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(Investigative Ophthalmology and Visual Science. 2006;47:397-404.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-0290
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Selective Relocalization and Proteasomal Downregulation of PKC{alpha} Induced by Platelet-Activating Factor in Retinal Pigment Epithelium

Zahra Faghiri and Nicolas G. Bazan

From the LSU Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center School of Medicine, New Orleans, Louisiana.

PURPOSE. Protein kinases C (PKCs) are key cell-signaling mediators in retinal physiology and pathophysiology. The cellular localization of PKC isoforms is important in defining their activity and specificity; the present study investigated the modulatory potential of the proinflammatory mediator platelet-activating factor (PAF) on the subcellular distribution of PKC{alpha}, ß, and {delta} isotypes.

METHODS. This study used real-time visualization of green fluorescent protein fused to PKC{alpha}, ß, or {delta} in the human retinal pigment epithelial (RPE) cell line ARPE-19.

RESULTS. In PAF-stimulated ARPE-19 cells, PKC{alpha} translocated to the plasma membrane and then colocalized with Golgi markers p230 and GM130; PKCß translocated to the plasma membrane but not to the Golgi; and PKC{delta} translocated to the Golgi. Pretreatment with PKC inhibitor calphostin C abolished the PAF-induced translocation of PKC{alpha} to the plasma membrane or to the Golgi, but the Golgi inhibitor Brefeldin A only prevented the accumulation of PKC{alpha} in Golgi, without affecting its membrane relocalization. PAF promoted depletion of PKC{alpha} and {delta} isoforms but not that of PKCß. Proteasome inhibitors lactacystin and MG-132 prevented the PAF-induced depletion of PKC{alpha}, but the inhibitor of lysosomal proteolysis E-64d was ineffective in rescuing PKC{alpha}.

CONCLUSIONS. These results suggest that the PAF-induced downregulation of PKC{alpha} occurs principally through the proteasomal pathway. This remarkable PAF-mediated diversity in PKC translocation and downregulation highlights the significance of isotype-specific PKC activation in signaling pathways in ARPE-19 cells. These signaling events may be critical during RPE responses to oxidative stress, inflammation, and retinal degenerations, when PAF production is enhanced.






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