Journal article
Protein Inhibitor of Retinal Membrane Guanylyl Cyclase Rescues Mouse Rod Photoreceptors from GUCY2D Retinal Dystrophy
The Journal of neuroscience, e0164262026
27 Apr 2026
PMID: 42045071
Featured in Collection : Drexel's Newest Publications
Abstract
Mutations in GUCY2D gene coding for retinal membrane guanylyl cyclase 1 (RetGC1, or GC-E) can deregulate cGMP synthesis in photoreceptors by guanylyl cyclase activating proteins (GCAPs) via negative Ca2+ feedback and elevate cGMP production in the dark, thus causing autosomal-dominant cone-rod dystrophy (GUCY2D adCORD). We expressed an engineered protein inhibitor of retinal guanylyl cyclase (PIGCY) in transgenic mice of either sex harboring the GUCY2D adCORD RetGC1 mutant Arg838Ser (R838STg) in order to suppress aberrant production of cGMP in their rods and prevent their fast degeneration. PIGCY did not return the abnormal Ca2+ sensitivity of cGMP synthesis in PIGCYTgR838STg retinas to the normal physiological range, but it reduced the overall rate of cGMP production. Decelerated cGMP production strongly suppressed degeneration of functional rods. By the age of 6 months, 70% of photoreceptor nuclei remained in PIGCYTgR838STg versus 20% in R838STg. Retinal response to light detected by electroretinography was preserved in PIGCYTgR838STg mice significantly better than in R838STg. The remaining altered calcium feedback affected the shape of PIGCYTgR838STg rod photoresponses, but overall light sensitivity was not drastically different from normal. Single-photon response amplitude and time-to-peak in PIGCYTgR838STg rods were increased and more variable, but were similar to wild type in fractional light sensitivity and half-saturating light intensity. Consistent with the still abnormal calcium feedback, desensitization under background light in PIGCYTgR838STg rods was increased and their noise was elevated under moderate background illumination as compared to wild type. In summary, PIGCY effectively rescued degenerating GUCY2D adCORD rods while maintaining their functional light sensitivity.
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Details
- Title
- Protein Inhibitor of Retinal Membrane Guanylyl Cyclase Rescues Mouse Rod Photoreceptors from GUCY2D Retinal Dystrophy
- Creators
- Shinya Sato - University of California, IrvineIgor V Peshenko - Drexel UniversityElena V Olshevskaya - Drexel UniversityVladimir J Kefalov - University of California, IrvineAlexander M Dizhoor - Drexel University
- Publication Details
- The Journal of neuroscience, e0164262026
- Publisher
- Society for Neuroscience
- Grant note
- This work was supported by NIH grants EY11522 (AMD), EY34861 (AMD), EY35884 (VJK), and EY35137 (VJK). The authors acknowledge support to the Gavin Herbert Eye Institute at the University of California, Irvine, from an unrestricted grant from Research to Prevent Blindness and from NIH core grant P30 EY034070.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Other Identifier
- 991022175177004721