May 2006
Volume 47, Issue 13
ARVO Annual Meeting Abstract  |   May 2006
Activation of PDE6 Cascade in the Dark Reverses Photoreceptor Degeneration Caused by Y99C Mutation in GCAP1
Author Affiliations & Notes
  • A.M. Dizhoor
    Pennsylvania College of Optometry, Elkins Park, PA
  • A.B. Savchenko
    Pennsylvania College of Optometry, Elkins Park, PA
  • M.L. Woodruff
    UCLA, Los Angeles, CA
  • I.V. Peshenko
    Pennsylvania College of Optometry, Elkins Park, PA
  • E.V. Olshevskaya
    Pennsylvania College of Optometry, Elkins Park, PA
  • R. Barrett
    Wayne State University, Detroit, MI
  • R.A. Bush
    NIDCD/NIH, Bethesda, MD
  • P.A. Sieving
    NEI/NIH, Bethesda, MD
  • G.L. Fain
    UCLA, Los Angeles, CA
  • Footnotes
    Commercial Relationships  A.M. Dizhoor, None; A.B. Savchenko, None; M.L. Woodruff, None; I.V. Peshenko, None; E.V. Olshevskaya, None; R. Barrett, None; R.A. Bush, None; P.A. Sieving, None; G.L. Fain, None.
  • Footnotes
    Support  NIH Grants EY11522, EY01844, NEI/NIDCD intramural
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 1093. doi:
  • Views
  • Share
  • Tools
    • Alerts
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      A.M. Dizhoor, A.B. Savchenko, M.L. Woodruff, I.V. Peshenko, E.V. Olshevskaya, R. Barrett, R.A. Bush, P.A. Sieving, G.L. Fain; Activation of PDE6 Cascade in the Dark Reverses Photoreceptor Degeneration Caused by Y99C Mutation in GCAP1 . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1093.

      Download citation file:

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

  • Supplements

Purpose: : The Y99C GCAP1 reduces Ca2+–sensitivity of retinal guanylyl cyclase (retGC), elevates the free intracellular cGMP and Ca2+ concentrations, and causes degeneration of photoreceptors in transgenic mice [1]. We hypothesize that activation of PDE6 in the dark can slow retinal degeneration in the Y99C mice by lowering the free cGMP and Ca2+concentrations.

Methods: : A mutation, G90D, in rhodopsin that activates the PDE6 cascade in the dark [2], was introduced into a fast degenerating mouse line, L53 [1], expressing the Y99C GCAP1 (Y99C+); a single allele for wild type rhodopsin (R) remained [2]. The Y99C+;G90D+;R+/– mice were analyzed for ERG, retinal morphology, Ca2+–sensitivity of retGC, and the intracellular free Ca2+concentrations [3].

Results: : Ca2+ sensitivity of retGC in the L53 mice (both Y99C+;R+/+ and Y99C+;R+/–) was shifted toward higher than normal dark–adapted free Ca2+ concentrations. They rapidly lost ERG responses and nearly all photoreceptor nuclei by the age of 6 months. The maximal amplitude of the ERG a–wave in the Y99C+;R+/– mice after 120 days was less than 5% of normal (15 µV ±15 SD, n=27), often with no measurable a–wave at saturating flash strength. In the Y99C+;G90D+;R+/– retinas, retGC also remained active at high free Ca2+ concentrations in vitro, but the dark adapted free intracellular Ca2+ level was closure to the wild type. The Y99C+;G90D+;R+/– mice had clear ERG–responses at > 8 months of age (the oldest age group tested). The light–sensitivity of ERG was reduced, but the maximal a–wave reached half the normal amplitude (227 µV±76 SD, n=58) and half of the rod nuclei remained in their retinas after 6 months of age; the morphology of the photoreceptors was similar to the wild type.

Conclusions: : Activation of PDE6 in the dark by G90D rhodopsin can effectively restore near–normal levels of cGMP and Ca2+ in Y99C rods thus rescuing them from degeneration caused by abnormal cGMP synthesis.

References: : [1]. Olshevskaya et al., (2004) J. Neuroscience 24, 6078; [2] Sieving et al., (2001) J. Neuroscience 21, 5449; [3] Woodruff et al., (2002) J.Physiol (London) 542, 843.

Keywords: proteins encoded by disease genes • photoreceptors • retinal degenerations: cell biology 

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.