Endoplasmic reticulum (ER) Ca2+-channel activity contributes to ER stress and cone death in cyclic nucleotide-gated channel deficiency.

摘要: Endoplasmic reticulum (ER) stress and mislocalization of improperly folded proteins have been shown to contribute photoreceptor death in models inherited retinal degenerative diseases. In particular, mice with cone cyclic nucleotide-gated (CNG) channel deficiency, a model for achromatopsia, display both early-onset ER opsin mistrafficking. By 2 weeks age, these show elevated signaling from all three arms the ER-stress pathway, by 1 month, is distributed away its normal outer segment location other layers. This work investigated role Ca2+-release channels stress, protein mislocalization, mouse CNG-channel deficiency. We examined whether preservation luminal Ca2+ stores through pharmacological genetic suppression efflux protects cones attenuating stress. demonstrated that inhibition Ca2+-efflux reduced while improving trafficking segments decreasing 20–35%. Cone-specific gene deletion inositol-1,4,5-trisphosphate receptor type I (IP3R1) also significantly increased density CNG-channel-deficient mice, suggesting IP3R1 contributes homeostasis survival. Consistent important contribution organellar this achromatopsia model, significant differences dynamic intraorganellar levels were detected cones. These results thus identify novel molecular link between degeneration, thereby revealing therapeutic targets preserve