Purchase this article with an account.
Tian Wang, Jeannie Chen, Stephen Tsang; Mechanism of cGMP-induced Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4189.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Several naturally occurring mutations in the phototransduction cascade lead to altered cGMP levels prior to cell death. These include guanylate cyclase activating proteins (GCAPs), guanylyl cyclases (GCs) and phosphodiesterase 6 (PDE6). Naturally occurring PDE6 mutations also occur in several mouse strains and are commonly used as models for retinitis pigmentosa (RP). The elevated [cGMP], due to the reduced or abolished PDE activity, is thought to be responsible for causing photoreceptor cell death through mechanisms that are still unclear. In this study we tested two targets of cGMP, cyclic nucleotide gated (CNG) channel and protein kinase G (PKG).
Two strains of mice bearing PDE mutations with different rates of retinal degeneration were crossed into the knockout background of either β-CNG or PKG genes to generate double mutant mice. The Pde6gtm1/Pde6gtm1 mice show a rapid rate of degeneration whereas the Pde6brd10/Pde6brd10 mice show a relatively slower rate. Protein levels were measured by western blotting and retinal structures at different ages were investigated by light microscopy.
Retinal morphology was significantly improved when The Pde6gtm1/Pde6gtm1 or Pde6brd10/Pde6brd10 was crossed into the Cngb1tm2/Cngb1tm2 knockout background despite elevated cGMP levels. In contrast, no improvement in cell viability was detected in the Prkg1tm1/Prkg1tm1 knockout background.
In this study, we found that the absence of CNG channels, but not PKG, offered significant protection against cGMP-induced photoreceptor cell death. Cngb1 knockdown prevented cation entry in Pde6b H620Q rods without affecting free cGMP levels. Our data support the hypothesis that cGMP toxicity is not directly responsible for early initiation of the cell-death pathway and, instead, Ca2 +/Na+ cation entry causes degeneration.Thus targeting rod CNG channels is a promising approach to treat cGMP-induced retinal degeneration.
This PDF is available to Subscribers Only