Defective trafficking of cone photoreceptor CNG channels induces the unfolded protein response and ER-stress-associated cell death

被引:33
作者
Duricka, Deborah L. [1 ,2 ]
Brown, R. Lane [1 ,2 ,3 ]
Varnum, Michael D. [1 ,2 ,4 ]
机构
[1] Washington State Univ, Dept Vet & Comparat Anat Pharmacol & Physiol, Pullman, WA 99164 USA
[2] Washington State Univ, Program Neurosci, Pullman, WA 99164 USA
[3] Washington State Univ, WWAMI Med Educ Program, Pullman, WA 99164 USA
[4] Washington State Univ, Ctr Integrated Biotechnol, Pullman, WA 99164 USA
基金
美国国家卫生研究院;
关键词
chaperone; ion channel subunit; membrane localization; misfolding; retinal disease; unfolded protein response (UPR); NUCLEOTIDE-GATED CHANNEL; ENDOPLASMIC-RETICULUM STRESS; LONG QT-SYNDROME; HERG POTASSIUM CHANNEL; CYSTIC-FIBROSIS; RETINITIS-PIGMENTOSA; MUTATIONS; SUBUNIT; ACHROMATOPSIA; EXPRESSION;
D O I
10.1042/BJ20111004
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations that perturb the function of photoreceptor CNG (cyclic nucleotide-gated) channels are associated with several human retinal disorders, but the molecular and cellular mechanisms leading to photoreceptor dysfunction and degeneration remain unclear. Many loss-of-function mutations result in intracellular accumulation of CNG channel subunits. Accumulation of proteins in the ER (endoplasmic reticulum) is known to cause ER stress and trigger the UPR (unfolded protein response), an evolutionarily conserved cellular programme that results in either adaptation via increased protein processing capacity or apoptotic cell death. We hypothesize that defective trafficking of cone photoreceptor CNG channels can induce UPR-mediated cell death. To test this idea, CNGA3 subunits bearing the R563H and Q655X mutations were expressed in photoreceptor-derived 661W cells with CNGB3 subunits. Compared with wild-type, R563H and Q655X subunits displayed altered degradation rates and/or were retained in the ER. ER retention was associated with increased expression of UPR-related markers of ER stress and with decreased cell viability. Chemical and pharmacological chaperones {TUDCA (tauroursodeoxycholate sodium salt), 4-PBA (sodium 4-phenylbutyrate) and the cGMP analogue CPT-cGMP [8-(4-chlorophenylthio)-cGMP]} differentially reduced degradation and/or promoted plasma-membrane localization of defective subunits. Improved subunit maturation was concordant with reduced expression of ER-stress markers and improved viability of cells expressing localization-defective channels. These results indicate that ER stress can arise from expression of localization-defective CNG channels, and may represent a contributing factor for photoreceptor degeneration.
引用
收藏
页码:685 / 696
页数:12
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