July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Deregulation of calcium feedback via calcium sensor proteins, GCAPs, triggers photoreceptor death in dominant cone-rod dystrophy CORD6 mouse model.
Author Affiliations & Notes
  • Elena V Olshevskaya
    Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania, United States
  • Shinya Sato
    Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
  • Igor V Peshenko
    Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania, United States
  • Alexander M Dizhoor
    Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania, United States
  • Vladimir J Kefalov
    Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
  • Footnotes
    Commercial Relationships   Elena Olshevskaya, None; Shinya Sato, None; Igor Peshenko, None; Alexander Dizhoor, None; Vladimir Kefalov, None
  • Footnotes
    Support  NIH grants EY11522, EY19312, EY25696, and EY27387; Research to Prevent Blindness.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4490. doi:
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      Elena V Olshevskaya, Shinya Sato, Igor V Peshenko, Alexander M Dizhoor, Vladimir J Kefalov; Deregulation of calcium feedback via calcium sensor proteins, GCAPs, triggers photoreceptor death in dominant cone-rod dystrophy CORD6 mouse model.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4490.

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

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Abstract

Purpose : Calcium sensor EF-hand proteins GCAPs regulate photoresponse in retinal rods and cones by activating retinal membrane guanylyl cyclase (RetGC) in the light, when Ca2+ concentrations fall, and decelerating the cyclase in the dark, when Ca2+ concentrations rise. Substitutions of Arg838 in human RetGC1 cause autosomal dominant cone-rod dystrophy type 6 (CORD6). The purpose of the study was to assess photoreceptor physiology and biochemistry in a transgenic mouse model expressing R838S RetGC1.

Methods : The R838S RetGC1 was expressed in mouse rods under control of rhodopsin promoter. The R838S mice were characterized by biochemical assays, immunohistochemistry, ERG, and single-cell physiology.

Results : The R838S RetGC1 transgenically expressed in mouse rod outer segments in vivo remains accelerated by GCAPs at calcium concentrations typical for dark-adapted rods and elevates influx of Na+ and Ca2+ through the cGMP-gated channels of the plasma membrane in the dark. Sensitivity and the shape of rod photoresponses recorded from individual rods change consistently with the dysregulation of the negative calcium feedback on R838S RetGC1. Rod vision in R838S mouse retinas rapidly declines between 1 and 6 months of age due to severe degeneration of the diseased rods. Elimination of the Ca2+ feedback on the cyclase by breeding the R838S RetGC1 mice into GCAPs knockout background rescues the diseased rods from degeneration.

Conclusions : Our study shows that CORD6 is a ‘phototransduction disease’, triggered by abnormal negative Ca feedback on guanylyl cyclase mediated by GCAPs.

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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