Abstract
A small number of mammalian retinal ganglion cells act as photoreceptors for regulating certain non-image forming photoresponses1,2,3,4,5,6,7,8,9,10. These intrinsically photosensitive retinal ganglion cells express the putative photopigment melanopsin11,12,13. Ablation of the melanopsin gene renders these cells insensitive to light14; however, the precise role of melanopsin in supporting cellular photosensitivity is unconfirmed. Here we show that heterologous expression of human melanopsin in a mouse paraneuronal cell line (Neuro-2a) is sufficient to render these cells photoreceptive. Under such conditions, melanopsin acts as a sensory photopigment, coupled to a native ion channel via a G-protein signalling cascade, to drive physiological light detection. The melanopsin photoresponse relies on the presence of cis-isoforms of retinaldehyde and is selectively sensitive to short-wavelength light. We also present evidence to show that melanopsin functions as a bistable pigment in this system, having an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Berson, D. M., Dunn, F. A. & Takao, M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002)
Hattar, S. et al. Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424, 75–81 (2003)
Panda, S. et al. Melanopsin is required for non-image-forming photic responses in blind mice. Science 301, 525–527 (2003)
Sekaran, S., Foster, R. G., Lucas, R. J. & Hankins, M. W. Calcium imaging reveals a network of intrinsically light-sensitive inner-retinal neurons. Curr. Biol. 13, 1290–1298 (2003)
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)
Lucas, R., Douglas, R. & Foster, R. Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nature Neurosci. 4, 621–626 (2001)
Lucas, R. J. et al. Identifying the photoreceptive inputs to the mammalian circadian system using transgenic and retinally degenerate mice. Behav. Brain Res. 125, 97–102 (2001)
Czeisler, C. A. et al. Suppression of melatonin secretion in some blind patients by exposure to bright light. N. Engl. J. Med. 332, 6–11 (1995)
Mrosovsky, N., Lucas, R. & Foster, R. Persistence of masking responses to light in mice lacking rods and cones. J. Biol. Rhythms 16, 585–587 (2001)
Lockley, S. W. et al. Relationship between melatonin rhythms and visual loss in the blind. J. Clin. Endocrinol. Metab. 82, 3763–3770 (1997)
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)
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)
Hannibal, J., Hindersson, P., Knudsen, S. M., Georg, B. & Fahrenkrug, J. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J. Neurosci. 22, RC191 (2002)
Lucas, R. J. et al. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299, 245–247 (2003)
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)
Hubbard, R. & St. George, R. The rhodopsin system of the squid. J. Gen. Physiol. 41, 501–528 (1958)
Liu, R. S., Crescitelli, F., Denny, M., Matsumoto, H. & Asato, A. E. Photosensitivity of 10-substituted visual pigment analogues: detection of a specific secondary opsin-retinal interaction. Biochemistry 25, 7026–7030 (1986)
Hao, W. & Fong, H. The endogenous chromophore of retinal G protein-coupled receptor opsin from the pigment epithelium. J. Biol. Chem. 274, 6085–6090 (1999)
Koyanagi, M. et al. Bistable UV pigment in the lamprey pineal. Proc. Natl Acad. Sci. USA 101, 6687–6691 (2004)
Brainard, G. et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J. Neurosci. 21, 6405–6412 (2001)
Thapan, K., Arendt, J. & Skene, D. An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans. J. Physiol. (Lond.) 535, 261–267 (2001)
Hankins, M. W. & Lucas, R. J. The primary visual pathway in humans is regulated according to long-term light exposure through the action of a nonclassical photopigment. Curr. Biol. 12, 191–198 (2002)
Newman, L. A., Walker, M. T., Brown, R. L., Cronin, T. W. & Robinson, P. R. Melanopsin forms a functional short-wavelength photopigment. Biochemistry 42, 12734–12738 (2003)
Provencio, I. et al. A novel human opsin in the inner retina. J. Neurosci. 20, 600–605 (2000)
Bellingham, J., Whitmore, D., Philp, A. R., Wells, D. J. & Foster, R. G. Zebrafish melanopsin: isolation, tissue localisation and phylogenetic position. Brain Res. Mol. Brain Res. 107, 128–136 (2002)
Beindl, W. et al. Inhibition of receptor/G protein coupling by suramin analogues. Mol. Pharmacol. 50, 415–423 (1996)
Gilman, A. G proteins and dual control of adenylate cyclase. Cell 36, 577–579 (1984)
Asano, T. & Ogasawara, N. Uncoupling of gamma-aminobutyric acid B receptors from GTP-binding proteins by N-ethylmaleimide: effect of N-ethylmaleimide on purified GTP-binding proteins. Mol. Pharmacol. 29, 244–249 (1986)
Zemelman, B. V., Lee, G. A., Ng, M. & Miesenbock, G. Selective photostimulation of genetically chARGed neurons. Neuron 33, 15–22 (2002)
Leszkiewicz, D., Kandler, K. & Aizenman, E. Enhancement of NMDA receptor-mediated currents by light in rat neurones in vitro . J. Physiol. (Lond.) 524, 365–374 (2000)
Qiu, X. et al. Induction of photosensitivity by heterologous expression of melanopsin. Nature doi:10.1038/nature03345 (this issue)
Panda, S. et al. Illumination of the melanopsin signaling pathway. Science 307, 600–604 (2005)
Acknowledgements
This work was supported by a Wellcome Trust Showcase Award (M.W.H. and R.J.L.) and in part by the BBSRC (R.J.L.) and NSBRI through NASA NCC 9-58 (R.J.L. and R. Foster). We are grateful to R.K. Crouch for the gift of 11-cis retinaldehyde, to R. Douglas for scientific discussions and comments on the manuscript, and to K. Wells for help and advice with cell culture.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Supplementary information
Supplementary Figure 1
Opsin gene expression in Neuro-2a cells by RT-PCR. (PDF 260 kb)
Supplementary Figure 2
Detection of melanopsin and EGFP proteins in Neuro-2a cells by western blot. (PDF 596 kb)
Rights and permissions
About this article
Cite this article
Melyan, Z., Tarttelin, E., Bellingham, J. et al. Addition of human melanopsin renders mammalian cells photoresponsive. Nature 433, 741–745 (2005). https://doi.org/10.1038/nature03344
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature03344
This article is cited by
-
Effects of Post-awakening Light Exposure on Heart Rate Variability in Healthy Male Individuals
Applied Psychophysiology and Biofeedback (2023)
-
A neuropsin-based optogenetic tool for precise control of Gq signaling
Science China Life Sciences (2022)
-
Non-visual Opsins and Novel Photo-Detectors in the Vertebrate Inner Retina Mediate Light Responses Within the Blue Spectrum Region
Cellular and Molecular Neurobiology (2022)
-
Protective role of melatonin in breast cancer: what we can learn from women with blindness
Cancer Causes & Control (2022)
-
Disinhibition of intrinsic photosensitive retinal ganglion cells in patients with X-linked congenital stationary night blindness
Graefe's Archive for Clinical and Experimental Ophthalmology (2019)
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.