BEHIND THE IRON CURTAIN: DEXRAS1 MEDIATES GLUTAMATEN-MDA INDUCED NEURONAL IRON UPTAKE
Cheah, Jaime H.
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Iron is an enigmatic molecule – a divalent metal absolutely required for life, but toxic in excess. Because of this dual nature, iron trafficking within the cell is tightly regulated, with little free iron available in the cytosol. Iron entry into the cell is mediated through two distinct pathways, both of which utilize the Divalent Metal Transporter (DMT1), a twelve-transmembrane protein which is the only known iron importer in the cell. Dexras1 is a small G-protein regulated by glucocorticoids and neuronal nitric oxide synthase (nNOS). Using yeast-two-hybrid analysis, we have discovered that Dexras1 interacts with DMT1 via an adaptor protein, the Peripheral Benzodiazepine Receptor Associated Protein (PAP7). We have identified a novel signaling cascade in neurons whereby stimulation of glutamate-NMDA receptors activates nNOS, leading to Snitrosylation of Dexras1, which by its interaction with PAP7 and DMT1, physiologically induces iron uptake. We have also investigated whether misregulation of this pathway participates in NMDA-mediated neuronal excitoxicity.