The Mammalian Cone Visual Cycle Promotes Rapid M/L-Cone Pigment Regeneration Independently of the Interphotoreceptor Retinoid-Binding Protein

Abstract

Rapid regeneration of the visual pigment following its photoactivation is critical for the function of cone photoreceptors throughout the day. Though the reactions of the visual cycle in the retinal pigment epithelium (RPE) that recycle chromophore for rod pigment regeneration are well characterized, the corresponding mechanisms that enable rapid regeneration of cone pigment are poorly understood. A key remaining question is the relative contribution of the recently discovered cone-specific retina visual cycle and the classic RPE-dependent visual cycle to mammalian cone pigment regeneration. In addition, it is not clear what role, if any, the abundant interphotoreceptor matrix protein, IRBP, presumed to facilitate the traffic of chromophore, plays in accelerating mammalian cone pigment regeneration. To address these issues we used transretinal recordings to evaluate M/L-cone pigment regeneration in isolated retinas and eyecups from control and IRBP-deficient mice. Remarkably, the mouse retina promoted M/L-cone dark adaptation 8-fold faster than the RPE. However, complete cone recovery required both visual cycles. We conclude that the retina visual cycle is critical for the initial rapid regeneration of mouse M/L-cone pigment during dark adaptation whereas the slower RPE visual cycle is required to complete the process. While the deletion of IRBP reduced the amplitude and slowed the kinetics of mouse M/L-cone photoresponses, cone adaptation in bright steady light and the kinetics of cone dark adaptation were not affected in isolated retina or in intact eyecup. Thus, IRBP does not accelerate cone pigment regeneration and is not critical for the function of mouse M/L-cones in bright light.

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

“…Biomicroscopic examination of eyes in vivo showed normal retinal vascular morphology (Fig. S3), and photopic visual acuity testing, as assessed by opto-kinetic tracking analysis (28), showed normal values of 0.86 ± 0.02 and 0.84 ± 0.02 cycles per degree (n = 5, P > 0.1) for DFF and DCKO mice, respectively. Taken together, these results suggest that BP, vascular reactivity, and visual function as measured by visual acuity testing are not perturbed under homeostatic conditions owing to Vegfr2 haploinsufficiency and loss of EC FGFR1/2.…”

CRALBP supports the mammalian retinal visual cycle and cone vision

“…This facilitated the isolation of cone function by ablating rod photoresponses while preserving normal retina morphology and cone function (6,23). The experiments were performed with LCD monitor white light, which would be expected to selectively activate mouse M-cones (peak absorption at 508 nm) but not S-cones (peak absorption at 360 nm) (24).…”

“…As expected, cone b-wave sensitivity in the control mice underwent robust recovery following the bleaching and returned within 50 minutes to an estimated 50% of the pre-bleaching level ( Figure 3A, black squares). An incomplete photoreceptor dark adaptation after bleaching, as detected in ERG recordings of WT mice, is not unusual (6) and is most likely caused by the general anesthetics (25). In striking contrast to the ERG response recovery in control mice, M-cones in Rlbp1 -/-mice recovered only a slight fraction of their sensitivity following an identical bleaching ( Figure 3A, red circles).…”

“…The 11-cis chromophore is then imported back into photoreceptors, where it combines with a molecule of free opsin to regenerate the visual pigment (1,2). The cone-specific visual cycle (3) has been suggested to enable cones, but not rods, to quickly recover from bright light exposure and to function over a wide range of light intensities (4)(5)(6). While an active area of research (7,8), to date, none of the putative molecular components in this pathway have been shown to actually affect mammalian cone function, casting doubt on the significance of this pathway.…”

RDH13L, an Enzyme Responsible for the Aldehyde-Alcohol Redox Coupling Reaction (AL-OL Coupling Reaction) to Supply 11-cis Retinal in the Carp Cone Retinoid Cycle

“…In Müller cells, all-trans retinol is isomerized to 11-cis retinol (10,11) and the product, 11-cis retinol, is sent back to cones where it is oxidized to 11-cis retinal to regenerate visual pigments (12)(13)(14). The cone-specific retinoid cycle is suggested to contribute to the effective pigment regeneration in cones (15). However, the enzyme catalyzing 11-cis retinol oxidation in cones has not been identified.…”