title: Visual arrestin interaction with clathrin adaptor AP-2 regulates photoreceptor survival in the vertebrate retina.
abstract: 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.
authors.affiliation: Neuroscience Graduate Program, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Hormoz
authors.initials: H
authors.lastname: Moaven
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Koike
authors.forename: Christine C
authors.initials: CC
authors.lastname: Jao
authors.forename: Vsevolod V
authors.initials: VV
authors.lastname: Gurevich
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chen
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology*; D004578:Electron Spin Resonance Spectroscopy; D004596:Electroretinography; D019204:GTP-Binding Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000502:physiology*; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology; D012243:Rhodopsin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; D033962:Adaptor Protein Complex 2; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D012243:Rhodopsin; D019204:GTP-Binding Proteins