Role of cellular prion protein in trafficking of GluA2-containing AMPA receptors to the neuronal lipid rafts

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For many of us the word prion reminds us of its devastating effects on cattle farmers and the beef industry in Canada almost a decade ago. Structural changes of the cellular prion protein in brain cells are responsible for all the related economic devastation. Although a variety of functions for the cellular prion protein have been proposed, the normal function of cellular prion protein (PrPc) is not well understood. PrPc is localized to special regions of the cell surface enriched with cholesterol and other lipid (fat) components called "lipid rafts". These lipid raft areas are actively involved in cell signaling. Glutamate is a major brain chemical that is involved in cell-to-cell signaling via a specific chemical-protein complex formation (through membrane receptors) like a key in a lock. These glutamate 'receptors' play important roles in many brain functions including learning and memory. Factors affecting the location of these receptors may influence brain functions. One type of glutamate receptor called the 'AMPA receptor' (AMPAR) is composed of four protein subunits; mostly GluA1 and GluA2. In our preliminary studies, using normal mice and mice in which cellular prion protein has been genetically knocked out, we found that PrPc associates with the GluA2 subunit of AMPARs in brain. After separating brain tissue into lipid raft and non-raft areas, we found that normal mouse brain GluA1 and GluA2 were localized in both lipid rafts and non-raft areas of plasma membrane whereas in the cellular prion knock out brain, GluA2 was completely absent from lipid raft areas; GluA1 was not affected. Therefore, we hypothesize that cellular prion protein plays an important role in targeting of GluA2-containing AMPARs to the cholesterol rich lipid raft areas of brain cells. We will use a variety of methods such as electron microscopy, fluorescent imaging, electrophysiology recording, protein-protein interaction techniques to confirm and prove our novel observation and hypothesis.