Departmental Papers (Dental)
The P2Y12 Receptor Antagonist Ticagrelor Reduces Lysosomal pH and Autofluorescence in Retinal Pigmented Epithelial Cells From the ABCA4-/- Mouse Model of Retinal Degeneration
Date of this Version
Frontiers in Pharmacology
Article number 242
The accumulation of partially degraded lipid waste in lysosomal-related organelles may contribute to pathology in many aging diseases. The presence of these lipofuscin granules is particularly evident in the autofluorescent lysosome-associated organelles of the retinal pigmented epithelial (RPE) cells, and may be related to early stages of age-related macular degeneration. While lysosomal enzymes degrade material optimally at acidic pH levels, lysosomal pH is elevated in RPE cells from the ABCA4-/- mouse model of Stargardt's disease, an early onset retinal degeneration. Lowering lysosomal pH through cAMP-dependent pathways decreases accumulation of autofluorescent material in RPE cells in vitro, but identification of an appropriate receptor is crucial for manipulating this pathway in vivo. As the P2Y12 receptor for ADP is coupled to the inhibitory Gi protein, we asked whether blocking the P2Y12 receptor with ticagrelor could restore lysosomal acidity and reduce autofluorescence in compromised RPE cells from ABCA4-/- mice. Oral delivery of ticagrelor giving rise to clinically relevant exposure lowered lysosomal pH in these RPE cells. Ticagrelor also partially reduced autofluorescence in the RPE cells of ABCA4-/- mice. In vitro studies in ARPE-19 cells using more specific antagonists AR-C69931 and AR-C66096 confirmed the importance of the P2Y12 receptor for lowering lysosomal pH and reducing autofluorescence. These observations identify P2Y12 receptor blockade as a potential target to lower lysosomal pH and clear lysosomal waste in RPE cells. © 2018 Lu, Gómez, Lim, Guha, O'Brien-Jenkins, Coffey, Campagno, McCaughey, Laties, Carlsson and Mitchell.
Age-related macular degeneration, Lysosomal pH, Lysosomal storage diseases, P2Y12 receptor, Retinal pigment epithelium, Ticagrelor, adenosine diphosphate, ar c66096, ar c69931, cangrelor, cyclic AMP, inhibitory guanine nucleotide binding protein, purinergic P2Y receptor antagonist, purinergic P2Y12 receptor, ticagrelor, unclassified drug, acidity, animal cell, animal experiment, animal model, ARPE-19 cell line, Article, autofluorescence, controlled study, drug effect, epithelium cell, gene expression, immunocytochemistry, in vitro study, lysosome, microscopy, mouse, nonhuman, pH, polymerase chain reaction, retinal pigment epithelium, Stargardt disease
Lu, W., Gómez, N. M., Lim, J. C., Guha, S., O'Brien-Jenkins, A., Coffey, E. E., Campagno, K. E., McCaughey, S. A., Laties, A. M., Carlsson, L. G., & Mitchell, C. H. (2018). The P2Y12 Receptor Antagonist Ticagrelor Reduces Lysosomal pH and Autofluorescence in Retinal Pigmented Epithelial Cells From the ABCA4-/- Mouse Model of Retinal Degeneration. Frontiers in Pharmacology, 9 (APR), Article number 242-. http://dx.doi.org/10.3389/fphar.2018.00242
Additional FilesImage_1_TheP2Y12ReceptorAntagonistTicagrelorReducesLysosomalpHandAutofluorescenceinRetinalPigmentedEpithelialCellsFromtheABCA4MouseModelofRetinalDegeneration.TIF (1540 kB)
Supplemental Figure 1
Date Posted: 09 February 2023
This document has been peer reviewed.