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 Ca2+-release channels in ER
stress, protein mislocalization, and cone death in a mouse model of CNG-channel deficiency. We examined whether preservation of
luminal Ca2+ stores through pharmacological and genetic suppression of ER Ca2+ efflux protects cones by attenuating ER stress. We demonstrated that the inhibition of ER Ca2+-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 (IP3R1) also significantly increased cone density in the CNG-channel-deficient mice, suggesting that IP3R1 signaling contributes to Ca2+ homeostasis and cone survival. Consistent with the important contribution of organellar Ca2+ signaling in this
achromatopsia mouse model, significant differences in dynamic intraorganellar Ca2+ levels were detected in CNG-channel-deficient cones. These results thus identify a novel molecular link between Ca2+ homeostasis and cone degeneration, thereby revealing novel therapeutic targets to preserve cones in inherited
retinal degenerative diseases.