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Mol Vis 2013 Jun 11;19:1268-81. doi: 10.1167/13.9.1268.
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Disease-associated mutations in CNGB3 promote cytotoxicity in photoreceptor-derived cells.

Liu C , Sherpa T , Varnum MD .

PURPOSE: To determine if achromatopsia associated F525N and T383fsX mutations in the CNGB3 subunit of cone photoreceptor cyclic nucleotide-gated (CNG) channels increases susceptibility to cell death in photoreceptor-derived cells. METHODS: Photoreceptor-derived 661W cells were transfected with cDNA encoding wild-type (WT) CNGA3 subunits plus WT or mutant CNGB3 subunits, and incubated with the membrane-permeable CNG channel activators 8-(4-chlorophenylthio) guanosine 3'',5''-cyclic monophosphate (CPT-cGMP) or CPT-adenosine 3'',5''-cyclic monophosphate (CPT-cAMP). Cell viability under these conditions was determined by measuring lactate dehydrogenase release. Channel ligand sensitivity was calibrated by patch-clamp recording after expression of WT or mutant channels in Xenopus oocytes. RESULTS: Coexpression of CNGA3 with CNGB3 subunits containing F525N or T383fsX mutations produced channels exhibiting increased apparent affinity for CPT-cGMP compared to WT channels. Consistent with these effects, cytotoxicity in the presence of 0.1 μM CPT-cGMP was enhanced relative to WT channels, and the increase in cell death was more pronounced for the mutation with the largest gain-of-function effect on channel gating, F525N. Increased susceptibility to cell death was prevented by application of the CNG channel blocker L-cis-diltiazem. Increased cytotoxicity was also found to be dependent on the presence of extracellular calcium. CONCLUSIONS: These results indicate a connection between disease-associated mutations in cone CNG channel subunits, altered CNG channel-activation properties, and photoreceptor cytotoxicity. The rescue of cell viability via CNG channel block or removal of extracellular calcium suggests that cytotoxicity in this model depends on calcium entry through hyperactive CNG channels.

PubMed ID: 23805033
PMC ID: PMC3692405
Article link: Mol Vis
Grant support: [+]

Species referenced: Xenopus
Genes referenced: actb actl6a adm cnga3 cngb3
GO keywords: cyclic nucleotide-gated ion channel activity [+]

Disease Ontology terms: achromatopsia 3 [+]

Article Images: [+] show captions
References [+] :
Azuma, Involvement of calpain isoforms in retinal degeneration in WBN/Kob rats. 2004, Pubmed