Visual arrestin interaction with clathrin adaptor AP-2 regulates photoreceptor survival in the vertebrate retina.

Moaven H, Koike Y, Jao CC, Gurevich VV, Langen R, Chen J
Proc Natl Acad Sci U S A. 2013 110 (23): 9463-8

PMID: 23690606 · PMCID: PMC3677467 · DOI:10.1073/pnas.1301126110

Arrestins bind ligand-activated, phosphorylated G protein-coupled receptors (GPCRs) and terminate the activation of G proteins. Additionally, nonvisual arrestin/GPCR complex can initiate G protein-independent intracellular signals through their ability to act as scaffolds that bring other signaling molecules to the internalized GPCR. Like nonvisual arrestins, vertebrate visual arrestin (ARR1) terminates G protein signaling from light-activated, phosphorylated GPCR, rhodopsin. Unlike nonvisual arrestins, its role as a transducer of signaling from internalized rhodopsin has not been reported in the vertebrate retina. Formation of signaling complexes with arrestins often requires recruitment of the endocytic adaptor protein, AP-2. We have previously shown that Lys296 → Glu (K296E), which is a naturally occurring rhodopsin mutation in certain humans diagnosed with autosomal dominant retinitis pigmentosa, causes toxicity through forming a stable complex with ARR1. Here we investigated whether recruitment of AP-2 by the K296E/ARR1 complex plays a role in generating the cell death signal in a transgenic mouse model of retinal degeneration. We measured the binding affinity of ARR1 for AP-2 and found that, although the affinity is much lower than that of the other arrestins, the unusually high concentration of ARR1 in rods would favor this interaction. We further demonstrate that p44, a splice variant of ARR1 that binds light-activated, phosphorylated rhodopsin but lacks the AP-2 binding motif, prevents retinal degeneration and rescues visual function in K296E mice. These results reveal a unique role of ARR1 in a G protein-independent signaling cascade in the vertebrate retina.

MeSH Terms (19)

Adaptor Protein Complex 2 Analysis of Variance Animals Arrestins beta-Arrestin 1 beta-Arrestins Blotting, Western Cell Survival Electron Spin Resonance Spectroscopy Electroretinography GTP-Binding Proteins Immunohistochemistry Mice Mice, Transgenic Mutation, Missense Photoreceptor Cells, Vertebrate Retinal Degeneration Rhodopsin Signal Transduction

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