Oh, NO! The Ironic Route to Neurotoxicity

Science's STKE  22 Aug 2006:
Vol. 2006, Issue 349, pp. tw289
DOI: 10.1126/stke.3492006tw289

Cheah et al. investigated the role of Dexras1, a Ras-family guanosine triphosphatase, and uncovered a pathway linking activation of the N-methyl-D-aspartate-type glutamate receptor (NMDAR) to regulation of iron homeostasis and implicating changes in iron uptake in NMDAR-mediated neurotoxicity. Both neuronal nitric oxide synthase (nNOS) and Dexras1 bind to the adaptor protein CAPON; NMDAR stimulation leads to the calcium-dependent activation of nNOS, enabling the S-nitrosylation and activation of Dexras1. The consequences of Dexras1 activation, however, have been unclear. Cheah et al. identified peripheral benzodiazepine receptor (PBR)-associated protein (PAP7) as a potential Dexras1 binding partner through a screen of a rat whole-brain cDNA library. The relationship was confirmed with pulldown assays using human embryonic kidney (HEK) 293 cells (which have little endogenous PAP7 and Dexras1) transfected with glutathione S-transferase-PAP7 and Myc-tagged Dexras1. PAP7 bound the iron importer divalent metal transporter (DMT1), and coimmunoprecipitation analysis revealed that Dexras1, PAP7, and DMT1 existed as a ternary complex in mouse brain. Overexpression of Dexras1 in HEK293 cells enhanced iron uptake, an effect that was markedly enhanced by cotransfection with PAP7. Exposure of cells to nitric oxide (NO) donors elicited S-nitrosylation of Dexras1 and stimulated Dexras1-dependent iron uptake in undifferentiated PC12 cells (which have abundant endogenous PAP7 and Dexras1). Furthermore, NMDA stimulated iron uptake in primary cortical neurons from wild-type but not nNOS knockout mice. Intriguingly, a cell-permeable iron chelator inhibited an NMDA-dependent increase in the formation of reactive oxygen species as well as NMDA-mediated neurotoxicity. Thus, the authors conclude that NMDA stimulates NO-dependent increase in iron uptake, which seems to play a role in NMDA-dependent neuronal death.

J. H. Cheah, S. F. Kim, L. D. Hester, K. W. Clancy, S. E. Patterson III, V. Papadopoulos, S. H. Snyder, NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. Neuron 51, 431-440 (2006). [PubMed]