Induction of the Unfolded Protein Response by Constitutive G-protein Signaling in Rod Photoreceptor Cells

Abstract

Background: Excessive light exposure and genetic mutations that act as "equivalent light" cause photoreceptor cell death. Results: Prolonged transducin signaling, but not channel closure, induces endoplasmic reticulum stress. Conclusion: Induction of UPR is a distinct cell death pathway caused by transducin signaling. Significance: Manipulation of UPR may prolong photoreceptor cell survival in transducin-induced retinal light damage.

Guanylate cyclase–activating protein 2 contributes to phototransduction and light adaptation in mouse cone photoreceptors

“…As expected, the GCAP2 signal was not observed in Gcap2 -/-or Gcaps -/-cones ( Fig. 1 bottom two panels), thereby confirming the specificity of the GCAP2 antibody (33). Together, these results clearly demonstrate that GCAP2 is expressed in mouse cones.…”

Structural and molecular bases of rod photoreceptor morphogenesis and disease

“…Moreover, the G90D mutation actually rescues the retinal degeneration induced by a mutation in the guanylate cyclase activating protein, GCAP-1, which leads to elevated levels of cGMP (Woodruff et al, 2007). Interestingly, a study of effects of phototransduction cascade mutants found evidence that constitutive G-protein activation due to inactivating mutations in rhodopsin kinase or arrestin, but not constitutive membrane hyperpolarization due to inactivation of the cGMP-gated cation channel that is the ultimate downstream target of the phototransduction cascade, led to activation of the Unfolded Protein Response (Wang and Chen, 2014). Thus, constitutive signaling may act on cell survival differently, depending on the step(s) of the cascade affected.…”

Regulation of calcium homeostasis in the outer segments of rod and cone photoreceptors

“…In addition, mutations of RPE65 that prevent formation of visual pigments are expected to lower [Ca 2+ ] due to the constitutive activity of free opsin proteins which continuously stimulate the phototransduction cascade (Woodruff et al, 2003). Other examples of mutations leading to uncontrolled phototransduction and photoreceptor cell death include the rod arrestin knockout (Chen et al, 1999b; Wang and Chen, 2014) and rhodopsin kinase knockout (Chen et al, 1999a) mouse models. Indeed, an “equivalent light” hypothesis has been put forward to explain how the dominantly active mutations in the phototransduction cascade lead to cell death (Fain, 2006; Fain and Lisman, 1993).…”