculpting reversed wavelength sensitivity into a photoswitchable iGluR. Proc Natl Acad Sci USA 106(16):6814–6819PubMedCentralCrossRefPubMedGoogle Scholar
  47. Petchprayoon C, Yan Y, Mao S, Marriott G (2011) Rational design, synthesis, and characterization of highly fluorescent optical switches for high-contrast optical lock-in detection (OLID) imaging microscopy in living cells. Bioorg Med Chem 19(3):1030–1040. doi:10.1016/j.bmc.2010.07.015PubMedCentralCrossRefPubMedGoogle Scholar
  48. Polosukhina A, Litt J, Tochitsky I, Nemargut J, Sychev Y, De Kouchkovsky I, Huang T, Borges K, Trauner D, Van Gelder RN, Kramer RH (2012) Photochemical restoration of visual responses in blind mice. Neuron 75(2):271–282. doi:10.1016/j.neuron.2012.05.022PubMedCentralCrossRefPubMedGoogle Scholar
  49. Rau H (1973) Spectroscopic properties of organic azo compounds. Angew Chem Int Ed Engl 12:224–235CrossRefGoogle Scholar
  50. Regner N, Herzog TT, Haiser K, Hoppmann C, Beyermann M, Sauermann J, Engelhard M, Cordes T, Ruck-Braun K, Zinth W (2012) Light-switchable hemithioindigo-hemistilbene-containing peptides: ultrafast spectroscopy of the Z –> E isomerization of the chromophore and the structural dynamics of the peptide moiety. J Phys Chem B 116(14):4181–4191. doi:10.1021/jp300982aCrossRefPubMedGoogle Scholar
  51. Reiter A, Skerra A, Trauner D, Schiefner A (2013) A photoswitchable neurotransmitter analogue bound to its receptor. BioChemistry 52(50):8972–8974. doi:10.1021/bi4014402CrossRefPubMedGoogle Scholar
  52. Ridge KD, Palczewski K (2007) Visual rhodopsin sees the light: structure and mechanism of G protein signaling. J Biol Chem 282(13):9297–9301CrossRefPubMedGoogle Scholar
  53. Rizzini L, Favory JJ, Cloix C, Faggionato D, O'Hara A, Kaiserli E, Baumeister R, Schafer E, Nagy F, Jenkins GI, Ulm R (2011) Perception of UV-B by the Arabidopsis UVR8 protein. Science 332(6025):103–106. doi:10.1126/science.1200660CrossRefPubMedGoogle Scholar
  54. Rockwell NC, Lagarias JC (2006) The structure of phytochrome: a picture is worth a thousand spectra. Plant Cell 18(1):4–14PubMedCentralCrossRefPubMedGoogle Scholar
  55. Samanta S, Woolley GA (2011) Bis-azobenzene crosslinkers for photocontrol of peptide structure. Chembiochem 12(11):1712–1723. doi:10.1002/cbic.201100204PubMedCentralCrossRefPubMedGoogle Scholar
  56. Sandoz G, Levitz J, Kramer RH, Isacoff EY (2012) Optical control of endogenous proteins with a photoswitchable conditional subunit reveals a role for TREK1 in GABA(B) signaling. Neuron 74(6):1005–1014. doi:10.1016/j.neuron.2012.04.026PubMedCentralCrossRefPubMedGoogle Scholar
  57. Standaert RF, Park SB (2006) Abc amino acids: design, synthesis, and properties of new photoelastic amino acids. J Org Chem 71(21):7952–7966CrossRefPubMedGoogle Scholar
  58. Stawski P, Sumser M, Trauner D (2012) A photochromic agonist of AMPA receptors. Angew Chem Int Ed Engl 51(23):5748–5751. doi:10.1002/anie.201109265CrossRefPubMedGoogle Scholar
  59. Stein M, Middendorp SJ, Carta V, Pejo E, Raines DE, Forman SA, Sigel E, Trauner D (2012) Azo-propofols: photochromic potentiators of GABA(A) receptors. Angew Chem Int Ed Engl 51(42):10500–10504. doi:10.1002/anie.201205475PubMedCentralCrossRefPubMedGoogle Scholar
  60. Szobota S, Gorostiza P, Del Bene F, Wyart C, Fortin DL, Kolstad KD, Tulyathan O, Volgraf M, Numano R, Aaron HL, Scott EK, Kramer RH, Flannery J, Baier H, Trauner D, Isacoff EY (2007) Remote control of neuronal activity with a light-gated glutamate receptor. Neuron 54(4):535–545CrossRefPubMedGoogle Scholar
  61. Tochitsky I, Banghart MR, Mourot A, Yao JZ, Gaub B, Kramer RH, Trauner D (2012) Optochemical control of genetically engineered neuronal nicotinic acetylcholine receptors. Nat Chem 4(2):105–111. doi:10.1038/nchem.1234CrossRefPubMedGoogle Scholar
  62. Tochitsky I, Polosukhina A, Degtyar VE, Gallerani N, Smith CM, Friedman A, Van Gelder RN, Trauner D, Kaufer D, Kramer RH (2014) Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells. Neuron 81(4):800–813. doi:10.1016/j.neuron.2014.01.003PubMedCentralCrossRefPubMedGoogle Scholar
  63. Volgraf M, Gorostiza P, Numano R, Kramer RH, Isacoff EY, Trauner D (2006) Allosteric control of an ionotropic glutamate receptor with an optical switch. Nat Chem Biol 2(1):47–52PubMedCentralCrossRefPubMedGoogle Scholar
  64. Volgraf M, Gorostiza P, Szobota S, Helix MR, Isacoff EY, Trauner D (2007) Reversibly caged glutamate: a photochromic agonist of ionotropic glutamate receptors. J Am Chem Soc 129(2):260–261. doi:10.1021/ja067269oCrossRefPubMedGoogle Scholar
  65. Wyart C, Bene FD, Warp E, Scott EK, Trauner D, Baier H, Isacoff EY (2009) Optogenetic dissection of a behavioural module in the vertebrate spinal cord. Nature 461(7262):407–410PubMedCentralCrossRefPubMedGoogle Scholar
  66. Yokoyama Y (2000) Fulgides for memories and switches. Chem Rev 100(5):1717–1740CrossRefPubMedGoogle Scholar
  67. Yue L, Pawlowski M, Dellal SS, Xie A, Feng F, Otis TS, Bruzik KS, Qian H, Pepperberg DR (2012) Robust photoregulation of GABA(A) receptors by allosteric modulation with a propofol analogue. Nat Commun 3:1095. doi:10.1038/ncomms2094PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Catherine K. McKenzie
    • 1
  • Inmaculada Sanchez-Romero
    • 1
  • Harald Janovjak
    • 1
    Email author
  1. 1.Institute of Science and Technology AustriaKlosterneuburgAustria

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