Abstract：
:Rhodopsin is a G protein-coupled receptor essential for vision and rod photoreceptor viability. Disease-associated rhodopsin mutations, such as P23H rhodopsin, cause rhodopsin protein misfolding and trigger endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR). The pathophysiologic effects of ER stress and UPR activation on photoreceptors are unclear. Here, by examining P23H rhodopsin knock-in mice, we found that the UPR inositol-requiring enzyme 1 (IRE1) signaling pathway is strongly activated in misfolded rhodopsin-expressing photoreceptors. IRE1 significantly upregulated ER-associated protein degradation (ERAD), triggering pronounced P23H rhodopsin degradation. Rhodopsin protein loss occurred as soon as photoreceptors developed, preceding photoreceptor cell death. By contrast, IRE1 activation did not affect JNK signaling or rhodopsin mRNA levels. Interestingly, pro-apoptotic signaling from the PERK UPR pathway was also not induced. Our findings reveal that an early and significant pathophysiologic effect of ER stress in photoreceptors is the highly efficient elimination of misfolded rhodopsin protein. We propose that early disruption of rhodopsin protein homeostasis in photoreceptors could contribute to retinal degeneration.
journal_name
Mol Neurobioljournal_title
Molecular neurobiologyauthors
Chiang WC,Kroeger H,Sakami S,Messah C,Yasumura D,Matthes MT,Coppinger JA,Palczewski K,LaVail MM,Lin JHdoi
10.1007/s12035-014-8881-8subject
Has Abstractpub_date
2015-08-01 00:00:00pages
679-95issue
1eissn
0893-7648issn
1559-1182pii
10.1007/s12035-014-8881-8journal_volume
52pub_type
杂志文章abstract：:Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and the BK channel are enriched at the presynaptic nerve terminal, where CaMKII associates with synaptic vesicles whereas the BK channel colocalizes with voltage-sensitive Ca(2+) channels in the plasma membrane. Mounting evidence suggests that these two proteins p...
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journal_title：Molecular neurobiology
pub_type： 杂志文章,评审
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