# The Role of Endoplasmic Reticulum Calcium Channels in Cone Degeneration Resulting from CNG Channel Deficiency

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $362,500

## Abstract

ABSTRACT
The cone photoreceptor cyclic nucleotide-gated (CNG) channel is essential for cone phototransduction.
Mutations in the CNGA3 and CNGB3 genes encoding the cone channel subunits account for about 80% of all
cases of achromatopsia, and are associated with progressive cone dystrophies. Cones in patients and in
mouse models of CNG channel deficiency degenerate over time. Using CNG channel-deficient (CCD) mouse
models, we found that CNG channel deficiency leads to endoplasmic reticulum (ER) stress-associated cone
death. We also observed that CCD retinas display increased activity and expression levels of the ER calcium-
releasing channels inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR), and treatment
with inhibitors of IP3R and RyR reduces ER stress and cone death. The objective of this study is to understand
the mechanisms of ER calcium channel-associated cone death in CNG channel deficiency. We will determine
whether the loss of functional CNG channels leads to impaired ER calcium homeostasis/ER calcium depletion,
impaired protein processing, and ER stress, and whether suppressing ER calcium channels will reduce ER
stress/cone death. Three specific aims will address our questions. Aim 1 is to determine the role of ER calcium
channels in CCD ER stress and cone death. We will evaluate the effects of IP3R and RyR inhibition on ER
stress and cone death. Conditional knockout and adeno-associated viral (AAV)-mediated CRISPR/Cas9
genome editing approaches will be used to deplete ER calcium channels. Aim 2 is to determine the role of ER
calcium channels in CCD cone opsin mistrafficking. CCD mice display cone opsin mistrafficking, and ER
chaperons and inhibitors for IP3R improve cone opsin trafficking. We will evaluate the effects of ER calcium
channel inhibition/depletion on the cellular localization of cone opsin and other cone outer segment proteins in
CCD mice. We will also investigate whether promoting ER protein processing/ER-associated protein
degradation improves cone protein trafficking. Aim 3 is to determine how cGMP/PKG (cGMP-dependent
protein kinase) signaling induces CCD ER stress and cone death, and whether ER calcium channels are the
significant targets. CCD retinas show elevated cGMP/PKG signaling, and suppressing cGMP/PKG signaling
reduces ER stress and cone death. We will examine the effects of cGMP/PKG signaling on the expression and
activity of the ER calcium channels. We will also evaluate the effects of cGMP/PKG signaling on other unfolded
protein response/ER stress components. Upon completion of the proposed study, we will better understand the
mechanisms of cone degeneration in CNG channel deficiency. Specifically, we will know whether ER calcium
channels play a role in ER stress and cone death. This information is vital for the development of ER calcium
channel-based therapeutic strategies for photoreceptor preservation.

## Key facts

- **NIH application ID:** 9965961
- **Project number:** 5R01EY027754-04
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** XI-QIN DING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,500
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965961

## Citation

> US National Institutes of Health, RePORTER application 9965961, The Role of Endoplasmic Reticulum Calcium Channels in Cone Degeneration Resulting from CNG Channel Deficiency (5R01EY027754-04). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/9965961. Licensed CC0.

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