Studies from our laboratory over the past two decades have shown that the retina and rod outer segments (ROS) have an active phosphoinositide (PI) metabolism (called PI Cycle) that generates several lipid second messengers. We have reported previously that light stimulates various components of the PI Cycle in vertebrate ROS, including DG kinase, PI synthetase, PIP kinase (PIPK), phospholipase C (PLC), and PI 3-kinase (PI3K). We have reported that G-protein coupled receptor rhodopsin regulates the phosphorylation of retinal insulin receptor in vivo and activates PI3K, which forms PI-3,4,5-P3 and other D3-phosphorylated PIs in ROS. In other tissues, these second messengers have been shown to affect a large number of intracellular events, including secretion, cell survival, membrane trafficking, and actin polymerization, all of which are important in the retina. It is our hypothesis that light-stimulation of this reaction in photoreceptor cell outer segments affects important photoreceptor cell function(s) not related to visual transduction. The long-term goal of our research is to elucidate the physiological role of these lipid second messengers in photoreceptor cells. Recently we have reported that deletion downstream effectors of PI3K, Akt2 and Bcl-xl, resulted in stress-induced photoreceptor degeneration. These studies clearly suggest that PI3K generated phosphoinositides are important regulators of photoreceptor survival and maintenance. To this end we will determine the functional role of PI3K in photoreceptor cells, identify and characterize protein targets for 3-phosphorylated phosphoinositides, determine Akt2 interacting proteins that are necessary for cell survival, and determine the mechanism of regulation of PI-4,5-P2 levels in rod outer segments. We will utilize a combination of genetic, molecular biological, and biochemical approaches to address the proposed studies. Results of these studies will lead to a better understanding of the role of PI3K generated phosphoinositides in photoreceptor structure, function, and survival. ? ? ?
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