Beyond the Visual Cycle

Science's STKE  11 Jul 2006:
Vol. 2006, Issue 343, pp. tw228
DOI: 10.1126/stke.3432006tw228

Although the role of photoreceptors in the outer retina in mediating vision has long been known, the ability of intrinsically photosensitive retinal ganglion cells (ipRGCs) in the inner retina to mediate nonvisual responses to light--such as pupil size or circadian entrainment--has been recognized more recently. Activation of opsin-based photopigments depends on absorption of light by a retinaldehyde chromophore and its photoconversion from a cis to an all-trans form. Regeneration of 11-cis-retinaldehyde in rods requires the enzymes lecithin retinol acyl transferase (LRAT) and RPE65; mice lacking LRAT or RPE65 show attenuated pupillary light responses even compared to mice with outer retinal degeneration, which suggests that regeneration of the chromophore for melanopsin, the photopigment found in ipRGCs, could involve the same visual cycle (see Lucas).

Two papers, however, suggest that melanopsin chromophore regeneration depends on a distinct mechanism. Tu et al. found that, when loss of LRAT or RPE65 was combined with mutations associated with rod degeneration, mice with both rod degeneration and loss of enzyme function (rpe65–/–; rdta and lrat–/–; rd/rd mice) showed increased pupillary light responses (PLRs) compared with mice that lacked only enzymes. Moreover, acute inhibition of the visual cycle with all-trans-retinylamine had no effect on rd/rd mice, whereas, in mice lacking melanopsin, all-trans-retinylamine nearly abolished PLRs. Furthermore, multielectrode array recording of inner retinal photoresponses in immature mice (in which signaling from rods and cones to RGCs has not developed) revealed light-induced ipRGC action potentials in both rpe65–/– and lrat–/– mice. In the second paper, Doyle et al. showed that, in mice lacking RPE65, circadian photoentrainment was impaired and the number of melanopsin-immunoreactive RGCs was decreased; circadian photosensitivity and numbers of melanopsin-immunoreactive RGCs were rescued in mice in which loss of RPE65 was combined with the rd/rd mutation. Thus, both papers indicate that the visual cycle is not required for ipRGC function (and melanopsin chromophore regeneration) and suggest that the inactive outer retina in mice in which the visual cycle has been abrogated exerts an inhibitory effect on ipRGC function.

D. C. Tu, L. A. Owens, L. Anderson, M. Golczak, S. E. Doyle, M. McCall, M. Menaker, K. Palczewski, R. N. Van Gelder, Inner retinal photoreception independent of the visual retinoid cycle. Proc. Natl. Acad. Sci. U.S.A. 103, 10426-10431 (2006). [Abstract] [Full Text]

S. E. Doyle, A. M. Castrucci, M. McCall, I. Provencio, M. Menaker, Nonvisual light responses in the Rpe65 knockout mouse: Rod loss restores sensitivity to the melanopsin system. Proc. Natl. Acad. Sci. U.S.A. 103, 10432-10437 (2006). [Abstract] [Full Text]

R. J. Lucas, Chromophore regeneration: Melanopsin does its own thing. Proc. Natl. Acad. Sci. U.S.A. 103, 10153-10154 (2006). [Full Text]