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
