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  3. Phosphodiesterase 5 expression in photoreceptors rescues retinal degeneration induced by deregulation of membrane guanylyl cyclase

Phosphodiesterase 5 expression in photoreceptors rescues retinal degeneration induced by deregulation of membrane guanylyl cyclase

  • J Biol Chem. 2025 Feb 3:108265. doi: 10.1016/j.jbc.2025.108265.
Alexander M Dizhoor 1,  Shinya Sato 2,  Zhuokai Luo 3,  Lyuqi Tan 3,  Fay E Levin 4,  Elena V Olshevskaya 4,  Igor V Peshenko 4,  Vladimir J Kefalov 5
Affiliations

Affiliations

  • 1 Pennsylvania College of Optometry, Salus at Drexel University, Elkins Park, Pennsylvania, United States; Graduate Program in Biomedicine, Salus at Drexel University, Elkins Park, Pennsylvania, United States; Department of Neurobiology and Anatomy, Drexel University, Philadelphia, Pennsylvania, United States. Electronic address: alexander.dizhoor@drexel.edu.
  • 2 Gavin Herbert Eye Institute, Department of Ophthalmology and Center for Translational Vision Research, University of California, Irvine, California, United States.
  • 3 Pennsylvania College of Optometry, Salus at Drexel University, Elkins Park, Pennsylvania, United States; Graduate Program in Biomedicine, Salus at Drexel University, Elkins Park, Pennsylvania, United States.
  • 4 Pennsylvania College of Optometry, Salus at Drexel University, Elkins Park, Pennsylvania, United States.
  • 5 Gavin Herbert Eye Institute, Department of Ophthalmology and Center for Translational Vision Research, University of California, Irvine, California, United States; Department of Physiology and Biophysics, University of California, Irvine, California, United States.
PMID: 39909376 DOI: 10.1016/j.jbc.2025.108265
Abstract

Mutations in retinal membrane guanylyl cyclase 1 (RetGC1) and its calcium-sensor protein (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 non-photoreceptor cGMP phosphodiesterase (PDE) isozyme PDE5. PDE5 primary structure was modified to direct the delivery of the recombinant PDE5 (PDE5r) to rod outer segments (ROS), 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 ROS. 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 ∼20-40 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.

Keywords

GCAP; GUCA1A; GUCY2D; PDE5; RetGC; calcium binding proteins; cyclic GMP (cGMP); eye; guanylate cyclase (guanylyl cyclase); phosphodiesterase; photoreceptor; retinal degeneration.

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