A novel cone visual cycle in the cone-dominated retina

Abstract

The visual processing of humans is primarily reliant upon the sensitivity of cone photoreceptors to light during daylight conditions. This underscores the importance of understanding how cone photoreceptors maintain the ability to detect light. The vertebrate retina consists of a combination of both rod and cone photoreceptors. Subsequent to light exposure, both rod and cone photoreceptors are dependent upon the recycling of vitamin A to regenerate photopigments, the proteins responsible for detecting light. Metabolic processing of vitamin A in support of rod photopigment renewal, the so-called "rod visual cycle", is well established. However, the metabolic processing of vitamin A in support of cone photopigment renewal remains a challenge for characterization in the recently discovered "cone visual cycle". In this review we summarize the research that has defined the rod visual cycle and our current concept of the novel cone visual cycle. Here, we highlight the research that supports the existence of a functional cone-specific visual cycle: the identification of novel enzymatic activities that contribute to retinoid recycling, the observation of vitamin A recycling in cone-dominated retinas, and the localization of some of these activities to the Müller cell. In the opinions of the authors, additional research on the possible interactions between these two visual cycles in the duplex retina is needed to understand visual detection in the human retina.

Fig. 1

Retinoid distribution during light and dark adaptation in the rod visual cycle in the rat (A) and the cone visual cycle in the chicken (B). A: Distribution of retinol in the retinal pigment epithelium (RPE) and in the retina of the rod-dominated eye of albino rat during light and dark adaptation. During light adaptation, retinal in the retina decreases as retinol/retinyl esters accumulate in the RPE. During dark adaptation, these processes are reversed. Rod pigments take about 100 min. to fully regenerate (i.e. recovery of retinal content in the retina) in the dark adapted rat eye and this process is supported by retinol/retinyl esters in the RPE. ○- retinol in retina , Δ -retinol/retinyl esters in the RPE, •- retinal in the retina. For details of experiments and results, see Dowling, 1960. B: Distribution of 11-cis retinyl ester ○ (solid line) and 11-cis retinal • (broken line) in the retina of the cone-dominated chicken eye during light and dark adaptation. During light adaptation, 11-cis retinal in the retina decreases while 11-cis retinyl esters accumulate in the retina. During dark adaptation, these processes are reversed. Cone pigments fully regenerate in the retina in less than 5 min. and this process is supported by 11-cis retinyl esters in the retina. Light adaptation, Dark adaptation For details of experiment and results see Trevino, Villazana-Espinoza et al. 2005.

Fig. 2

Light dependency of the chicken cone visual cycle: effect of light intensity (A, B) and duration of light exposure (C) on the accumulation of 11-cis retinyl esters in the chicken retina. A-B: Increase in retinyl ester accumulation in the chicken retina in response to increase in light intensity. Retinyl ester content in the retina increased with higher light intensity (A), indicating that this process is light-dependent. A reciprocal decrease of 11-cis retinal (B) suggests that retinyl ester in the retina is derived from retinal chromophore from bleached visual pigments. C. Increase in retinyl ester accumulation in the chicken retina in response to an increase in the duration of light exposure. At 2000 Lux, an increase in the duration of light exposure resulted in a significant increase in the amount of retinyl ester in the retina, indicating that this process is light-driven. light adaptation, dark adaptation. For details of experiments and results, see Villazana-Espinoza, Hatch et al. 2006.

Fig. 2

Light dependency of the chicken cone visual cycle: effect of light intensity (A, B) and duration of light exposure (C) on the accumulation of 11-cis retinyl esters in the chicken retina. A-B: Increase in retinyl ester accumulation in the chicken retina in response to increase in light intensity. Retinyl ester content in the retina increased with higher light intensity (A), indicating that this process is light-dependent. A reciprocal decrease of 11-cis retinal (B) suggests that retinyl ester in the retina is derived from retinal chromophore from bleached visual pigments. C. Increase in retinyl ester accumulation in the chicken retina in response to an increase in the duration of light exposure. At 2000 Lux, an increase in the duration of light exposure resulted in a significant increase in the amount of retinyl ester in the retina, indicating that this process is light-driven. light adaptation, dark adaptation. For details of experiments and results, see Villazana-Espinoza, Hatch et al. 2006.

Figure 3

Novel properties of 11-cis retinyl ester synthase (A) and retinol isomerase (B) enzyme activities in chicken retinal membrane. A: Synthesis of 11-cis-retinyl esters by chicken retinal membranes is dependent on both CRALBP and palmitoyl CoA. B: Synthesis of 11-cis retinol from all-trans retinol by chicken retinal membranes is enhanced in the presence of CRALBP. For details of experiment and results, see Mata, Radu et al. 2002.

Figure 4

11-cis retinyl ester synthase activity in Müller cell of the chicken retina. A-C: Photomicrographs showing primary culture of chicken Müller cells. Freshly explanted Müller cells were cultured to confluence (A) and immunostained with anti-CRALBP antibody for identification of cell type (B), and negative control (C). D: Production of 11-cis retinyl ester by Müller cell membranes is specific for 11-cis retinol and requires both CRALBP and palmitoyl CoA. This 11-cis retinyl ester synthase activity in the Müller cell provides an explanation for the accumulation of 11-cis retinyl ester in the cone-dominated chicken retina. ◆ 11-cis retinyl esters under condition 1; • 11-cis retinyl esters under condition 2; ▲ all-trans retinyl esters under condition 3. For details of experiments and results, see Muniz, Villazana-Espinoza et al. 2006.

Figure 5

Comparison of pathways of the rod (A) and the cone (B) visual cycles. A: Pathways of the classical rhodopsin visual cycle in the retina and RPE of the eye (see sections A-1 and A-2 for details). B: Pathways of the novel cone visual cycle in the cone-dominated retina. (see Section C-4 for details). Enzymes that have been characterized with apparent kinetic constants in the cone visual pathway are indicated with bold font and they include Isomerase II (Mata, Ruiz et al. 2005), 11-cis and all-trans retinyl ester hydrolase (REH) (Bustamante, Ziari et al. 1995), 11-cis Acyl CoA Retinol Acyl Transferase (ARAT) (Mata, Radu et al. 2002; Muniz, Villazana-Espinoza et al. 2006) and retinyl dehydrogenase (RDH-oxidase) (Mata, Radu et al. 2002). Uncharacterized enzymes are indicated with normal font; these include all-trans retinyl dehydrogenase (RDH-reductase) in the cone outer segment, all-trans retinyl ester synthase, and 11-cis retinol dehydrogenase in the Müller cell. The retinoid binding proteins IRBP and CRBP/CRALBP have been located in the interphotoreceptor matrix and Müller cells, respectively (Bunt-Milam and Saari 1983; Okajima, Pepperberg et al. 1989; Crouch, Hazard et al. 1992).