Abstract：
:Optimal neuronal activity requires that supporting cells provide both efficient nutrient delivery and waste disposal. The incomplete processing of engulfed waste by their lysosomes can lead to accumulation of residual material and compromise their support of neurons. As most degradative lysosomal enzymes function best at an acidic pH, lysosomal alkalinization can impede enzyme activity and increase lipofuscin accumulation. We hypothesize that treatment to reacidify compromised lysosomes can enhance degradation. Here, we demonstrate that degradation of ingested photoreceptor outer segments by retinal pigmented epithelial cells is increased by stimulation of D5 dopamine receptors. D1/D5 receptor agonists reacidified lysosomes in cells alkalinized by chloroquine or tamoxifen, with acidification dependent on protein kinase A. Knockdown with siRNA confirmed acidification was mediated by the D5 receptor. Exposure of cells to outer segments increased lipofuscin-like autofluorescence, but SKF 81297 reduced autofluorescence. Likewise, SKF 81297 increased the activity of lysosomal protease cathepsin D in situ. D5DR stimulation also acidified lysosomes of retinal pigmented epithelial cells from elderly ABCA4(-/-) mice, a model of recessive Stargardt's retinal degeneration. In conclusion, D5 receptor stimulation lowers compromised lysosomal pH, enhancing degradation. The reduced accumulation of lipofuscin-like autofluorescence implies the D5 receptor stimulation may enable cells to better support adjacent neurons.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Guha S,Baltazar GC,Tu LA,Liu J,Lim JC,Lu W,Argall A,Boesze-Battaglia K,Laties AM,Mitchell CHdoi
10.1111/j.1471-4159.2012.07804.xsubject
Has Abstractpub_date
2012-08-01 00:00:00pages
823-33issue
4eissn
0022-3042issn
1471-4159journal_volume
122pub_type
杂志文章abstract：:Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of 'bath salts' and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the a...
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更新日期：1996-12-01 00:00:00
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更新日期：2009-04-01 00:00:00
abstract：:Neurofibrillary tangles (NFTs) consisting of the hyperphosphorylated microtubule-associated protein tau are a defining pathological characteristic of Alzheimer's disease (AD). Hyperphosphorylation of tau is hypothesized to impair the microtubule stabilizing function of tau, leading to the formation of paired helical f...
journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2003.02070.x
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pub_type： 杂志文章
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journal_title：Journal of neurochemistry
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journal_title：Journal of neurochemistry
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journal_title：Journal of neurochemistry
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更新日期：2009-10-01 00:00:00
