Phosphoinositide 3-kinase signaling in retinal rod photoreceptors.

The expression and activity of phosphoinositide 3-kinase (PI3K) and the formation of PI3K-generated D3 phosphoinositides have been demonstrated in intact retinal rod outer segment (ROS) membranes.1–4 To date, studies have implicated D3 phosphoinositides in a variety of cellular activities such as vesicular trafficking, cytoskeletal reorganization, cell growth, adhesion, and survival,4,5 as well as photoreceptor-specific functions such as modulation of phototransduction,6 disc biogenesis,7 protein translocation,8 synaptic ribbon formation, and glutamate release.9 These studies clearly demonstrate that phosphoinositides generated by PI3K could facilitate intracellular protein trafficking and modulate phototransduction. However, the functional role of PI3K in any of these activities in rod photoreceptors is not fully established. In adult retina, our previous in vivo studies have shown that moderate light exposure activates PI3K/Akt survival signaling pathway in rod photoreceptor outer segments through light-induced tyrosine phosphorylation of the retinal insulin receptor (IR).10,11 Also, in retina, deletion of the IR leads to photoreceptor degeneration due to increased susceptibility to damage from light-induced stress, in part because of the inability to activate the PI3K/Akt survival pathway.12 Receptor activation of PI3K has been shown to protect 661W,13,14 R28,15 and retinal ganglion cells16 from stress-induced cell death. These findings demonstrate the biological significance of the PI3K signaling pathway in neuroprotection of retinal photoreceptor cells. Systemic deletion of p85α regulatory or p110α catalytic subunits of PI3K results in embryonic or neonatal lethality.17,18 To circumvent the problems associated with the global PI3K KO and to investigate functional significance of PI3K in a particular tissue or subset of cells, several studies have used the Cre-lox technology. Conditional deletion of cardiac pik3r1 resulted in attenuated Akt signaling, reduced heart size, and altered cardiac gene expression.19 Conditional deletion of pik3r1 in skeletal muscle resulted in reduced muscle weight and size.20 The functional role of PI3K in the retina or photoreceptor cells is not known, although earlier studies from our laboratory have suggested its involvement in neuroprotection through the IR/PI3K/Akt signaling pathway.21–23 In the present study, using Cre-lox technology, we conditionally deleted the p85α (pik3r1) regulatory subunit of PI3K in rod photoreceptors to evaluate the functional significance of PI3K in these cells.