Cone photoreceptors mediate our daytime vision and function under bright and rapidly-changing light conditions. As their visual pigment is destroyed in the process of photoactivation, the continuous function of cones imposes the need for rapid recycling of their chromophore and regeneration of their pigment. The canonical retinoid visual cycle through the retinal pigment epithelium cells recycles chromophore and supplies it to both rods and cones. However, shortcomings of this pathway, including its slow rate and competition with rods for chromophore, have led to the suggestion that cones might use a separate mechanism for recycling of chromophore. In the past four decades biochemical studies have identified enzymatic activities consistent with recycling chromophore in the retinas of cone-dominant animals, such as chicken and ground squirrel. These studies have led to the hypothesis of a cone-specific retina visual cycle. The physiological relevance of these studies was controversial for a long time and evidence for the function of this visual cycle emerged only in very recent studies and will be the focus of this review. The retina visual cycle supplies chromophore and promotes pigment regeneration only in cones but not in rods. This pathway is independent of the pigment epithelium and instead involves the Müller cells in the retina, where chromophore is recycled and supplied selectively to cones. The rapid supply of chromophore through the retina visual cycle is critical for extending the dynamic range of cones to bright light and for their rapid dark adaptation following exposure to light. The importance of the retina visual cycle is emphasized also by its preservation through evolution as its function has now been demonstrated in species ranging from salamander to zebrafish, mouse, primate, and human.

Summary Some vertebrate species have evolved means of extending their visual sensitivity beyond the range of human vision. One mechanism of enhancing sensitivity to long-wavelength light is to replace the 11-cis retinal chromophore in photopigments with 11-cis 3,4-didehydroretinal. Despite over a century of research on this topic, the enzymatic basis of this perceptual switch remains unknown. Here, we show that a cytochrome P450 family member, Cyp27c1, mediates this switch by converting vitamin A1 (the precursor of 11-cis retinal) into vitamin A2 (the precursor of 11-cis 3,4-didehydroretinal). Knockout of cyp27c1 in zebrafish abrogates production of vitamin A2, eliminating the animal's ability to red-shift its photoreceptor spectral sensitivity, and reducing its ability to see and respond to near-infrared light. Thus, the expression of a single enzyme mediates dynamic spectral tuning of the entire visual system by controlling the balance of vitamin A1 and A2 in the eye.

Retinal rods and cones share a phototransduction pathway involving cyclic GMP 1 . Cones are typically 100 times less photosensitive than rods and their response kinetics are several times faster 2 , but the underlying mechanisms remain largely unknown. Almost all proteins involved in phototransduction have distinct rod and cone variants. Differences in properties between rod and cone pigments have been described, such as a 10-fold shorter lifetime of the meta-II state (active conformation) of cone pigment 3, 4, 5, 6 and its higher rate of spontaneous isomerization 7, 8 , but their contributions to the functional differences between rods and cones remain speculative. We have addressed this question by expressing human or salamander red cone pigment in Xenopus rods, and human rod pigment in Xenopus cones. Here we show that rod and cone pigments when present in the same cell produce light responses with identical amplification and kinetics, thereby ruling out any difference in their signalling properties. However, red cone pigment isomerizes spontaneously 10,000 times more frequently than rod pigment. This high spontaneous activity adapts the native cones even in darkness, making them less sensitive and kinetically faster than rods. Nevertheless, additional factors are probably involved in these differences.Human or salamander red cone pigment, together with green fluorescent protein (GFP) for facilitating screening, was introduced as a transgene into Xenopus under the control of the cytomegalovirus (CMV) promoter. In a wild-type or GFP control Xenopus retina, an antibody to red cone pigment labelled only the outer segments of sporadic red cones. In a frog expressing transgenic red cone pigment, however, immunolabelling included the abundant rod outer segments (Fig. 1a). The concentrated labelling of rod outer segments suggested that the localization signal that targets cone pigment to the outer segment is also recognized by rods. The immunostaining was usually non-uniform across the whole retina, suggesting variable expression of the transgenic pigment among the rods (see below).Outer-segment membrane current was recorded from single principal ('red') rods with a suction pipette. Rods expressing transgenic cone pigment showed no marked changes in their flash responses (Fig. 1b), but their sensitivity was, on average, half that of wild-type or GFP control rods ( Fig. 2a and Table 1). In darkness, these rods also showed considerably higher current noise, which was suppressible by light (Fig. 1c). The photosensitivity of the noise, together with its kinetic characteristics (see below), suggested that it originated in the phototransduction pathway. In other control experiments with transgenic human rod pigment expressed in Xenopus rods, no increase in dark noise was observed (data not shown).The increase in dark noise in rods expressing transgenic red cone pigment suggested that cone pigment was more prone to spontaneous isomerization than rod pigment, and that it was coupled functionally to the rod phototrans...