Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Photochemical control of endogenous ion channels and cellular excitability


Light-activated ion channels provide a precise and noninvasive optical means for controlling action potential firing, but the genes encoding these channels must first be delivered and expressed in target cells. Here we describe a method for bestowing light sensitivity onto endogenous ion channels that does not rely on exogenous gene expression. The method uses a synthetic photoisomerizable small molecule, or photoswitchable affinity label (PAL), that specifically targets K+ channels. PALs contain a reactive electrophile, enabling covalent attachment of the photoswitch to naturally occurring nucleophiles in K+ channels. Ion flow through PAL-modified channels is turned on or off by photoisomerizing PAL with different wavelengths of light. We showed that PAL treatment confers light sensitivity onto endogenous K+ channels in isolated rat neurons and in intact neural structures from rat and leech, allowing rapid optical regulation of excitability without genetic modification.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The PAL approach for imparting light sensitivity onto native ion channels.
Figure 2: Photocontrol of K+ channels expressed in HEK293 cells.
Figure 3: Photocontrol of native K+ current in cultured hippocampal neurons.
Figure 4: Photocontrol of neuronal firing.
Figure 5: Modulation of neuronal excitability with light.
Figure 6: Local illumination during PAL treatment imprints photosensitivity onto specific neurons.
Figure 7: Photocontrol of action potential firing in intact neural circuits.

Similar content being viewed by others


  1. Callaway, E.M. & Yuste, R. Stimulating neurons with light. Curr. Opin. Neurobiol. 12, 587–592 (2002).

    Article  CAS  Google Scholar 

  2. Kramer, R.H., Chambers, J.J. & Trauner, D. Photochemical tools for remote control of ion channels in excitable cells. Nat. Chem. Biol. 1, 360–365 (2005).

    Article  CAS  Google Scholar 

  3. Miesenbock, G. & Kevrekidis, I.G. Optical imaging and control of genetically designated neurons in functioning circuits. Annu. Rev. Neurosci. 28, 533–563 (2005).

    Article  Google Scholar 

  4. Zhang, F., Wang, L.P., Boyden, E.S. & Deisseroth, K. Channelrhodopsin-2 and optical control of excitable cells. Nat. Methods 3, 785–792 (2006).

    Article  CAS  Google Scholar 

  5. Ellis-Davies, G.C. Caged compounds: photorelease technology for control of cellular chemistry and physiology. Nat. Methods 4, 619–628 (2007).

    Article  CAS  Google Scholar 

  6. Dalva, M.B. & Katz, L.C. Rearrangements of synaptic connections in visual cortex revealed by laser photostimulation. Science 265, 255–258 (1994).

    Article  CAS  Google Scholar 

  7. Callaway, E.M. & Katz, L.C. Photostimulation using caged glutamate reveals functional circuitry in living brain slices. Proc. Natl. Acad. Sci. USA 90, 7661–7665 (1993).

    Article  CAS  Google Scholar 

  8. Shepherd, G.M., Pologruto, T.A. & Svoboda, K. Circuit analysis of experience-dependent plasticity in the developing rat barrel cortex. Neuron 38, 277–289 (2003).

    Article  CAS  Google Scholar 

  9. Nikolenko, V., Poskanzer, K.E. & Yuste, R. Two-photon photostimulation and imaging of neural circuits. Nat. Methods 4, 943–950 (2007).

    Article  CAS  Google Scholar 

  10. Banghart, M., Borges, K., Isacoff, E., Trauner, D. & Kramer, R.H. Light-activated ion channels for remote control of neuronal firing. Nat. Neurosci. 7, 1381–1386 (2004).

    Article  CAS  Google Scholar 

  11. Volgraf, M. et al. Allosteric control of an ionotropic glutamate receptor with an optical switch. Nat. Chem. Biol. 2, 47–52 (2006).

    Article  CAS  Google Scholar 

  12. Szobota, S. et al. Remote control of neuronal activity with a light-gated glutamate receptor. Neuron 54, 535–545 (2007).

    Article  CAS  Google Scholar 

  13. Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007).

    Article  CAS  Google Scholar 

  14. Boyden, E.S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 (2005).

    Article  CAS  Google Scholar 

  15. Bi, A. et al. Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron 50, 23–33 (2006).

    Article  CAS  Google Scholar 

  16. Li, X. et al. Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin. Proc. Natl. Acad. Sci. USA 102, 17816–17821 (2005).

    Article  CAS  Google Scholar 

  17. Han, X. & Boyden, E.S. Multiple-color optical activation, silencing, and desynchronization of neural activity, with single-spike temporal resolution. PLoS ONE 2, e299 (2007).

    Article  Google Scholar 

  18. Petreanu, L., Huber, D., Sobczyk, A. & Svoboda, K. Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections. Nat. Neurosci. 10, 663–668 (2007).

    Article  CAS  Google Scholar 

  19. Arenkiel, B.R. et al. In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2. Neuron 54, 205–218 (2007).

    Article  CAS  Google Scholar 

  20. Nagel, G. et al. Light activation of channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses. Curr. Biol. 15, 2279–2284 (2005).

    Article  CAS  Google Scholar 

  21. Wang, H. et al. High-speed mapping of synaptic connectivity using photostimulation in channelrhodopsin-2 transgenic mice. Proc. Natl. Acad. Sci. USA 104, 8143–8148 (2007).

    Article  CAS  Google Scholar 

  22. Schroll, C. et al. Light-induced activation of distinct modulatory neurons triggers appetitive or aversive learning in Drosophila larvae. Curr. Biol. 16, 1741–1747 (2006).

    Article  CAS  Google Scholar 

  23. Wold, F. Affinity labeling–an overview. Methods Enzymol. 46, 3–14 (1977).

    Article  CAS  Google Scholar 

  24. Gorostiza, P. et al. Mechanisms of photoswitch conjugation and light activation of an ionotropic glutamate receptor. Proc. Natl. Acad. Sci. USA 104, 10865–10870 (2007).

    Article  CAS  Google Scholar 

  25. Nadim, F. & Calabrese, R.L. A slow outward current activated by FMRFamide in heart interneurons of the medicinal leech. J. Neurosci. 17, 4461–4472 (1997).

    Article  CAS  Google Scholar 

  26. Hill, A.A., Lu, J., Masino, M.A., Olsen, O.H. & Calabrese, R.L. A model of a segmental oscillator in the leech heartbeat neuronal network. J. Comput. Neurosci. 10, 281–302 (2001).

    Article  CAS  Google Scholar 

  27. Hattar, S., Liao, H.W., Takao, M., Berson, D.M. & Yau, K.W. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295, 1065–1070 (2002).

    Article  CAS  Google Scholar 

  28. Lakhanpal, R.R. et al. Advances in the development of visual prostheses. Curr. Opin. Ophthalmol. 14, 122–127 (2003).

    Article  Google Scholar 

  29. Xia, Z., Dudek, H., Miranti, C.K. & Greenberg, M.E. Calcium influx via the NMDA receptor induces immediate early gene transcription by a MAP kinase/ERK-dependent mechanism. J. Neurosci. 16, 5425–5436 (1996).

    Article  CAS  Google Scholar 

  30. Hoshi, T., Zagotta, W.N. & Aldrich, R.W. Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250, 533–538 (1990).

    Article  CAS  Google Scholar 

  31. An, W.F. et al. Modulation of A-type potassium channels by a family of calcium sensors. Nature 403, 553–556 (2000).

    Article  CAS  Google Scholar 

  32. Higgins, D. & Banker, G.A. Primary dissociated cell cultures. in Culturing Nerve Cells (eds. Banker, G.A. & Goslin, K.) 37–78 (MIT Press, Cambridge, Massachusetts, 1998).

    Google Scholar 

  33. Masino, M.A. & Calabrese, R.L. Phase relationships between segmentally organized oscillators in the leech heartbeat pattern generating network. J. Neurophysiol. 87, 1572–1585 (2002).

    Article  Google Scholar 

Download references


We thank E. Isacoff, J. Chambers, S.-Y. Choi and S. Jackman for helpful comments, J. Flannery and K. Greenberg for help with RGC experiments, D. Johnston (University of Texas at Austin), B. Rothberg (University of Texas Health Science Center at San Antonio), B. Rudy (New York University), W. Catterall (University of Washington) and J. Trimmer (University of California Davis) for providing plasmids. This work was supported by the Howard Hughes Medical Institute (K.B.), the US National Science Foundation (IOB-0523959 to W.B.K.), Microsoft Research Labs (to W.B.K.) and the US National Institutes of Health (GM057027 to D.T., MH43396 to W.B.K., and EY16249 to R.H.K.). D.A.W., Q.G. and W.B.K. thank A. Blankenship and M. Feller for the loan of their xenon lamp.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Dirk Trauner or Richard H Kramer.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1, Supplementary Methods (PDF 468 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fortin, D., Banghart, M., Dunn, T. et al. Photochemical control of endogenous ion channels and cellular excitability. Nat Methods 5, 331–338 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing