May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Enhanced Arrestin Mutant Protects Rod Photoreceptors and Facilitates Photoresponse Recovery in the Absence of Rhodopsin Phosphorylation
Author Affiliations & Notes
  • X. Song
    Pharmacology, Vanderbilt University, Nashville, Tennessee
  • S. A. Vishnivetskiy
    Pharmacology, Vanderbilt University, Nashville, Tennessee
  • O. P. Gross
    2University of California, Davis, Davis, California
  • K. Emelianoff
    University of California, Davis, Davis, California
  • E. V. Gurevich
    Pharmacology, Vanderbilt University, Nashville, Tennessee
  • M. E. Burns
    University of California, Davis, Davis, California
  • V. V. Gurevich
    Pharmacology, Vanderbilt University, Nashville, Tennessee
  • Footnotes
    Commercial Relationships  X. Song, None; S.A. Vishnivetskiy, None; O.P. Gross, None; K. Emelianoff, None; E.V. Gurevich, None; M.E. Burns, None; V.V. Gurevich, None.
  • Footnotes
    Support  NIH grants EY11500 (VVG) and EY14047 (MEB).
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1669. doi:https://doi.org/
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      X. Song, S. A. Vishnivetskiy, O. P. Gross, K. Emelianoff, E. V. Gurevich, M. E. Burns, V. V. Gurevich; Enhanced Arrestin Mutant Protects Rod Photoreceptors and Facilitates Photoresponse Recovery in the Absence of Rhodopsin Phosphorylation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1669. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Rapid recovery of rod photoresponses requires inactivation of light-activated rhodopsin (Rh*) via its phosphorylation by rhodopsin kinase (RK) followed by arrestin (Arr) binding. Impaired phosphorylation results in dramatically slowed recovery. Here we test whether an arrestin mutant with increased affinity for unphosphorylated Rh* can restore normal photoresponse recovery to rods with impaired rhodopsin phosphorylation.

Methods: : We created transgenic mice expressing enhanced arrestin-3A at levels 240% (3A-240) or 50% (3A-50) of endogenous wild type (WT) arrestin on Arr-/- and Arr-/-RK-/- background. Retinal morphology and rod function using single cell recording and ERG were evaluated.

Results: : The transgene in 3A-240arr-/- and 3A-50arr-/- lines was fully functional: suction electrode recordings revealed light responses of normal amplitude and time course, and the light sensitivity measured by ERG was indistinguishable from WT. In the absence of RK (3A-240arr-/-rk-/- and 3A-50arr-/-rk-/- lines compared to RK-/- and Arr-/-RK-/-), expression of the mutant arrestin increased the length and improved the organization of the outer segments and promoted photoreceptor survival. Although single photon responses in RK-/- and 3A-240arr-/-rk-/- mice were similar, the enhanced arrestin mutant speeded up the recovery from bright flashes. Double-flash ERG showed that in the absence of rhodopsin phosphorylation, enhanced arrestin yielded much faster recovery than WT arrestin in RK-/- mice. Halftime of a-wave recovery was reduced from 18670ms in RK-/- to 10200ms (p=0.0143) and 6571ms (p=0.0019) in 3A-240arr-/-rk-/- and 3A-50 arr-/-rk-/-, respectively.

Conclusions: : In the absence of rhodopsin phosphorylation, arrestin-3A with enhanced Rh* binding promotes photoreceptor survival in cyclic light much better than WT arrestin. In the absence of RK, the enhanced arrestin mutant deactivates Rh* more efficiently than WT arrestin. This is the first in vivo demonstration that a mutation in arrestin can partially compensate for the lack of rhodopsin phosphorylation in rods.

Keywords: photoreceptors • signal transduction • gene transfer/gene therapy 
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