Protein Kinase A in Human Retina: Differential Localization of C beta, C alpha, RII alpha, and RII beta in Photoreceptors Highlights Non-redundancy of Protein Kinase A Subunits

Protein kinase A (PKA) signaling is essential for numerous processes but the subcellular localization of specific PKA regulatory (R) and catalytic (C) subunits has yet to be explored comprehensively. Additionally, the localization of the C beta subunit has never been spatially mapped in any tissue even though similar to 50% of PKA signaling in neuronal tissues is thought to be mediated by C beta. Here we used human retina with its highly specialized neurons as a window into PKA signaling in the brain and characterized localization of PKA C alpha, C beta, RII alpha, and RII beta subunits. We found that each subunit presented a distinct localization pattern. C alpha and C beta were localized in all cell layers (photoreceptors, interneurons, retinal ganglion cells), while RII alpha and RII beta were selectively enriched in photoreceptor cells where both showed distinct patterns of co-localization with C alpha but not C beta. Only C alpha was observed in photoreceptor outer segments and at the base of the connecting cilium. C beta in turn, was highly enriched in mitochondria and was especially prominent in the ellipsoid of cone cells. Further investigation of C beta using RNA BaseScope technology showed that two C beta splice variants (C beta 4 and C beta 4ab) likely code for the mitochondrial C beta proteins. Overall, our data indicates that PKA C alpha, C beta, RII alpha, and RII beta subunits are differentially localized and are likely functionally non-redundant in the human retina. Furthermore, C beta is potentially important for mitochondrial-associated neurodegenerative diseases previously linked to PKA dysfunction.