July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Suppression of GCAP-activated retinal guanylyl cyclase by RD3 protein is essential for preventing rd3 photoreceptor degeneration.
Author Affiliations & Notes
  • Alexander M Dizhoor
    Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania, United States
  • Elena V Olshevskaya
    Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania, United States
  • Igor V Peshenko
    Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Alexander Dizhoor, None; Elena Olshevskaya, None; Igor Peshenko, None
  • Footnotes
    Support  NIH grant EY011522; CURE Formula grant from Pennsylvania Department of Health .
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4489. doi:
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      Alexander M Dizhoor, Elena V Olshevskaya, Igor V Peshenko; Suppression of GCAP-activated retinal guanylyl cyclase by RD3 protein is essential for preventing rd3 photoreceptor degeneration.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4489.

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

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Abstract

Purpose : Retinal membrane guanylyl cyclase (RetGC) in photoreceptors undergoes activation by calcium sensor proteins (GCAPs) and inhibition by RD3, a protein that is also required for accumulation of RetGC in the outer segment. Photoreceptors in rd3 mice rapidly degenerate, similarly to human LCA12 patients lacking RD3. Low presence of the cyclase in the rd3 photoreceptor outer segment could account for their weak photoresponse, but cannot explain the severity of the rd3 photoreceptor degeneration. We hypothesized that the inhibitory activity of RD3 protects photoreceptors from aberrant activation of RetGC.

Methods : We compared the progression of photoreceptor degeneration in mouse models that differed in RetGC, GCAPs and RD3 expression. The models were bred into C57BL6 strain background for ten generations prior to conducting the experiments.

Results : The photoreceptor guanylyl cyclase activity in young rd3 mice was much lower than in wild type, but remained GCAP-stimulated at low calcium. Yet, nearly all rd3 photoreceptors died by 3 months of age while in RetGCs-/- mice, completely devoid of the cyclase activity, their majority survived past 5 months. In rd3 hybrids with GCAPs-/-, which still had the same low basal activity of RetGC as in rd3 but no longer activated by GCAP-mediated calcium feedback, the rd3 photoreceptors were dramatically rescued from degeneration. At least 70% of the rd3GCAPs-/- rods survived past 6 months and retained typical morphological features, while less than 4% of photoreceptor nuclei and no photoreceptor outer segments remained identifiable in the parental rd3 line at that age. RD3 immunoreactivity in wild type mice was detected in the inner rather the outer segment of photoreceptors and transgenically expressed GFP-tagged RD3 also predominantly accumulated in the inner segment, in contrast to the RetGC, which accumulates in the outer segments.

Conclusions : The evidence suggests that RD3 prevents photoreceptor degeneration by suppressing activation of retinal guanylyl cylase by GCAPs - presumably in the inner segment, before the cyclase arrives in the outer segment to regulate phototresponse.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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