Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

Jul 15, 2005Proceedings of the National Academy of Sciences of the United States of America

Special retinal cells sense light using a vitamin A-based pigment called melanopsin

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Abstract

Rpe65-/- ipRGCs exhibited approximately 20- to 40-fold reduced photosensitivity compared to normal.

Melanopsin is expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs), which mediate non-image-forming visual functions.
The study indicates that a vitamin A-based chromophore is necessary for the photosensitivity of ipRGCs.
Exogenous 9-cis-retinal can restore photosensitivity in Rpe65-/- ipRGCs but not in melanopsin-ablated ipRGCs.
The ability of all-trans-retinal to rescue photosensitivity in Rpe65-/- ipRGCs suggests that melanopsin may act as a bistable pigment.
No melanopsin was found in the retinal pigment epithelium, and rod and cone sensitivities were unchanged with melanopsin ablation.

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In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate non-image-forming visual functions such as pupillary light reflex (PLR) and circadian photoentrainment. This photosensitivity requires melanopsin, an invertebrate opsin-like protein expressed by the ipRGCs. The precise role of melanopsin remains uncertain. One suggestion has been that melanopsin may be a photoisomerase, serving to regenerate an unidentified pigment in ipRGCs. This possibility was echoed by a recent report that melanopsin is expressed also in the mouse retinal pigment epithelium (RPE), a key center for regeneration of rod and cone pigments. To address this question, we studied mice lacking RPE65, a protein essential for the regeneration of rod and cone pigments. Rpe65-/- ipRGCs were approximately 20- to 40-fold less photosensitive than normal at both single-cell and behavioral (PLR) levels but were rescued by exogenous 9-cis-retinal (an 11-cis-retinal analog), indicating the requirement of a vitamin A-based chromophore for ipRGC photosensitivity. In contrast, 9-cis-retinal was unable to restore intrinsic photosensitivity to melanopsin-ablated ipRGCs, arguing against melanopsin functioning merely in photopigment regeneration. Interestingly, exogenous all-trans-retinal was also able to rescue the low sensitivity of rpe65-/- ipRGCs, suggesting that melanopsin could be a bistable pigment. Finally, we detected no melanopsin in the RPE and no changes in rod and cone sensitivities due to melanopsin ablation. Together, these results strongly suggest that melanopsin is the photopigment in the ipRGCs.

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Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

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