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Hum Mol Genet. 2017 Jun 15;26(12):2299-2306. doi: 10.1093/hmg/ddx121.

Two pathways of rod photoreceptor cell death induced by elevated cGMP.

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Zilkha Neurogenetic Institute, Department of Cell & Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology and Pathology & Cell Biology, Institute of Human Nutrition, Herbert Irving Comprehensive Cancer Center, Columbia University, NY 10032, USA.
Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, NY 10032, USA.


Cyclic-GMP is a second messenger in phototransduction, a G-protein signaling cascade that conveys photon absorption by rhodopsin to a change in current at the rod photoreceptor outer segment plasma membrane. Basal cGMP level is strictly controlled by the opposing actions of phosphodiesterase (PDE6) and retinal guanylyl cyclases (GCs), and mutations in genes that disrupt cGMP homeostasis leads to retinal degeneration in humans through mechanisms that are incompletely understood. The purpose of this study is to examine two distinct cellular targets of cGMP: the cGMP-gated (CNG) channels and protein kinase G (PRKG), and how each may contribute to rod cell death. Using a mouse genetic approach, we found that abolishing expression of CNG channels prolongs rod survival caused by elevated cGMP in a PDE6 mutant mouse model. This observation supports the use of channel blockers to delay rod death, which is expected to prolong useful vision through enhanced cone survival. However, the absence of CNG channel alone also caused abnormal cGMP accumulation. In a mouse model of CNG channel loss-of-function, abolishing PRKG1 expression had a long-lasting effect in promoting rod cell survival. Our data strongly implicate two distinct cGMP-mediated cell death pathways, and suggest that therapeutic designs targeting both pathways will be more effective at slowing photoreceptor cell death caused by elevated cGMP.

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