June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Inhibition of Ryanodine Receptor 1 Reduces Endoplasmic Reticulum (ER) Stress and Promotes ER Protein Degradation in Cyclic Nucleotide-gated Channel Deficiency
Xi-Qin Ding; Fan Yang; Hongwei Ma; Rekha Garg; Alfred S Lewin
Author Affiliations & Notes
  • Xi-Qin Ding
    The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Fan Yang
    The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Hongwei Ma
    The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Rekha Garg
    University of Florida, Gainesville, Florida, United States
  • Alfred S Lewin
    University of Florida, Gainesville, Florida, United States
  • Footnotes
    Commercial Relationships   Xi-Qin Ding None; Fan Yang None; Hongwei Ma None; Rekha Garg None; Alfred Lewin None
  • Footnotes
    Support  This work was supported by grants from the National Eye Institute (R01EY027754 and P30EY021725), the Oklahoma Center for the Advancement of Science and Technology, the Presbyterian Health Foundation, and support to Dr. Lewin from the Shaler Richardson Professorship endowment and an unrestricted grant to the University of Florida from Research to Prevent Blindness.
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1778 – F0327. doi:
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      Xi-Qin Ding, Fan Yang, Hongwei Ma, Rekha Garg, Alfred S Lewin; Inhibition of Ryanodine Receptor 1 Reduces Endoplasmic Reticulum (ER) Stress and Promotes ER Protein Degradation in Cyclic Nucleotide-gated Channel Deficiency. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1778 – F0327.

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Abstract

Purpose : The cone photoreceptor cyclic nucleotide-gated (CNG) channel plays a pivotal role in cone phototransduction. Mutations in genes encoding the channel subunits CNGA3 and CNGB3 account for about 80% of all cases of achromatopsia and are associated with progressive cone dystrophies. CNG channel deficiency leads to cellular/endoplasmic reticulum (ER) calcium dysregulation and ER stress-associated cone apoptosis. This work investigated the role of the ER calcium channel ryanodine receptor 1 (Ryr1) in ER stress and cone degeneration in CNG channel deficiency.

Methods : The Nrl-/- and Cnga3-/-/Nrl-/- mouse lines were used. The AAV-mediated CRISPR/SaCas9 genome editing was used to knockdown Ryr1 specifically in cones. Mice at postnatal day 5 (P5) received AAV2/5-SaCas9/gRNA-Ryr1 via subretinal injection (4.4x109 vg, 1.0 µl), and were analyzed for expression levels of Ryr1, cone specific proteins, ER stress markers, and ER retrotranslocation/ER-associated protein degradation (ERAD) proteins at P45-50 days, using western blotting and immunofluorescence labeling.

Results : The expression level of Ryr1 was increased in Cnga3-/-/Nrl-/- retinas, compared with that in Nrl-/- controls. Treatment with AAV2/5-SaCas9/gRNA-Ryr1 nearly completely abolished this elevation. The expression level of cone arrestin (CAR) was reduced in Cnga3-/-/Nrl-/- retinas, and treatment with the viral vector increased expression level of CAR by about 50%, compared with the vehicle-treated controls. The expression levels of the ER stress marker phospho-IRE1α and phospho-eIF2α were significantly elevated in retinas of Cnga3-/-/Nrl-/- mice, and treatment with AAV2/5-SaCas9/gRNA-Ryr1 reversed these elevations. Furthermore, treatment with AAV2/5-SaCas9/gRNA-Ryr1 significantly increased expression levels of the ER retrotranslocation/ERAD protein E3 ubiquitin-protein ligase synoviolin 1 and degradation in ER protein 1 in Cnga3-/-/Nrl-/- retinas, compared with the vehicle-treated controls.

Conclusions : This work demonstrates that Ryr1/ER calcium dysregulation contributes to ER stress/cone degeneration in CNG channel deficiency. The findings support strategies targeting ER calcium regulation to reduce cone degeneration.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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Copyright © 2025 Association for Research in Vision and Ophthalmology.
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