The Cone-specific visual cycle

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Abstract

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.

Introduction

The description and discussion of the retina visual cycle requires a brief introduction of the morphology, pigment, and phototransduction in both rods and cones. The differences in these features between rods and cones either impose the requirements for a second retinoid cycle in cones, or underlie the specificity of the retina visual cycle for cones.

Photoreceptors in the retina are the neurons responsible for light detection and the initiation of our visual perception. Most vertebrates have two types of image-forming photoreceptors — rods and cones, which were initially classified based on their morphological appearance. In addition to their structural differences, rods and cones also have distinct functional properties, including light sensitivity, response kinetics, and adaptation range, that make them suitable for dim- and bright-light function, respectively (Fu and Yau, 2007, Kefalov, 2010).

Rods are so sensitive to light stimuli that they are able to detect even a single photon. This makes rods perfect for scotopic (dim light/night time) conditions where they mediate our vision. While rods function well under dim light conditions, they are saturated easily and lose their light-sensing abilities even under moderately bright conditions. Rod responses to dim light are slow and, in addition, they have a long refractory period following exposure to bright light.

In contrast to rods, cones are less sensitive and function under bright light. Together with their wide dynamic range, this makes cones perfect for photopic (bright light/day time) conditions where cones mediate vision. Cone photoresponses to dim light are fast and, in addition, they recover rapidly following exposure to bright light.

Each photoreceptor usually contains one type of opsin, the protein moiety of visual pigment, determining the absorption spectrum of its related pigment and the spectral sensitivity of the photoreceptor. Mouse cones are unusual, as S-opsin and M-opsin are co-expressed in most cones (Applebury et al., 2000).

The functional differences between rods and cones outlined above can, in part, be attributed to the structural differences in their outer segments. Photoreceptors have outer segments (OS), inner segments (IS), nuclear regions, and synaptic terminals. In the rod outer segments (ROS), disc membranes are separated from and surrounded by the plasma membrane. In contrast, cone outer segments (COS) are formed from stacked invaginations of the plasma membrane (Mustafi et al., 2009). As a result, whereas rod discs are isolated from the extracellular space by the plasma membrane, cone discs are open to the extracellular matrix. This configuration of cone outer segments greatly increases the surface of their disc membrane and the cone surface-to-volume ratio. It is believed that the continuous and open structure of cone outer segments facilitates the fast reactions of phototransduction and metabolism in cones and assures the rapid material transport between cones and interphotoreceptor matrix (IPM) (Yau, 1994).

Most vertebrates have retinas populated predominantly by rods (rod-dominant) with relatively few cones. For example, the ratio of rods to cones is 97:3 in mouse (Carter-Dawson and LaVail, 1979), 92:8 in bovine (Krebs and Krebs, 1982), and 65:35 in salamander (Mariani, 1986) retinas. Human and primate retinas are also rod-dominant with rods outnumbering cones by a ratio of 95:5. However, the central area of the human retina, the fovea, is populated exclusively by cones. Several cone-dominant animals, such as chicken with 60% cones (Meyer and May, 1973), and ground squirrel with 96% cones (West and Dowling, 1975), have been very useful for cone-specific biochemical studies. In addition, the larval zebrafish at 15 days post fertilization (dpf) or younger is also considered cone-dominant as its rods do not contribute to vision before this age (Bilotta et al., 2001, Branchek, 1984). For physiological studies of vertebrate cones, the preferred animal has long been the larval tiger salamander. More recently, methods have been developed for biochemical and physiological studies from carp cone photoreceptors that have yielded some very interesting insights into the function of cones (Miyazono et al., 2008, Takemoto et al., 2009).

The photon-capturing molecule in photoreceptors is the visual pigment (rhodopsin in rods, and cone pigment in cones), which consists of light-sensing chromophore, covalently attached to a protein, opsin. Opsin, a member of the G-protein-coupled receptors family (Palczewski, 2006), has seven transmembrane helices and represents the most abundant protein on the disc membranes of both rods and cones. The pigment density is quite uniform, 25,000 molecules μm−2 (corresponding to concentration of ∼3.5 mM), in either type of photoreceptor across different species (Harosi, 1975). The most common chromophore in vertebrate photoreceptors is 11-cis retinal (11-cis RAL, also referred to as A1). Some aquatic animals also use 11-cis-3,4-dehydroretinal (also referred to as A2) (Dartnall and Lythgoe, 1965).

The apo-opsin (free opsin without chromophore) has weak constitutive activity and can trigger the transduction cascade (Cornwall and Fain, 1994, Cornwall et al., 1995). In darkness, 11-cis RAL, serving as an antagonist, binds to opsin via a Schiff-base linkage at a conservative lysine in opsin (K296 in mammalian rhodopsin) to form a holo-pigment, which is the inactive ground state of the visual pigment (Dartnall and Lythgoe, 1965). Photon absorption by 11-cis RAL converts it to the all-trans form, which is a strong agonist for opsin. The photoisomerization of the retinoid induces a series of rapid conformational changes of the pigment molecule that convert it to the physiologically active state (Meta II) within ∼1 ms (Lamb and Pugh, 2004, Okada et al., 2001). Meta II is the form of rhodopsin that activates the visual G-protein, transducin (Gt), and thus Meta II is also called R∗ (activated receptor). Eventually, Meta II decays to an inactive form, Meta III, and following the hydrolysis of the Schiff-base bond dissociates into free opsin and all-trans RAL. This decay takes minutes in rods but only seconds in cones (Shichida et al., 1994). The inactivation of R∗ in photoreceptors will be discussed below (see Section 1.4).

Phototransduction, the process of converting light into electrical neural signals, takes place in the outer segments of photoreceptors. The mechanisms of phototransduction and the proteins involved are highly conserved in rods and cones across different species (Arshavsky et al., 2002, Lamb and Pugh, 1992, Pugh and Lamb, 1993). The second messenger conveying photo-signal to neural signal is cGMP, which opens nonselective cyclic nucleotide-gated (CNG) cation channels located on the outer segment plasma membrane (Yau, 1994). In darkness, when bound to cGMP, a fraction of CNG channels are open, allowing the steady influx of Na+ and Ca2+ driven by the electrochemical gradient across the plasma membrane of the outer segment. This inward current (denoted as “dark current”) depolarizes the photoreceptors and maintains the steady release of neurotransmitter (glutamate) from their synaptic terminals in darkness.

The cGMP concentration within the outer segment is equilibrated by the balance between its synthesis by guanylyl cyclase (GC) and its hydrolysis by phosphodiesterase (PDE). Upon light absorption, R∗ activates the G-protein transducin (Gt), which in turn activates PDE. PDE∗ hydrolyzes cGMP into GMP, lowering cGMP concentration. The resulting closure of the CNG channels blocks the dark current and hyperpolarizes the photoreceptor membrane. As a result, the rate of glutamate release from the synapses is reduced, thus converting and relaying the light signal to the postsynaptic neurons as electrical signal (Lamb and Pugh, 2006, Yau and Hardie, 2009).

To maintain the continuous responsiveness of rods and cones, phototransduction in the outer segment has to be terminated by inactivating all the transduction components, including R∗, G∗, and PDE∗, and finally recovering the level of cGMP. Refer to (Fu and Yau, 2007, Lamb and Pugh, 2004) for detailed review of the termination of phototransduction. Here we will focus on R∗ termination.

R∗ inactivation occurs in two steps: phosphorylation and capping with arrestin. First, the activity of R∗ is partially blocked when it is phosphorylated by rhodopsin kinase (GRK) (Kuhn and Wilden, 1987, Whitlock and Lamb, 1999, Wilden et al., 1986). The capping protein – arrestin then binds to the phosphorylated R∗ on its cytoplasmic face. The formation of this complex inactivates R∗ completely by blocking its access to transducin (Schleicher et al., 1989, Wilden et al., 1986, Xu et al., 1997).

Due to the conformational changes in R∗, the retinyl-lysine Schiff-base bond becomes more exposed and accessible to water, and thus susceptible to hydrolysis. R∗ can either decay into free opsin and all-trans RAL or convert to the inactive Meta III form, the latter eventually also dissociating into apo-opsin and retinoid (Kolesnikov et al., 2003). Notably, this spontaneous decay is substantially slower than the inactivation of R∗ by GRK and arrestin and, as a result, it does not affect the flash response (Imai et al., 2007, Kefalov et al., 2003).

Exposure to bright light results in the activation and subsequent decay (bleaching) of substantial fraction of the visual pigment. This reduces the sensitivity of photoreceptors by two mechanisms: first, it reduces the amount of pigment available for subsequent light activation, and second, it produces constitutive activity due to the buildup of apo-opsin as the bleached pigment decays. Thus, complete restoration of dark-adapted sensitivity of photoreceptors requires regeneration of the bleached visual pigment with 11-cis RAL (Cornwall and Fain, 1994, Cornwall et al., 1995, Pepperberg et al., 1978, Surya et al., 1995). The continuous function of photoreceptors in steady background light also requires constant renewal of their visual pigment with 11-cis RAL.

Section snippets

The canonical RPE visual cycle

The process of recycling all-trans RAL, released from the bleached pigment, to 11-cis RAL, required for pigment regeneration, is known as the visual cycle. The canonical visual cycle involves the retinal pigment epithelium (RPE), a monolayer of epithelial cells adjacent to the outer segments of photoreceptors. In 1878, Willy Kühne found that the bleached frog retina recovers only partially its level of visual purple (Rhodopsin) if it is detached from the RPE, and photoreceptors have to contact

The cone-specific retina visual cycle

Rods and cones function in different light conditions that impose different requirements for the properties of their visual pigments. Yet, light exposure bleaches rod and cone pigment at equal rates because the pigment concentration and density in both photoreceptors are similar across species (Harosi, 1975). The quantum efficiency, defined as the ratio of the number of photoactivated pigment molecules to the number of such molecules that absorbed a photon, is also identical in rods and cones (

Potential involvement of Müller cells in the retinoid recycling pathway

The expression of the retinoid binding proteins CRBP and CRALBP in Müller (radial glial) cells suggested that Müller cells might be involved in the chromophore processing pathway (Bok et al., 1984, Bunt-Milam and Saari, 1983, Eisenfeld et al., 1985) as both retinoid binding proteins are critical in the RPE visual cycle. The soma of Müller cells is located in the inner nuclear layer (INL) and gives rise to two opposite trunk processes spanning the retina from ganglion cell layer (GCL) to the

The traffic of chromophore in the retina

Both the canonical RPE visual cycle and the putative retina visual cycle involve two cellular compartments, one is the photoreceptors and the other is RPE or Müller cells. Thus, transport of the highly hydrophobic retinoid to and from photoreceptors is critical for the function of both visual cycles and for the regeneration of visual pigment in rods and cones. The mechanism for traffic of retinoid between Müller cells and cones is unknown. Notably, the processes of Müller cells end at the outer

Physiological evidence for the retina visual cycle in rod-dominant species

A recent review described in detail the parallel visual cycles in zebrafish (Fleisch and Neuhauss, 2010), thus we will focus on the cone-specific visual cycle in other vertebrates and in mammals. Because of the difficulties of investigating biochemically or physiologically the function of mammalian cones in rod-dominant species, all the evidence discussed above in support of a retina visual cycle came from in vitro biochemical studies and only from cone-dominant species. The small fraction of

Overview of the cone-specific retina visual cycle

Based on the current knowledge from biochemical and physiological studies, the cone-specific visual cycle could be depicted briefly as follows (Fig. 8). After photolysis, all-trans RAL is reduced to all-trans ROL, which is then released and transported across the interphotoreceptor matrix to Müller cells, possibly with the help of IRBP (Crouch et al., 1992, Jin et al., 2009, Okajima et al., 1989, Parker et al., 2009, Pepperberg et al., 1991). In Müller cells, binding with CRBP, all-trans ROL is

Future directions

The mechanisms underlying the retina visual cycle are still not well understood and its molecular components have not been identified. Specifically, the role of chromophore-binding proteins expressed in the retina is not known and the enzymes involved in the recycling of retinoid in the retina have not been identified.

Acknowledgements

We thank Carter Cornwall (Boston University School of Medicine) and Peter Lukasiewicz (Washington University School of Medicine) for their valuable comments on this manuscript.

This work was supported by Career Development Award from Research to Prevent Blindness, NIH grants EY019312 and EY019543 (V.J.K.), and unrestricted grant from Research to Prevent Blindness and EY02687 (Department of Ophthalmology and Visual Sciences at Washington University).

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