Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

6-27-2012

Publication Source

J Neurochem

Volume

122

Issue

4

Start Page

823

Last Page

833

DOI

10.1111/j.1471-4159.2012.07804.x

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 (RPE) 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 RPE 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.

Copyright/Permission Statement

This is the peer reviewed version of the following article: [Guha, S., Baltazar, G. C., Tu, L.-A., Liu, J., Lim, J. C., Lu, W., … Mitchell, C. H. (2012). Stimulation of the D5 dopamine receptor acidifies the lysosomal pH of retinal pigmented epithelial cells and decreases accumulation of autofluorescent photoreceptor debris. Journal of Neurochemistry, 122(4), 823–833. http://doi.org/10.1111/j.1471-4159.2012.07804.x], which has been published in final form at [http://doi.org/10.1111/j.1471-4159.2012.07804.x]I]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

Keywords

Dopamine, lysosomal pH, autophagy, lipofuscin, retina

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Dentistry Commons

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Date Posted: 01 March 2022

This document has been peer reviewed.