Skip to main content

Thank you for visiting nature.com. 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.

Photon capture and signalling by melanopsin retinal ganglion cells

Nature volume 457, pages 281–287 (2009)Cite this article

Abstract

A subset of retinal ganglion cells has recently been discovered to be intrinsically photosensitive, with melanopsin as the pigment. These cells project primarily to brain centres for non-image-forming visual functions such as the pupillary light reflex and circadian photoentrainment. How well they signal intrinsic light absorption to drive behaviour remains unclear. Here we report fundamental parameters governing their intrinsic light responses and associated spike generation. The membrane density of melanopsin is 104-fold lower than that of rod and cone pigments, resulting in a very low photon catch and a phototransducing role only in relatively bright light. Nonetheless, each captured photon elicits a large and extraordinarily prolonged response, with a unique shape among known photoreceptors. Notably, like rods, these cells are capable of signalling single-photon absorption. A flash causing a few hundred isomerized melanopsin molecules in a retina is sufficient for reaching threshold for the pupillary light reflex.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: IpRGCs of melanopsin–tdTomato transgenic mice.
Figure 2: Intensity–response relationships of ipRGCs.
Figure 3: Single-photon response of ipRGCs.
Figure 5: Flash threshold for modulation of ipRGC spike frequency.
Figure 4: Kinetics of dim-flash response.
Figure 6: Flash threshold for ipRGC-driven consensual pupillary light reflex.

References

  1. Hankins, M. W., Peirson, S. N. & Foster, R. G. Melanopsin: an exciting photopigment. Trends Neurosci. 31, 27–36 (2008)

    Article  CAS  Google Scholar 

  2. Berson, D. M., Dunn, F. A. & Takao, M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002)

    Article  ADS  CAS  Google Scholar 

  3. 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  ADS  CAS  Google Scholar 

  4. Guler, A. D. et al. Melanopsin cells are the principal conduits for rod–cone input to non-image-forming vision. Nature 453, 102–105 (2008)

    Article  ADS  Google Scholar 

  5. Hatori, M. et al. Inducible ablation of melanopsin-expressing retinal ganglion cells reveals their central role in non-image forming visual responses. PLoS ONE 3, e2451 (2008)

    Article  ADS  Google Scholar 

  6. Hattar, S. et al. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424, 76–81 (2003)

    Article  ADS  CAS  Google Scholar 

  7. Provencio, I., Jiang, G., De Grip, W. J., Hayes, W. P. & Rollag, M. D. Melanopsin: An opsin in melanophores, brain, and eye. Proc. Natl Acad. Sci. USA 95, 340–345 (1998)

    Article  ADS  CAS  Google Scholar 

  8. Provencio, I., Rollag, M. D. & Castrucci, A. M. Photoreceptive net in the mammalian retina. This mesh of cells may explain how some blind mice can still tell day from night. Nature 415, 493 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Melyan, Z., Tarttelin, E. E., Bellingham, J., Lucas, R. J. & Hankins, M. W. Addition of human melanopsin renders mammalian cells photoresponsive. Nature 433, 741–745 (2005)

    Article  ADS  CAS  Google Scholar 

  10. Qiu, X. et al. Induction of photosensitivity by heterologous expression of melanopsin. Nature 433, 745–749 (2005)

    Article  ADS  CAS  Google Scholar 

  11. Panda, S. et al. Illumination of the melanopsin signaling pathway. Science 307, 600–604 (2005)

    Article  ADS  CAS  Google Scholar 

  12. Fu, Y. et al. Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin. Proc. Natl Acad. Sci. USA 102, 10339–10344 (2005)

    Article  ADS  CAS  Google Scholar 

  13. Gooley, J. J., Lu, J., Chou, T. C., Scammell, T. E. & Saper, C. B. Melanopsin in cells of origin of the retinohypothalamic tract. Nature Neurosci. 4, 1165 (2001)

    Article  CAS  Google Scholar 

  14. Lucas, R. J. et al. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299, 245–247 (2003)

    Article  ADS  CAS  Google Scholar 

  15. Panda, S. et al. Melanopsin is required for non-image-forming photic responses in blind mice. Science 301, 525–527 (2003)

    Article  ADS  CAS  Google Scholar 

  16. Walker, M. T., Brown, R. L., Cronin, T. W. & Robinson, P. R. Photochemistry of retinal chromophore in mouse melanopsin. Proc. Natl Acad. Sci. USA 105, 8861–8865 (2008)

    Article  ADS  CAS  Google Scholar 

  17. Qiu, X. & Berson, D. M. Melanopsin bistability in ganglion cell photoreceptors. Invest. Ophthalmol. Vis. Sci. 48, E-Abstract 612 (2007)

  18. Koyanagi, M., Kubokawa, K., Tsukamoto, H., Shichida, Y. & Terakita, A. Cephalochordate melanopsin: evolutionary linkage between invertebrate visual cells and vertebrate photosensitive retinal ganglion cells. Curr. Biol. 15, 1065–1069 (2005)

    Article  CAS  Google Scholar 

  19. Mure, L. S., Rieux, C., Hattar, S. & Cooper, H. M. Melanopsin-dependent nonvisual responses: evidence for photopigment bistability in vivo . J. Biol. Rhythms 22, 411–424 (2007)

    Article  Google Scholar 

  20. Yang, X. W., Model, P. & Heintz, N. Homologous recombination based modification in Escherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome. Nature Biotechnol. 15, 859–865 (1997)

    Article  CAS  Google Scholar 

  21. Shaner, N. C. et al. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nature Biotechnol. 22, 1567–1572 (2004)

    Article  CAS  Google Scholar 

  22. Dacey, D. M. et al. Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN. Nature 433, 749–754 (2005)

    Article  ADS  CAS  Google Scholar 

  23. Tu, D. C. et al. Physiologic diversity and development of intrinsically photosensitive retinal ganglion cells. Neuron 48, 987–999 (2005)

    Article  CAS  Google Scholar 

  24. Warren, E. J., Allen, C. N., Brown, R. L. & Robinson, D. W. Intrinsic light responses of retinal ganglion cells projecting to the circadian system. Eur. J. Neurosci. 17, 1727–1735 (2003)

    Article  Google Scholar 

  25. Schmidt, T. M., Taniguchi, K. & Kofuji, P. Intrinsic and extrinsic light responses in melanopsin-expressing ganglion cells during mouse development. J. Neurophysiol. 100, 371–384 (2008)

    Article  CAS  Google Scholar 

  26. Baylor, D. A., Hodgkin, A. L. & Lamb, T. D. The electrical response of turtle cones to flashes and steps of light. J. Physiol. 242, 685–727 (1974)

    Article  CAS  Google Scholar 

  27. Baylor, D. A., Lamb, T. D. & Yau, K. W. The membrane current of single rod outer segments. J. Physiol. 288, 589–611 (1979)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Luo, D.-G., Kefalov, V. & Yau, K.-W. in The Senses: A Comprehensive Reference (ed. Basbaum, A. I.) (Elsevier/Academic Press, 2008)

    Google Scholar 

  29. Wong, K. Y., Dunn, F. A. & Berson, D. M. Photoreceptor adaptation in intrinsically photosensitive retinal ganglion cells. Neuron 48, 1001–1010 (2005)

    Article  CAS  Google Scholar 

  30. Lamb, T. D., McNaughton, P. A. & Yau, K. W. Spatial spread of activation and background desensitization in toad rod outer segments. J. Physiol. 319, 463–496 (1981)

    Article  CAS  Google Scholar 

  31. Wong, K. Y., Ecker, J. L., Dumitrescu, O. N., Berson, D. M. & Hattar, S. Multiple morphological types of melanopsin ganglion cells with distinct light responses and axonal targets. Invest. Ophthalmol. Vis. Sci. 49, E-Abstract 1518 (2008)

  32. Raport, C. J. et al. Downregulation of cGMP phosphodiesterase induced by expression of GTPase-deficient cone transducin in mouse rod photoreceptors. Invest. Ophthalmol. Vis. Sci. 35, 2932–2947 (1994)

    CAS  PubMed  Google Scholar 

  33. Nikonov, S. S., Kholodenko, R., Lem, J. & Pugh, E. N. Physiological features of the S- and M-cone photoreceptors of wild-type mice from single-cell recordings. J. Gen. Physiol. 127, 359–374 (2006)

    Article  Google Scholar 

  34. Baylor, D. A., Lamb, T. D. & Yau, K. W. Responses of retinal rods to single photons. J. Physiol. 288, 613–634 (1979)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen, C. K. et al. Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase. Proc. Natl Acad. Sci. USA 96, 3718–3722 (1999)

    Article  ADS  CAS  Google Scholar 

  36. Kraft, T. W. Photocurrents of cone photoreceptors of the golden-mantled ground squirrel. J. Physiol. (Lond.) 404, 199–213 (1988)

    Article  CAS  Google Scholar 

  37. Hardie, R. C. & Postma, M. in The Senses: A Comprehensive Reference (ed. Basbaum, A. I.) (Elsevier Science/Academic Press, 2008)

    Google Scholar 

  38. Dorlochter, M. & Stieve, H. The Limulus ventral photoreceptor: light response and the role of calcium in a classic preparation. Prog. Neurobiol. 53, 451–515 (1997)

    Article  CAS  Google Scholar 

  39. Baylor, D. A. & Hodgkin, A. L. Detection and resolution of visual stimuli by turtle photoreceptors. J. Physiol. 234, 163–198 (1973)

    Article  CAS  Google Scholar 

  40. Liebman, P. A., Parker, K. R. & Dratz, E. A. The molecular mechanism of visual excitation and its relation to the structure and composition of the rod outer segment. Annu. Rev. Physiol. 49, 765–791 (1987)

    Article  CAS  Google Scholar 

  41. Belenky, M. A., Smeraski, C. A., Provencio, I., Sollars, P. J. & Pickard, G. E. Melanopsin retinal ganglion cells receive bipolar and amacrine cell synapses. J. Comp. Neurol. 460, 380–393 (2003)

    Article  Google Scholar 

  42. Lucas, R. J., Douglas, R. H. & Foster, R. G. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nature Neurosci. 4, 621–626 (2001)

    Article  CAS  Google Scholar 

  43. Cahill, H. & Nathans, J. The optokinetic reflex as a tool for quantitative analyses of nervous system function in mice: application to genetic and drug-induced variation. PLoS ONE 3, e2055 (2008)

    Article  ADS  Google Scholar 

  44. Grozdanic, S. et al. Characterization of the pupil light reflex, electroretinogram and tonometric parameters in healthy mouse eyes. Curr. Eye Res. 26, 371–378 (2003)

    Article  Google Scholar 

  45. Wong, K. Y., Dunn, F. A., Graham, D. M. & Berson, D. M. Synaptic influences on rat ganglion-cell photoreceptors. J. Physiol. 582, 279–296 (2007)

    Article  CAS  Google Scholar 

  46. Perez-Leon, J. A., Warren, E. J., Allen, C. N., Robinson, D. W. & Lane Brown, R. Synaptic inputs to retinal ganglion cells that set the circadian clock. Eur. J. Neurosci. 24, 1117–1123 (2006)

    Article  Google Scholar 

  47. Hecht, S., Shlaer, S. & Pirenne, M. H. Energy, quanta, and vision. J. Gen. Physiol. 25, 819–840 (1942)

    Article  CAS  Google Scholar 

  48. Lisman, J. E. & Bering, H. Electrophysiological measurement of the number of rhodopsin molecules in single Limulus photoreceptors. J. Gen. Physiol. 70, 621–633 (1977)

    Article  CAS  Google Scholar 

  49. Harosi, F. I. Absorption spectra and linear dichroism of some amphibian photoreceptors. J. Gen. Physiol. 66, 357–382 (1975)

    Article  CAS  Google Scholar 

  50. Dartnall, H. J. A. in Photochemistry of Vision (ed. Dartnall, H. J. A.) 122–145 (Springer, 1972)

    Book  Google Scholar 

Download references

Acknowledgements

Supported by an NRSA fellowship and a VNTP Training Grant to M.T.H.D., and NIH grants to K.-W.Y. and D.E.B. We thank Y. Koutalos, V. Bhandawat, D.-G. Luo, V. Kefalov, D. Liu, G. Maimon and C.-Y. Su for discussions, and Y. Wang, J. Hsieh and N. Nishiyama for technical assistance. We also thank J. Nathans and R. Reeves for suggestions on transgenic lines, J. Nathans and H. Cahill for the Gnat1-/- cl mouse line, and T. Shelley for machining. We dedicate this work to the Champalimaud Foundation, Portugal.

Author Contributions M.T.H.D. and K.-W.Y. designed the experiments and wrote the paper. All experiments were performed by M.T.H.D., except for pupil measurements, which were done by T.X. and M.T.H.D. The melanopsin-tdTomato BAC-transgenic mouse was generated by S.H.K. in the laboratory of D.E.B. Important early observations of the intensity–response relationship and kinetics were made by H.Z. using animals retrograde-labelled by H.-W.L.

Author information

Author notes

  1. Haining Zhong & Hsi-Wen Liao

    Present address: Present addresses: Janelia Farm Research Campus, HHMI, Ashburn, Virginia 20147, USA (H.Z.); Department of Neurobiology, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA (H.-W.L.).,

Authors and Affiliations

  1. Solomon H. Snyder Department of Neuroscience,,

    Michael Tri H. Do, Shin H. Kang, Tian Xue, Haining Zhong, Hsi-Wen Liao, Dwight E. Bergles & King-Wai Yau

  2. Department of Ophthalmology, and,

    King-Wai Yau

  3. Center for Sensory Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA ,

    Michael Tri H. Do, Tian Xue & King-Wai Yau

Authors
  1. Michael Tri H. Do
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shin H. Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tian Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haining Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hsi-Wen Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dwight E. Bergles
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. King-Wai Yau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Michael Tri H. Do or King-Wai Yau.

Supplementary information

Supplementary Information

This file contains Supplementary Material, Supplementary Methods, Supplementary References and Supplementary Figures S1-S5 (PDF 1917 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Do, M., Kang, S., Xue, T. et al. Photon capture and signalling by melanopsin retinal ganglion cells. Nature 457, 281–287 (2009). https://doi.org/10.1038/nature07682

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07682

This article is cited by

Comments

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.

Search

Advanced search

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