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.