Endoplasmic reticulum (ER) Ca-channel activity contributes to ER stress and cone death in cyclic nucleotide-gated channel deficiency.

Endoplasmic reticulum (ER) stress and mislocalization of improperly folded proteins have been shown to contribute to photoreceptor death in models of inherited retinal degenerative diseases. In particular, mice with cone cyclic nucleotide-gated (CNG) channel deficiency, a model for achromatopsia, display both early-onset ER stress and opsin mistrafficking. By 2 weeks of age, these mice show elevated signaling from all three arms of the ER-stress pathway, and by 1 month, cone opsin is improperly distributed away from its normal outer segment location to other retinal layers. This work investigated the role of Ca-release channels in ER stress, protein mislocalization, and cone death in a mouse model of CNG-channel deficiency. We examined whether preservation of luminal Ca stores through pharmacological and genetic suppression of ER Ca efflux protects cones by attenuating ER stress. We demonstrated that the inhibition of ER Ca-efflux channels reduced all three arms of ER-stress signaling while improving opsin trafficking to cone outer segments and decreasing cone death by 20-35%. Cone-specific gene deletion of the inositol-1,4,5-trisphosphate receptor type I (IPR1) also significantly increased cone density in the CNG-channel-deficient mice, suggesting that IPR1 signaling contributes to Ca homeostasis and cone survival. Consistent with the important contribution of organellar Ca signaling in this achromatopsia mouse model, significant differences in dynamic intraorganellar Ca levels were detected in CNG-channel-deficient cones. These results thus identify a novel molecular link between Ca homeostasis and cone degeneration, thereby revealing novel therapeutic targets to preserve cones in inherited retinal degenerative diseases.