期刊
JOURNAL OF NEUROSCIENCE
卷 26, 期 46, 页码 11929-11937出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3212-06.2006
关键词
photoreceptor; retina; GPCR; retinal degeneration; light damage; blindness
资金
- NEI NIH HHS [R01 EY007965, R01 EY012155, EY12155] Funding Source: Medline
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.
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