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The Journal of Neuroscience, November 15, 2006, 26(46):11929-11937; doi:10.1523/JNEUROSCI.3212-06.2006

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Neurobiology of Disease
Stable Rhodopsin/Arrestin Complex Leads to Retinal Degeneration in a Transgenic Mouse Model of Autosomal Dominant Retinitis Pigmentosa

Jiayan Chen,^1,2 Guang Shi,¹ Francis A. Concepcion,^1,3 Guifu Xie,⁴ Daniel Oprian,⁴ and Jeannie Chen^1,2,3

¹Zilkha Neurogenetic Institute, ²Neuroscience Graduate Program, and ³Department of Cell and Neurobiology and Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, and ⁴Department of Biochemistry and Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts 02545

Correspondence should be addressed to Jeannie Chen, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Room 223, Los Angeles, CA 90033. Email: jeannie{at}usc.edu

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.

Key words: photoreceptor; retina; GPCR; retinal degeneration; light damage; blindness

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Received July 26, 2006; revised Oct. 5, 2006; accepted Oct. 6, 2006.

Correspondence should be addressed to Jeannie Chen, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Room 223, Los Angeles, CA 90033. Email: jeannie{at}usc.edu

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