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 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.
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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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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.
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Craft, C.M., Deming, J.D. (2014). Cone Arrestin: Deciphering the Structure and Functions of Arrestin 4 in Vision. In: Gurevich, V. (eds) Arrestins - Pharmacology and Therapeutic Potential. Handbook of Experimental Pharmacology, vol 219. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-41199-1_6
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