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1 Physiology, University of Pennsylvania, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: chm{at}mail.med.upenn.edu.
The retinal pigment epithelium (RPE) faces the photoreceptor outer segments and regulates composition of the subretinal space in between. ATP enhances fluid movement from subretinal space across the RPE. RPE cells can themselves release ATP, but the mechanisms and polarity of this release are unknown. The RPE expresses the cystic fibrosis transmembrane conductance regulator (CFTR), and CFTR is associated with ATP release in other epithelial cells. However, an increasing number of reports suggest that the exocytotic pathway contributes to release. The involvement of CFTR and the vesicular pathway in ATP release from RPE cells is examined here. Release from cultured human ARPE-19 cells and across the apical membrane of fresh bovine RPE cells in an eyecup was studied. A cAMP cocktail to activate CFTR triggered ATP release from fresh and cultured RPE cells. Release from both RPE preparations was largely prevented by the broad-acting blocker glybenclamide and the specific thiazolidinone CFTR inhibitor CFTR-172. The block by CFTR-172 was enhanced by preincubation and prevented ATP release with IC50=3.5 µM. The rise in intracellular Ca2+ accompanying hypotonic challenge was prevented by CFTR-172. The vesicular transport inhibitor brefeldin A (BFA) prevented ATP release following stimulation with both hypotonic and cAMP conditions, suggesting vesicular insertion was also involved. These results show an intimate involvement of CFTR in ATP release from RPE cells which can autostimulate receptors on the apical membrane to modify Ca2+ signaling. The requirement for both CFTR and vesicular transport pathways suggests vesicular insertion of CFTR may underlie the release of ATP.
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