title: Stable rhodopsin/arrestin complex leads to retinal degeneration in a transgenic mouse model of autosomal dominant retinitis pigmentosa.
abstract: Over 100 rhodopsin mutation alleles have been associated with autosomal dominant retinitis pigmentosa (ADRP). These mutations appear to cause photoreceptor cell death through diverse molecular mechanisms. We show that K296E, a rhodopsin mutation associated with ADRP, forms a stable complex with arrestin that is toxic to mouse rod photoreceptors. This cell death pathway appears to be conserved from flies to mammals. A genetics approach to eliminate arrestin unmasked the constitutive activity of K296E and caused photoreceptor cell death through a transducin-dependent mechanism that is similar to light damage. Expressing K296E in the arrestin/transducin double knock-out background prevented transducin signaling and led to substantially improved retinal morphology but did not fully prevent cell death caused by K296E. The adverse effect of K296E in the arrestin/transducin knock-out background can be mimicked by constant exposure to low light. Furthermore, we found that arrestin binding causes K296E to mislocalize to the wrong cellular compartment. Accumulation of stable rhodopsin/arrestin complex in the inner segment may be an important mechanism for triggering the cell death pathway in the mammalian photoreceptor cell.
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Chen
authors.forename: Guang
authors.initials: G
authors.lastname: Shi
authors.forename: Francis A
authors.initials: FA
authors.lastname: Concepcion
authors.forename: Guifu
authors.initials: G
authors.lastname: Xie
authors.forename: Daniel
authors.initials: D
authors.lastname: Oprian
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D019393:Arrestin / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D025063:Chromosome Disorders / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D008027:Light / Q000009:adverse effects; D046911:Macromolecular Substances / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015293:Transducin / Q000235:genetics
chemical_list: D019393:Arrestin; D046911:Macromolecular Substances; D012243:Rhodopsin; D015293:Transducin