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.

Temporally precise in vivo control of intracellular signalling


In the study of complex mammalian behaviours, technological limitations have prevented spatiotemporally precise control over intracellular signalling processes. Here we report the development of a versatile family of genetically encoded optical tools (‘optoXRs’) that leverage common structure–function relationships1 among G-protein-coupled receptors (GPCRs) to recruit and control, with high spatiotemporal precision, receptor-initiated biochemical signalling pathways. In particular, we have developed and characterized two optoXRs that selectively recruit distinct, targeted signalling pathways in response to light. The two optoXRs exerted opposing effects on spike firing in nucleus accumbens in vivo, and precisely timed optoXR photostimulation in nucleus accumbens by itself sufficed to drive conditioned place preference in freely moving mice. The optoXR approach allows testing of hypotheses regarding the causal impact of biochemical signalling in behaving mammals, in a targetable and temporally precise manner.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: OptoXR: optogenetic control of intracellular signal transduction.
Figure 2: Signalling specificity and in vivo functionality.
Figure 3: In vivo optoXR modulation of neural activity.
Figure 4: Optical control of reward-related behaviour.


  1. 1

    Karnik, S. S. et al. Activation of G-protein-coupled receptors: A common molecular mechanism. Trends Endocrinol. Metab. 14, 431–437 (2003)

    CAS  Article  Google Scholar 

  2. 2

    Kim, J. M. et al. Light-driven activation of β2-adrenergic receptor signaling by a chimeric rhodopsin containing the β2-adrenergic receptor cytoplasmic loops. Biochemistry 44, 2284–2292 (2005)

    CAS  Article  Google Scholar 

  3. 3

    Pierce, K. L., Premont, R. T. & Lefkowitz, R. J. Seven-transmembrane receptors. Nature Rev. Mol. Cell Biol. 3, 639–650 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Zhang, F. et al. Channelrhodopsin-2 and optical control of excitable cells. Nature Meth. 3, 785–792 (2006)

    CAS  Article  Google Scholar 

  5. 5

    Oliveira, L., Paiva, A. C. M. & Vriend, G. A low resolution model for the interaction of G proteins with G protein-coupled receptors. Protein Eng. 12, 1087–1095 (1999)

    CAS  Article  Google Scholar 

  6. 6

    Palczewski, K. G protein-coupled receptor rhodopsin. Annu. Rev. Biochem. 75, 743–767 (2006)

    CAS  Article  Google Scholar 

  7. 7

    Azzi, M. et al. β-Arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proc. Natl Acad. Sci. USA 100, 11406–11411 (2003)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Kenakin, T. Special issue on allosterism and collateral efficacy. Trends Pharmacol. Sci. 28, 359–446 (2007)

    CAS  Article  Google Scholar 

  9. 9

    Shukla, A. K. et al. Distinct conformational changes in β-arrestin report biased agonism at seven-transmembrane receptors. Proc. Natl Acad. Sci. USA 105, 9988–9993 (2008)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Rich, T. C. et al. In vivo assessment of local phosphodiesterase activity using tailored cyclic nucleotide-gated channels as cAMP sensors. J. Gen. Physiol. 118, 63–78 (2001)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Wilson, C. J. in The Synaptic Organization of the Brain (ed. Shepherd, G.) 361–413 (Oxford Univ. Press, 2003)

    Google Scholar 

  12. 12

    Gradinaru, V. et al. Targeting and readout strategies for fast optical neural control in vitro and in vivo. J. Neurosci. 27, 14231–14238 (2007)

    CAS  Article  Google Scholar 

  13. 13

    Deisseroth, K. et al. Signaling from synapse to nucleus: The logic behind the mechanisms. Curr. Opin. Neurobiol. 13, 354–365 (2003)

    CAS  Article  Google Scholar 

  14. 14

    White, F. J. & Wang, R. Y. Electrophysiological evidence for the existence of both D-1 and D-2 dopamine receptors in the rat nucleus accumbens. J. Neurosci. 6, 274–280 (1986)

    CAS  Article  Google Scholar 

  15. 15

    Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neural mechanisms of addiction: The role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006)

    CAS  Article  Google Scholar 

  16. 16

    Tobler, P. N., Fiorillo, C. D. & Schultz, W. Adaptive coding of reward value by dopamine neurons. Science 307, 1642–1645 (2005)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Potts, J. T. & Waldrop, T. G. Discharge patterns of somatosensitive neurons in the nucleus tractus solitarius of the cat. Neuroscience 132, 1123–1134 (2005)

    CAS  Article  Google Scholar 

  18. 18

    Pettit, D. L. et al. Chemical two-photon uncaging: A novel approach to mapping glutamate receptors. Neuron 19, 465–471 (1997)

    CAS  Article  Google Scholar 

  19. 19

    Furuta, T. et al. Brominated 7-hydroxycoumarin-4-ylmethyls: Photolabile protecting groups with biologically useful cross-sections for two photon photolysis. Proc. Natl Acad. Sci. USA 96, 1193–1200 (1999)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Conklin, B. R. et al. Engineering GPCR signaling pathways with RASSLs. Nature Meth. 5, 673–678 (2008)

    CAS  Article  Google Scholar 

  21. 21

    Lima, S. Q. & Miesenböck, G. Remote control of behavior through genetically targeted photostimulation of neurons. Cell 121, 141–152 (2005)

    CAS  Article  Google Scholar 

  22. 22

    Zemelman, B. V. et al. Selective photostimulation of genetically chARGed neurons. Neuron 33, 15–22 (2002)

    CAS  Article  Google Scholar 

  23. 23

    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)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Schroder-Lang, S. et al. Fast manipulation of cellular cAMP level by light in vivo. Nature Meth. 4, 39–42 (2007)

    Article  Google Scholar 

  25. 25

    Cohen, G. B. et al. Constitutive activation of opsin: Influence of charge at position 134 and size at position 296. Biochemistry 32, 6111–6115 (1993)

    CAS  Article  Google Scholar 

  26. 26

    Carelli, R. M. & Wightman, R. M. Functional microcircuitry in the accumbens underlying drug addiction: Insights from real-time signaling during behavior. Curr. Opin. Neurobiol. 14, 763–768 (2004)

    CAS  Article  Google Scholar 

  27. 27

    Dunn, T. A. et al. Imaging of cAMP levels and protein kinase A activity reveals that retinal waves drive oscillations in second-messenger cascades. J. Neurosci. 26, 12807–12815 (2006)

    CAS  Article  Google Scholar 

  28. 28

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

    ADS  CAS  Article  Google Scholar 

  29. 29

    Petreanu, L. et al. Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections. Nature Neurosci. 10, 663–668 (2007)

    CAS  Article  Google Scholar 

  30. 30

    Airan, R. D. et al. Integration of light-controlled neuronal firing and fast circuit imaging. Curr. Opin. Neurobiol. 17, 587–592 (2007)

    CAS  Article  Google Scholar 

Download references


We thank B. Kobilka, B. Knutson, M. P. Bokoch, T. Sudhof, R. Malenka and the Deisseroth Laboratory for comments and discussion. We appreciate the gifts of pCNGA2-C460W/E583M from J. W. Karpen, pcDNA3.1-β2AR from B. Kobilka and pDT-α1AR from C. Hague. We thank T. Jardetzky for use of a Biotek Synergy4 plate reader. R.D.A. is supported by a NIH/NIMH National Research Service Award and the Stanford Medical Scientist Training Program. K.R.T. is supported by a NARSAD Young Investigator Award. K.D. is supported by CIRM, McKnight, Coulter, Klingenstein, Keck, NSF, NIMH, NIDA, the NIH Pioneer Award, the Albert Yu and Mary Bechmann Foundation and the Kinetics Foundation.

Author information



Corresponding author

Correspondence to Karl Deisseroth.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Figures S1-S4 with Legends, Supplementary Tables S1-S4 and Supplementary References (PDF 913 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Airan, R., Thompson, K., Fenno, L. et al. Temporally precise in vivo control of intracellular signalling. Nature 458, 1025–1029 (2009).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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