April 2010
Volume 51, Issue 13
ARVO Annual Meeting Abstract  |   April 2010
Cytotoxicity of Monomeric Arrestin1 Explains Its Robust Self-Association
Author Affiliations & Notes
  • V. V. Gurevich
    Pharmacology, Vanderbilt University, Nashville, Tennessee
  • X. Song
    Pharmacology, Vanderbilt University, Nashville, Tennessee
  • S. A. Vishnivetskiy
    Pharmacology, Vanderbilt University, Nashville, Tennessee
  • M. Kim
    University of California Los Angeles, Los Angeles, California
  • S. M. Hanson
    Pharmacology, Vanderbilt University, Nashville, Tennessee
  • J. C. Chen
    Cell & Neurobiology, Univ of Southern California, Los Angeles, California
  • W. L. Hubbell
    Ophthalmology, CHS/UCLA, Los Angeles, California
  • E. V. Gurevich
    Pharmacology, Vanderbilt University, Nashville, Tennessee
  • Footnotes
    Commercial Relationships  V.V. Gurevich, None; X. Song, None; S.A. Vishnivetskiy, None; M. Kim, None; S.M. Hanson, None; J.C. Chen, None; W.L. Hubbell, None; E.V. Gurevich, None.
  • Footnotes
    Support  NIH grants EY11500 (VVG), EY005216 (WLH), NS065868 (EVG), EY012155 (JC)
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 1104. doi:
  • Views
  • Share
  • Tools
    • Alerts
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      V. V. Gurevich, X. Song, S. A. Vishnivetskiy, M. Kim, S. M. Hanson, J. C. Chen, W. L. Hubbell, E. V. Gurevich; Cytotoxicity of Monomeric Arrestin1 Explains Its Robust Self-Association. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1104.

      Download citation file:

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

  • Supplements

Purpose: : To determine the biological role of arrestin1 self-association.

Methods: : Transgenic mice expressing wild type (WT) and oligomerization-deficient arrestin1 mutant at different levels were used to determine the functionality and health of rod photoreceptors

Results: : Arrestin1 ensures timely signal shutoff by binding light-activated phosphorhodopsin. Engineered arrestin1 mutant with increased affinity for Rh* partially compensates for lack of rhodopsin phosphorylation, improving the functional performance of rhodopsin kinase knockout rods. However, self-association of this mutant is greatly impaired. We found that high expression of "enhanced" arrestin1 results in progressive light-independent rod degeneration via apoptosis involving the activation of caspases-9 and -3. In contrast, similar high expression of WT arrestin1 does not affect rod survival. Increasing co-expression of WT arrestin1 dose-dependently alleviates the damage induced by enhanced mutant. Due to "closed" shape of arrestin1 tetramer, where each monomer engages two "sister" subunits via two different interfaces, WT arrestin1 promotes self-association of the mutant with only one "damaged" interface by forming mixed oligomers. Thus, our data indicate that excess of monomeric arrestin1 induces apoptosis of rod photoreceptors in vivo.

Conclusions: : Arrestin1 is expressed in rods at very high level, at 0.8:1 ratio to rhodopsin. Cytotoxicity of the arrestin1 monomer explains why it acquired propensity to oligomerize, even though only the monomer is the active rhodopsin-binding species. The inability of cone arrestin4 to self-associate likely explains why cones express much more arrestin1 than their "own" arrestin4 subtype.

Keywords: photoreceptors • apoptosis/cell death • protein structure/function 

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.