Journal article
Phosphodiesterase 5 expression in photoreceptors rescues retinal degeneration induced by deregulation of membrane guanylyl cyclase
The Journal of biological chemistry, v 301(3), p108265
01 Mar 2025
PMID: 39909376
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Mutations in retinal membrane guanylyl cyclase 1 (RetGC1) and its calcium-sensor protein (guanylyl cyclase activating protein 1, GCAP1) cause congenital dominant retinopathies by elevation of cGMP synthesis in photoreceptors in the dark. We explored counteracting the elevated cGMP synthesis causing photoreceptor degeneration using ectopic expression of a nonphotoreceptor cGMP phosphodiesterase (PDE) isozyme PDE5. PDE5 primary structure was modified to direct the delivery of the recombinant PDE5 (PDE5r) to rod outer segments, by placing a C-terminal fragment derived from a cone-specific alpha-subunit of PDE6C at the C terminus of the PDE5, which allowed PDE5r expressed under control of mouse rod opsin promoter to accumulate in rod outer segments. Expression of PDE5r did not affect calcium-sensitivity of RetGC regulation in PDE5rTg transgenic retinas, but increased cGMP hydrolysis in the dark, which partially desensitized PDR5rTg rods in the dark via an “equivalent light” effect, analogous to exposure to a constant dim light of ∼20 to 40 photons μm−2 sec−1. The calcium-sensitivity of RetGC regulation remained drastically shifted outside the normal physiological range in hybrid R838STgPDE5rTg rods expressing both PDE5r and R838S RetGC1, the mutant causing GUCY2D dominant retinopathy, but the hybrid rods demonstrated a dramatic rescue from degeneration caused by the R838S RetGC1. In a similar fashion, PDE5r expression rescued degeneration of rods harboring Y99C GCAP1, one of the GCAP1 mutants most frequently causing GUCA1A dominant retinopathy. Our results open a possibility that ectopic expression of PDE5 can be used as an approach to rescue presently incurable dominant GUCY2D and GUCA1A retinopathies at the expense of a moderate reduction in rod light-sensitivity.
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Details
- Title
- Phosphodiesterase 5 expression in photoreceptors rescues retinal degeneration induced by deregulation of membrane guanylyl cyclase
- Creators
- Alexander M. Dizhoor - Drexel University, Neurobiology and AnatomyShinya Sato - Vision Eye InstituteZhuokai Luo - Pennsylvania College of Optometry, Salus at Drexel University, Elkins Park, Pennsylvania, United StatesLyuqi Tan - Salus UniversityFay E. Levin - Salus UniversityElena V. Olshevskaya - Drexel University, Pennsylvania College of Optometry (PCO)Igor V. Peshenko - Drexel University, Pennsylvania College of Optometry (PCO)Vladimir J. Kefalov - College Station Medical Center
- Publication Details
- The Journal of biological chemistry, v 301(3), p108265
- Publisher
- Elsevier Inc
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:001439640700001
- Scopus ID
- 2-s2.0-85219117245
- Other Identifier
- 991022035258104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology