Cone Arrestin: Deciphering the Structure and Functions of Arrestin 4 in Vision Cheryl Mae Craft and Janise D. Deming

Contents 1 Discovery of Cone Arrestin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Cellular Localization and Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Evolution of Cone Arrestin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Crystal Structure and G Protein-Coupled Receptor Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Role in S- and M-Cone Opsin Shutoff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Other Potential Binding Partners of Arr4 Are Identified . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Role in Visual Perception Phenotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Potential Therapeutic Use of Cone Arrestin Promoter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Cone arrestin (Arr4) was discovered 20 years ago as a human X-chromosomal gene that is highly expressed in pinealocytes and cone photoreceptors. Subsequently, specific antibodies were developed to identify Arr4 and to distinguish cone photoreceptor morphology in health and disease states. These reagents were used to demonstrate Arr4 translocation from cone inner segments in the dark to outer segments with light stimulation, similarly to Arrestin 1 (Arr1) translocation in rod photoreceptors. A decade later, the Arr4 crystal structure was solved, which provided more clues about Arr4’s mechanisms of action. With the creation of genetically engineered visual arrestin knockout mice, one critical function of Arr4 was clarified. In single living cones, both visual arrestins bind to light-activated, G protein receptor kinase 1 (Grk1) phosphorylated cone opsins to desensitize them, and in their absence, mouse cone pigment shutoff is delayed. Still under investigation are additional functions; however, it is clear that Arr4 has non-opsin-binding partners and diverse synaptic roles, including cellular anchoring C.M. Craft (*) • J.D. Deming Mary D. Allen Laboratory for Vision Research, Doheny Eye Institute, Departments of Ophthalmology and Cell and Neurobiology, , Keck School of Medicine, University of Southern California, 1355 San Pablo Street, DVRC 405, Los Angeles, CA 90033, USA e-mail: [email protected] V.V. Gurevich (ed.), Arrestins - Pharmacology and Therapeutic Potential, Handbook of Experimental Pharmacology 219, DOI 10.1007/978-3-642-41199-1_6, © Springer-Verlag Berlin Heidelberg 2014

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and trafficking. Recent studies reveal Arr4 is involved in high temporal resolution and contrast sensitivity, which opens up a new direction for research on this intriguing protein. Even more exciting is the potential for therapeutic use of the Arr4 promoter with an AAV-halorhodopsin that was shown to be effective in using the remaining cones in retinal degeneration mouse models to drive inner retinal circuitry for motion detection and light/dark discrimination. Keywords Visual arrestins • Phototransduction • Gene regulation • Evolution • AAV-halorhodopsin

1 Discovery of Cone Arrestin After “rod” Arrestin 1 (Arr1) and the two β-arrestins were identified (Attramadal et al. 1992; Lohse et al. 1990; Shinohara et al. 1987), the molecular search continued for other novel arrestins (Craft et al. 1990). The fourth arrestin was independently discovered using two distinct molecular cloning strategies. The first approach employed a technique that identified expressed retinal-specific genes on the X chromosome using a retinal cDNA library and northern blot screen analysis. Based on the sequence similarity to Arr1, this arrestin was named “X-arrestin” (Murakami et al. 1993). Simultaneously, Craft, Whitmore, and Wiechmann characterized the arrestin family using a pineal gland cDNA expression library by targeting an epitope domain-shared anchor of the three known arrestins in a novel polymerase chain reaction technology (PCR) approach (Craft et al. 1994). In addition to the known arrestins, they also identified a unique cDNA, which encoded an arrestin-like protein that was localized to human chromosome Xq13.1. Based on in situ hybridization studies, the transcript’s cellular expression pattern demonstrated that it was highly enriched in pinealocytes and cone photoreceptors and was named “cone arrestin.” Arrestin 4 (Arr4) is used to distinguish it from the other three arrestins (Craft et al. 1995).1

1 Systematic names of arrestin proteins: Arrestin-1 (historic names S-antigen, 48 kDa protein, visual or rod arrestin), Arrestin-2 (β-arrestin1 or ARRB1), Arrestin-3 (β-arrestin2, hTHY-ARRX or ARRB2), and Arrestin-4 (cone or X-arrestin; its human gene is designated “Arrestin 3” (ARR3) in the HUGO nomenclature database).

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2 Cellular Localization and Expression With the identification of the protein encoding Arr4, specific peptide antibodies were created that were helpful in resolving results from earlier immunohistochemical studies (Zhu et al. 2002a, b). Arr4 was shown to be specifically expressed in all cones (Zhang et al. 2001); however, it has reduced expression in S cones (Haverkamp et al. 2005). In contrast, a monoclonal antibody panel of S-antigen recognized Arr1expression in baboon rods and S-opsin cones, which was absent in LM-opsin cone photoreceptors (Nir and Ransom 1992). The same expression pattern is also observed in Macaca, chimpanzee, and human retinas (Zhang et al. 2001; Craft et al. 2013). In addition, these and other reagents are being used in numerous studies to identify cones in multiple species during development in normal retinas and retinoblastomas, cone survival in macula translocation, retinal degeneration models, and in cone rescue with gene therapy (Albini et al. 2004; Busskamp et al. 2010; Haire et al. 2006; Nikonov et al. 2006; Smith et al. 2000; Yu et al. 2011; Zhang et al. 2004). By immunohistochemical localization using specific antibodies unique for mouse Arr4 (Luminaire junior—mouse cone arrestin [LUMIj-mCAR]), Arr4 is expressed in several cone photoreceptor cellular compartments before and after light exposure (Zhu et al. 2002a). Similar to Arr1 translocation studies in rod photoreceptors (Whelan and McGinnis 1988), Arr4 undergoes a light-dependent translocation from the cone pedicles, cell bodies, and inner segments to the cone outer segments. Similar light/dark Arr4 translocation is observed in bovine cone photoreceptors with the 7G6 monoclonal antibody, which also recognizes cone arrestin (Zhang et al. 2003a). However, the translocation of Arr4 is not as robust as that of Arr1; even after bright light exposure, a residual amount of Arr4 remains in the cone pedicle, while Arr1 nearly completely translocates to the outer segments (Zhu et al. 2002a). In Grk1/ mice with or without simultaneous knockout of transducin α-subunit, Arr4 translocation to outer segments is light dependent, even without opsin phosphorylation (Zhang et al. 2003b). This implies that the classical “on” pathway through the opsins to alpha-transducin is not required for Arr4 translocation, and there is likely to be another light-dependent pathway driving the translocation of Arr4. It has also been shown that light-dependent Arr4 translocation does not take place in Guanylyl Cyclase 1 knockout (GC1/) mice; however, Arr4 translocation can be restored when GC1/ mice are treated with AAV-GC1, which rescues guanylyl cyclase 1 cone function (Coleman and SempleRowland 2005; Haire et al. 2006). The concentration of the visual arrestins in dark-adapted cones was measured and compared to previous studies to reveal their combined total quantity is about 70 % of cone opsin (Nikonov et al. 2008). In this study in a single wild-type cone, Arr1estimated expression level was ~1.7  108 and Arr4 was ~3.3  106 molecules using whole cone volume of 950  220 μm3. Even more surprising, this quantitative analysis of immunofluorescence distribution of staining by Arr1-specific antibody D9F2 compared to Arr4-specific LUMIj-mCAR revealed differences in various cone compartments showing that Arr1 concentration is approximately 50-fold higher (Fig. 6.1).

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Fig. 6.1 Immunohistochemical staining of Arr1 and Arr4 in mouse cone photoreceptors. The four panels depict confocal images of a cryosection of a C57Bl/6J mouse retina with anti-mouse monoclonal D9F2-Arr1 (b) and anti-rabbit polyclonal LUMIj-mCAR (c) double labeled fluorescently with appropriate secondary antibodies (Zhu et al. 2002a). The overlay (d) reveals dual localization of Arr1 with Arr4 in the cone photoreceptor (white arrow). In panel (a), phase-contrast image is shown. Retinal pigment epithelia (RPE), outer segments (OS), inner segments (IS), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), and ganglion cell layer (GCL)

3 Evolution of Cone Arrestin The phylogeny of the vertebrate arrestins was summarized previously in an excellent review (Gurevich and Gurevich 2006). The visual and beta (β)-arrestins diverged from a family of ancient, alpha-arrestins and likely coevolved with the opsins (Alvarez 2008). Although Arr4 was so named because it was most recently discovered, it may not be the most recently evolved of the arrestins. With the understanding that early pineal photoreceptor cells were more similar to cones than to rods, it is likely that the cone arrestin emerged as the first member in the super family of the arrestins (Craft and Whitmore 1995). At least nine vertebrate species of Arr4 are in the NCBI database and range from Danio rerio to Homo sapiens (http://www.ncbi.nlm.nih.gov/homologene? cmd¼Retrieve&dopt¼MultipleAlignment&list_uids¼3182). Phylogenetic analysis of visual arrestins suggests that Arr1 and Arr4 are likely to have diverged from Ciona intestinalis arrestin (Ci-Arr) around the same time (Nikonov et al. 2008). The Ci-Arr is expressed in ciliated, hyperpolarizing photoreceptors of the larval tunicate plus their axons and synaptic specializations (Horie et al. 2005) (Fig. 6.2). Based on the similarities, additional Arr4-binding partners in synaptic specializations of cones are a reasonable prediction.

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Arr L polyphemus

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Arr1 O latipesR2 Arr1 D rerio Arr1 O latipesR1 Arr1 G gallus Arr1 A tigrinum Arr1 X laevis Arr1 X tropicalis Arr1 R pipiens Arr1 R catesbeiana Arr N vectensis

Arr L pealei

Arr C intestinalis

Arr4 G gecko Arr4 G gallus Arr4 A tigrinum

Arr4 O latipesC Arr4 D rerio Arr4 X laevis Arr4 R pipiens Arr4 R catesbeiana

Fig. 6.2 Phylogenetic analysis of arrestin sequences from lower organisms. Primary sequences of arrestin proteins from the indicated species were aligned and an unrooted phylogenetic tree was generated using ClustalW (Thompson et al. 1994). Tree data were rendered with Dendroscope (Huson et al. 2007). Subtrees are color coded according to visual arrestin type (Arr1—green, top, Arr4—red, lower) where such designation has been reported; the branches in black (middle) correspond to species of identified visual arrestin sequences either not assigned or whose ancestors diverged from the line leading to vertebrates prior to the divergence of Arr1 and Arr4. R1, R2, and C designations for the O. latipes sequences are as described by the authors (Imanishi et al. 1999). Original from supplemental figure 9S (Nikonov et al. 2008) with permission for use granted by Elsevier: http:// dx.doi.org/10.1016/j.neuron.2008.06.011 DOI:10.1016/j.neuron.2008.06.011#doilink

4 Crystal Structure and G Protein-Coupled Receptor Binding Another critical piece of the puzzle in deciphering Arr4’s functions was the generation of a crystal structure of the protein. In 2005, a crystal structure of the salamander cone arrestin was solved (Sutton et al. 2005). It was similar to the other arrestin structures that were previously identified, having the canonical arrestin fold consisting of two domains, each containing a β-strand “sandwich.” The β-strand sandwich consists of two β-strand sheets joined by hydrophobic interactions. There was also a single α-helix in the amino (N)-domain. These investigators explored the binding selectivity of Arr4 compared to Arr1 and β-arr1. While Arr1 is highly selective for light-activated, phosphorylated-rhodopsin (P-Rh*), and β-arr1 is able to bind many G protein-coupled receptors (GPCRs), Arr4 has an intermediate binding selectivity. Its highest binding affinity was for human green cone opsin, but it was also able to bind to the M2 muscarinic cholinergic receptor. Thus, while the molecular structural details of Arr1 function have been well characterized, there is still much to discover regarding Arr4 and its function in cone photoreceptors and pinealocytes.

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While the β-arrestins share a high sequence similarity (76 % identical), the visual arrestins are less similar to each other (58 % identical). Arr4 shares the same degree of similarity to β-arr2 as to Arr1 (58 %) (Craft and Whitmore 1995). Perhaps this similarity to the β-arrestins is what confers Arr4 with its binding capacity for GPCRs outside of the opsins, while Arr1 maintains a very high preference for P-Rh*.

5 Role in S- and M-Cone Opsin Shutoff Given its amino acid sequence identity and similarity to Arr1 and enrichment in cone photoreceptors, researchers hypothesized that Arr4 acts in a similar physiological manner to Arr1: binding to light-activated, phosphorylated cone opsins and subsequently desensitizing them. This binding would prevent the phosphatase 2A from dephosphorylating the opsin complex and allowing it to be reactivated. However, until a decade after the initial discovery of Arr4, there was insufficient evidence to support this hypothesis. Because of the rod dominance of the mouse retina, it was difficult to isolate cone photoreceptors and determine whether or not the Arr4 was involved in cone pigment shutoff and how that involvement occurred. In 2001, using retinas isolated from the neural retina leucine zipper knockout mouse (Nrl/), in which the rod progenitor cells develop into an enhanced S-cone phenotype, Swaroop and his collaborators observed high expression of coneenriched proteins. Using immunoprecipitation, in vitro phosphorylation, and isoelectric focusing, Craft and her collaborators verified that Arr4 binding was specific to light-activated, G protein receptor kinase 1- (Grk1) phosphorylated Sand M-opsins in mice (Zhu et al. 2003; Mears et al. 2001). Backcrossing Nrl/ with Grk1/ mice to create double knockout mice, they revealed that when Grk1 is absent, the cone pigments are not phosphorylated and Arr4 is unable to bind them in a light-dependent manner. This was the first clear evidence that Arr4 acts in the way it had been hypothesized since its discovery. Additional in vitro studies suggested Arr4 participated in binding to light-activated phosphorylated cone opsins (Sutton et al. 2005; Zhu et al. 2002a). However, it still did not show that Arr4 is required for the cone pigment shutoff, but only that it binds to the cone opsins after they were light activated and subsequently phosphorylated by Grk1. Craft and Pugh collaborated to clarify Arr4’s contribution to cone pigment shutoff utilizing the Arr4 mouse knockout (Nikonov et al. 2008). To their surprise, their initial studies revealed no significant difference in the Arr4/ cone pigment shutoff response compared to the control in native murine cones. An earlier study demonstrated that in a transgenic mouse model where cone arrestin expression was driven by the rhodopsin promoter to be highly expressed in rods that Arr4 could only partially rescue the light-induced rod degeneration and activated rhodopsin shutoff and recovery in Arr1/ retinas (Chan et al. 2007). Although Arr4 is expressed in cone photoreceptors and pinealocytes, Arr1 was discovered to be highly expressed in all mouse rods and co-expressed with Arr4 in cones (Nikonov et al. 2008; Zhu et al. 2005) (Fig. 6.1). They hypothesized that the

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Arr1 may contribute to the cone pigment shutoff. Therefore, they employed single Arr1/, Arr4/, and double knockout Arr1/Arr4/ mice to determine if one or both visual arrestins were necessary and sufficient for normal cone pigment shutoff. Using electrophysiological recording from single cones of normal control mice, they showed that after a bright light stimulus, there is essentially no response difference in the cone recovery time between WT, Arr1/, and Arr4/. In contrast, Arr1/Arr4/ double knockout (Arr-DKO) response had a significantly longer recovery time compared to the single arrestin knockout genotypes. For the first time, this study established a function for Arr4 in living cones (Fig. 6.3, left panel). Further experiments probed the time course of phototransduction activated by Sand M-cone opsins, respectively. Previously, it was shown that in a “dim-flash” response to 360 and 510 nm light, the response is a linear function of flash intensity and can independently be evaluated (Nikonov et al. 2006). Surprisingly, the ArrDKO cones exhibited a similar waveform response to the other genotypes until they achieve 60 % of their recovery to baseline; then, the recovery response of the ArrDKO cone “peeled off,” exhibiting a much slower tail phase than the others, regardless of whether S- or M-opsin was activated by the flash (Fig. 6.3a–d, right panel). Therefore, the normal inactivation of each isomerized S- or M-opsin molecule requires at least one visual arrestin (Arr1 or Arr4) after a strong bright light stimulus. This avoidance of saturation in steady illumination implies that the phosphodiesterase activity generated by each photoisomerized cone opsin is prolonged. Thus, the current state of Arr4 research indicates that Arr4 binds to and desensitizes light-activated, phosphorylated cone pigments; however, Arr1 fulfills a similar functional role if Arr4 is absent.

6 Other Potential Binding Partners of Arr4 Are Identified As with the other arrestins, Arr4 has other identifiable nonreceptor-binding partners, including c-Jun N-terminal kinase (Jnk3) and E3 ubiquitin ligase Mdm2. Arr4 works together with these proteins to regulate their subcellular localization and relocalize them from the nucleus to the cytoplasm (Song et al. 2007). Both of these proteins can also bind the other arrestins to serve as scaffolds to recruit modules (Lefkowitz and Shenoy 2005; Shenoy et al. 2001). Using a cell-based assay, Song and collaborators identified individual N- and C-domains of cone and rod arrestins that contain elements to bind JNK3 and to remove it from the nucleus. In contrast, unlike the interaction of the N-domain of Arr3, Mdm2 preferentially interacts with full-length Arr4 in the “frozen” basal configuration, which mimics the conformation of free Arr4. Their Arr4 studies exclude residues in the receptor-binding elements, plus set the stage to analyze the precise identification of Jnk3- and Mdm2-binding sites by site-directed mutagenesis. In yeast two hybrid screens of retinal cDNA libraries, other potential interactions between Arr4 and novel candidates were identified, including Rnd2 (Zuniga 2010)

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Fig. 6.3 (continued)

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Fig. 6.3 Recovery times of S-dominant cones of WT, Arr4/, Arr1/, and Arr-DKO mice. The three panels are each Pepperberg plots, i.e., show as a function of the logarithm of the flash intensity the time TC for cones of each genotype to recover criterion levels (C) of 20, 40, or 60 %, respectively, of their light-sensitive current after saturating flashes. The values at a set of discrete intensities were interpolated from individual cone’s records and then averaged over genotype; the error bars are 2 s.e.m. For WT, Arr4/ and Arr1/ cones the slopes of the “TC vs log I” data are roughly constant across level C and genotype, in contrast, with the Arr-DKO data, for which the slope change strongly with C. These points are illustrated in the inset in the lowermost panel that plots the Slopes vs. C for each genotype. Original from figure 5 (Nikonov et al. 2008) and used

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and a cilia protein, Als2Cr4/TMEM 237 (Zuniga and Craft 2010). Rnd2 belongs to a family of small GTP-binding proteins that alter many important cellular functions by affecting the actin cytoskeletal structure and stability (Tanaka et al. 2002). TMEM 237 is involved in the cilia transition zone and a gene defect contributes to Joubert syndrome (Huang et al. 2011) . In addition, in an in vitro proteomic study in cultured HEK 293 cells, β-arrestins were shown to interact with both visual arrestins after stimulation with the betaadrenergic agonist, isoproterenol (Xiao et al. 2007). So far, no evidence exists that the heteromerization of β-arrestins and visual arrestins has any functional significance, but they may work synergistically and in conjunction with one another, leading to an intriguing, unexplored area of inquiry (Deming et al. 2013). Arr4 is highly expressed in cones and pinealocytes, and it is reasonable to hypothesize that it actively participates in other cellular interactions and other GPCR pathways besides cone opsin pigment shutoff, especially since pinealocytes do not express cone opsins. These interactions with other proteins could be responsible for the Arr4 remaining in the cone pedicle after light exposure.

7 Role in Visual Perception Phenotypes Zebrafish studies have also provided evidence of the physiological role of Arr4 in vision. Zebrafish have two genes homologous to mouse Arr4, which are called Arr3a and Arr3b. Unlike mouse cones, which express both visual arrestins, zebrafish cone photoreceptors only express one visual arrestin per cone. M- and L-cones express Arr3b, while S-cones express exclusively Arr3a. Morpholino knockdown technology of Arr3b causes a delay in M- and L-cone photoreceptor recovery (Renninger et al. 2011). Because of technical limitations, S-cone photoreceptor recovery could not be measured, but the group predicted that Arr3a is required for S-cone recovery. In addition, Arr3b was shown to be necessary for high temporal resolution in the L- and M-cones (Renninger et al. 2011). Fig. 6.3 (continued) with permission by Elsevier: http://dx.doi.org/10.1016/j.neuron.2008.06.011 DOI:10.1016/j.neuron.2008.06.011#doilink. (a–d) Response tail phases depend on visual arrestin genotype. (a) Dim flash responses. The noisy black trace presents the grand average dim-flash responses of cones that express only Arr4 (Arr1/), only Arr1 (Arr4/), or both arrestins (WT); the noisy gray trace is the averaged dim-flash response of Arr-DKO cones. Both averages combine S- and M-opsin driven responses, which had indistinguishable forms in each genotype. (b–c) Responses to saturating flashes of Arr4/ cone and of Arr1/ cone. The tail phases of the responses have been fitted with first-order exponential decays. (d) Summary analysis of the tail phase responses of all the cones investigated. The tail phase of each saturating response of every cone was fitted with exponential decays as in panel (b), (c), and the amplitude of the tail estimated from the fitted curve at t ¼ 1.0 s after the flash; the values at a set of discrete intensities were interpolated and averaged over genotype. Original figure 8 (Nikonov et al. 2008) reproduced with permission granted by Elsevier: http://dx.doi.org/10.1016/j.neuron.2008.06.011 DOI:10.1016/j. neuron.2008.06.011#doilink

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Mouse models utilizing the visual arrestin knockouts have a similar phenotype as the morpholino knockout of Arr3b. Arr4/ mice have a significant decrease in contrast sensitivity compared to Arr1/ or wildtype controls (Brown et al. 2012). Thus, although Arr1 can substitute for Arr4 in cone pigment shutoff, it may not be able to substitute all of the functional roles that Arr4 has in cones. Likewise, Arr4 expression will not substitute for Arr1 in restoring the light adaption ERG phenotype or synaptic modulation of N-ethylmaleimide sensitive factor in Arr1/ (Brown et al. 2010; Huang et al. 2010). Other cone arrestin roles are under investigation, but the existence of the Arr4/ mouse model will allow further discovery of the divergent cellular pathways in which the arrestins are involved.

8 Potential Therapeutic Use of Cone Arrestin Promoter The mouse (mCAR) and human Arr4 (hCAR) gene spans over 13.5 kilobases (kb), which includes 17 exons and 16 introns (Sakuma et al. 1998; Zhu et al. 2002a). Similar to the other arrestins, mCAR also has alternative splicing with at least 5 transcripts. Both CAR promoters are well characterized and contain multiple ciselements, including the cone rod homeobox (CRX), to regulate and target specific cone photoreceptor transcription. However, other specific promoter elements found in the mouse and human gene differ, including the AP4, c-Myb, and p53 elements in the former, and E-box, thyroid hormone/retinoic acid responsive, and derepression elements in the latter (Sakuma et al. 1998; Zhu et al. 2002a). These promoter elements were carefully studied in vitro in Y79 and WERI retinoblastoma cell lines and in vivo in Xenopus laevis. A region of less than 500 base pairs was shown to be necessary and sufficient to drive high levels of gene expression to a subpopulation of cultured retinoblastoma cells and cone photoreceptors and pinealocytes, respectively (Fujimaki et al. 2004; Li et al. 2002, 2003; Pickrell et al. 2004). In 2010, the mCAR promoter was successfully used to target expression and to restore light-evoked activity in light-insensitive cone photoreceptors. Busscamp and colleagues genetically targeted a light-activated chloride pump, enhanced Natronomonas pharaonis halorhodopsin (eNpHR), to photoreceptors by means of adeno-associated viruses (AAVs) (Busskamp et al. 2010). Light-activated chloride pumps are rational candidates for reactivating vertebrate photoreceptors, as both eNpHR-expressing cells and healthy photoreceptors hyperpolarize in response to increases in light intensity. Two animal models of retinitis pigmentosa for gene therapy were tested. One of the targeted expression vectors of eNpHR was created with the use of the cell-specific promoter for mouse cone arrestin-4 (Zhu et al. 2002b). Virus was delivered after cones could not respond to light; however, the treated retinas could use their remaining inner retinal circuitry for motion detection and light/dark discrimination. Also, the NpHR did not elicit an immune response nor lead to toxicity after over 1 year. The translation of gene therapy achieved in these mice to humans requires the use of promoters and AAV serotypes that drive photoreceptor-specific eNpHR

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expression in human retinas. As part of the eNpHR studies, the AAVs were tested on human ex vivo retinal explants and they visualized eNpHR–EYFP protein expression in the cultured human retinas using the mCAR promoter-directed expression of eNpHR, which was specifically expressed in human photoreceptors (Busskamp et al. 2010). AAV vectors have proved to be stable and free of side effects when used to infect the human eye. The future hope is that AAV-halorhodopsin will be nontoxic and effective enough within the normal range of light intensities to prolong vision in humans with retinitis pigmentosa and perhaps other genetic diseases as well. The potential use of the AAV-halorhodopsin extends earlier work with gene therapy treatment with AAV-RPE65 of children with another form of genetic blindness, Leber’s congenital amaurosis, which is currently approved (Testa et al. 2013). Alternatively, in the future a combination therapy of antioxidants, enzymes, and/or growth factors, and AAV-halorhodopsin might prolong cone survival and function (Cepko 2012). These exciting groundbreaking experiments that utilized the cone arrestin promoter are proof-of-principle examples toward realizing the therapeutic goal of restoring vision and demonstrate that expression and function of halorhodopsin in human cone photoreceptors are feasible. Acknowledgments Dr. Craft is the Mary D. Allen Chair in Vision Research, Doheny Eye Institute (DEI). This work was supported, in part, by EY015851 (CMC), Core grant EY03040 (DEI), Research to Prevent Blindness, Dorie Miller (JDD), Tony Gray Foundation (JDD), William Hansen Sandberg Memorial Foundation (JDD). We wish to dedicate this chapter in memory of Stephen J. Ryan, M.D. for his lifelong commitment to DEI, ophthalmology and our vision research program. We thank Bruce M. Brown for 40 years of outstanding contributions to vision research, plus the members of the Mary D. Allen Laboratory for Vision Research, DEI, our collaborators and colleagues for their contributions in this work.

References Albini TA, Rao NA, Li A, Craft CM, Fujii GY, de Juan E Jr (2004) Limited macular translocation: a clinicopathologic case report. Ophthalmology 111:1209–1214 Alvarez CE (2008) On the origins of arrestin and rhodopsin. BMC Evol Biol 8:222 Attramadal H, Arriza JL, Aoki C, Dawson TM, Codina J, Kwatra MM, Snyder SH, Caron MG, Lefkowitz RJ (1992) Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family. J Biol Chem 267:17882–17890 Brown BM, Ramirez T, Rife L, Craft CM (2010) Visual Arrestin 1 contributes to cone photoreceptor survival and light adaptation. Invest Ophthalmol Vis Sci 51:2372–2380 Brown BM, Kim M, Aung M, Rife L, Pardue M, Craft C (2012) Abnormal photopic ERG responses and defective contrast sensitivity in cone arrestin 4 knockout mice reveal potential regulatory functions. Invest Ophthalmol Vis Sci, ARVO E-Abstract 759 Busskamp V, Duebel J, Balya D, Fradot M, Viney TJ, Siegert S, Groner AC, Cabuy E, Vr F, Seeliger M, Biel M, Humphries P, Paques M, Mohand-Said S, Trono D, Deisseroth K, Sahel JA, Picaud S, Roska B (2010) Genetic reactivation of cone photoreceptors restores visual responses in Retinitis Pigmentosa. Science 329:413–417 Cepko CL (2012) Emerging gene therapies for retinal degenerations. J Neurosci 32:6415–6420

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Chan S, Rubin WW, Mendez A, Liu X, Song X, Hanson SM, Craft CM, Gurevich VV, Burns ME, Chen J (2007) Functional comparisons of visual arrestins in rod photoreceptors of transgenic mice. Invest Ophthalmol Vis Sci 48:1968–1975 Coleman JE, Semple-Rowland SL (2005) GC1 deletion prevents light-dependent arrestin translocation in mouse cone photoreceptor cells. Invest Ophthalmol Vis Sci 46:12–16 Craft CM, Whitmore DH (1995) The arrestin superfamily: cone arrestins are a fourth family. FEBS Lett 362:247–255 Craft CM, Whitmore DH, Donoso LA (1990) Differential expression of mRNA and protein encoding retinal and pineal S-antigen during the light/dark cycle. J Neurochem 55:1461–1473 Craft CM, Whitmore DH, Wiechmann AF (1994) Cone arrestin identified by targeting expression of a functional family. J Biol Chem 269:4613–4619 Craft CM, Huang J, Possin D, Hendrickson A (2013) Primate short-wavelength cones share molecular markers with rods. In: Ash J, Hollyfield JG, LaVail MM, Anderson RE, Grimm C, Bowes Rickman C (eds) Retinal degenerative diseases. Springer, Heidelberg, Chapter 7 Deming JD, Lim K, Brown BM, Pak JS, Van Cranenbroeck K, Craft CM (2013) Interactions between dopamine receptor D4 and visual arrestins. Invest Ophthalmol Vis Sci, ARVO E-Abstract 2452 Fujimaki T, Huang ZY, Kitagawa H, Sakuma H, Murakami A, Kanai A, McLaren MJ, Inana G (2004) Truncation and mutagenesis analysis of the human X-arrestin gene promoter. Gene 339:139–147 Gurevich EV, Gurevich VV (2006) Arrestins: ubiquitous regulators of cellular signaling pathways. Genome Biol 7:236 Haire SE, Pang J, Boye SL, Sokal I, Craft CM, Palczewski K, Hauswirth WW, Semple-Rowland SL (2006) Light-Driven Cone Arrestin translocation in cones of postnatal Guanylate Cyclase-1 knockout mouse retina treated with AAV-GC1. Invest Ophthalmol Vis Sci 47:3745–3753 Haverkamp S, Wassle H, Duebel J, Kuner T, Augustine GJ, Feng G, Euler T (2005) The primordial, blue-cone color system of the mouse retina. J Neurosci 25:5438–5445 Horie T, Orii H, Nakagawa M (2005) Structure of ocellus photoreceptors in the ascidian Ciona intestinalis larva as revealed by an anti-arrestin antibody. J Neurobiol 65:241–250 Huang SP, Brown BM, Craft CM (2010) Visual Arrestin 1 acts as a modulator for N-Ethylmaleimide-sensitive factor in the photoreceptor synapse. J Neurosci 30:9381–9391 Huang L, Szymanska K, Jensen VL, Janecke AR, Innes AM, Davis EE, Frosk P, Li C, Willer JR, Chodirker BN, Greenberg CR, McLeod DR, Bernier FP, Chudley AE, Muller T, Shboul M, Logan CV, Loucks CM, Beaulieu CL, Bowie RV, Bell SM, Adkins J, Zuniga FI, Ross KD, Wang J, Ban MR, Becker C, Nurnberg P, Douglas S, Craft CM, Akimenko MA, Hegele RA, Ober C, Utermann G, Bolz HJ, Bulman DE, Katsanis N, Blacque OE, Doherty D, Parboosingh JS, Leroux MR, Johnson CA, Boycott KM (2011) TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am J Hum Genet 89:713–730 Huson DH, Richter DC, Rausch C, Dezulian T, Franz M, Rupp R (2007) Dendroscope: an interactive viewer for large phylogenetic trees. BMC Bioinformatics 8:460 Imanishi Y, Hisatomi O, Tokunaga F (1999) Two types of arrestins expressed in medaka rod photoreceptors. FEBS Lett 462:31–36 Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308:512–517 Li A, Zhu X, Craft CM (2002) Retinoic acid upregulates cone arrestin expression in retinoblastoma cells through a Cis element in the distal promoter region. Invest Ophthalmol Vis Sci 43:1375–1383 Li A, Zhu X, Brown B, Craft CM (2003) Gene expression networks underlying retinoic acidinduced differentiation of human retinoblastoma cells. Invest Ophthalmol Vis Sci 44:996–1007 Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ (1990) beta-Arrestin: a protein that regulates beta-adrenergic receptor function. Science 248:1547–1550

130

C.M. Craft and J.D. Deming

Mears AJ, Kondo M, Swain PK, Takada Y, Bush RA, Saunders TL, Sieving PA, Swaroop A (2001) Nrl is required for rod photoreceptor development. Nat Genet 29:447–452 Murakami A, Yajima T, Sakuma H, McLaren MJ, Inana G (1993) X-arrestin: a new retinal arrestin mapping to the X chromosome. FEBS Lett 334:203–209 Nikonov SS, Kholodenko R, Lem J, Pugh EN Jr (2006) Physiological features of the S- and M-cone photoreceptors of wild-type mice from single-cell recordings. J Gen Physiol 127:359–374 Nikonov SS, Brown BM, Davis JA, Zuniga FI, Bragin A, Pugh EN Jr, Craft CM (2008) Mouse cones require an arrestin for normal inactivation of phototransduction. Neuron 59:462–474 and Supplement Nir I, Ransom N (1992) S-antigen in rods and cones of the primate retina: different labeling patterns are revealed with antibodies directed against specific domains in the molecule. J Histochem Cytochem 40:343–352 Pickrell SW, Zhu X, Wang X, Craft CM (2004) Deciphering the contribution of known cis-elements in the mouse cone arrestin gene to its cone-specific expression. Invest Ophthalmol Vis Sci 45:3877–3884 Renninger SL, Gesemann M, Neuhauss SCF (2011) Cone arrestin confers cone vision of high temporal resolution in zebrafish larvae. Eur J Neurosci 33:658–667 Sakuma H, Murakami A, Fujimaki T, Inana G (1998) Isolation and characterization of the human X-arrestin gene. Gene 224:87–95 Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294:1307–1313 Shinohara T, Dietzschold B, Craft CM, Wistow G, Early JJ, Donoso LA, Horwitz J, Tao R (1987) Primary and secondary structure of bovine retinal S antigen (48-kDa protein). Proc Natl Acad Sci USA 84:6975–6979 Smith WC, Gurevich EV, Dugger DR, Vishnivetshkiy SA, Shelamer CL, McDowell JH, Gurevich VV (2000) Cloning and functional characterization of salamander rod and cone arrestins. Invest Ophthalmol Vis Sci 41:2445–2455 Song X, Gurevich EVE, Gurevich VVV (2007) Cone arrestin binding to JNK3 and Mdm2: conformation preference and localization of interaction sites. J Neurochem 103:1053–1062 Sutton RB, Vishnivetskiy S, Robert J, Hanson SM, Raman D, Knox BE, Kono M, Navarro J, Gurevich VV (2005) Crystal structure of cone arrestin at 2.3A: evolution of receptor specificity. J Mol Biol 354:1069–1080 Tanaka H, Fujita H, Katoh H, Mori K, Negishi M (2002) Vps4-A (vacuolar protein sorting 4-A) is a binding partner for a novel Rho family GTPase, Rnd2. Biochem J 365:349–353 Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K, Banfi S, Surace EM, Sun J, Acerra C, Wright JF, Wellman J, High KA, Auricchio A, Bennett J, Simonelli F (2013) Threeyear follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber Congenital Amaurosis type 2. Ophthalmology 120(6):1283–1291 Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680 Whelan JP, McGinnis JF (1988) Light-dependent subcellular movement of photoreceptor proteins. J Neurosci Res 20:263–270 Xiao K, McClatchy DB, Shukla AK, Zhao Y, Chen M, Shenoy SK, Yates JR III, Lefkowitz RJ (2007) Functional specialization of beta-arrestin interactions revealed by proteomic analysis. Proc Natl Acad Sci USA 104:12011–12016 Yu J, Lei K, Zhou M, Craft CM, Xu G, Xu T, Zhuang Y, Xu R, Han M (2011) KASH protein Syne2/Nesprin-2 and SUN proteins SUN1/2 mediate nuclear migration during mammalian retinal development. Hum Mol Genet 20:1061–1073 Zhang Y, Li A, Zhu X, Wong CH, Brown B, Craft CM (2001) Cone arrestin expression and induction in retinoblastoma cells. In: Anderson RE, LaVail MM, Hollyfield JG (eds) Retinal

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degeneration diseases and experimental therapy. Kluwer Academic/Plenum, Durango, CO, pp 309–317 Zhang H, Cuenca N, Ivanova T, Church-Kopish J, Frederick JM, MacLeish PR, Baehr W (2003a) Identification and light-dependent translocation of a cone-specific antigen, Cone Arrestin, recognized by monoclonal antibody 7G6. Invest Ophthalmol Vis Sci 44:2858–2867 Zhang H, Huang W, Zhang H, Zhu X, Craft CM, Baehr W, Chen CK (2003b) Light-dependent redistribution of visual arrestins and transducin subunits in mice with defective phototransduction. Mol Vis 9:231–237 Zhang J, Gray J, Wu L, Leone G, Rowan S, Cepko CL, Zhu X, Craft CM, Dyer MA (2004) Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nat Genet 36:351–360 Zhu X, Li A, Brown B, Weiss ER, Osawa S, Craft CM (2002a) Mouse cone arrestin expression pattern: light induced translocation in cone photoreceptors. Mol Vis 8:462–471 Zhu X, Ma B, Babu S, Murage J, Knox BE, Craft CM (2002b) Mouse cone arrestin gene characterization: promoter targets expression to cone photoreceptors. FEBS Lett 524:116–122 Zhu X, Brown B, Li A, Mears AJ, Swaroop A, Craft CM (2003) GRK1-dependent phosphorylation of S and M opsins and their binding to cone arrestin during cone phototransduction in the mouse retina. J Neurosci 23:6152–6160 Zhu X, Wu K, Rife L, Brown B, Craft CM (2005) Rod Arrestin expression and function in cone photoreceptors. Invest Ophthalmol Vis Sci, ARVO E-Abstract 46 Zuniga FI (2010) Identification of novel protein-protein interactions and functional analysis in the mouse photoreceptor of the hypothetical protein FLJ33282-ALS2CR4 and the small Rho GTPase, Rnd2. Doctoral dissertation Zuniga FI, Craft CM (2010) Deciphering the structure and function of Als2cr4 in the mouse retina. Invest Ophthalmol Vis Sci 51:4407–4415

Cone arrestin: deciphering the structure and functions of arrestin 4 in vision.

Cone arrestin (Arr4) was discovered 20 years ago as a human X-chromosomal gene that is highly expressed in pinealocytes and cone photoreceptors. Subse...
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