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Regulation of Membrane Transporters by Reactive Oxygen Species

Principal Investigator: Dr. Leah Chase

In living organisms, routine metabolic processes result in the formation of many free radicals within the cellular environment that can be toxic to the cells themselves. My research tests the hypothesis that the neurotransmitter transport system, System xc-, provides neurons and glia with the precursors required to synthesize glutathioine in the cellular defense against oxidative insult. Specifically, the build up of H2O2 and other reactive oxygen species leads to depletion of cellular glutathione, and ultimately oxidative stress-mediated neuronal death. The molecular events that underlie the development of increased oxidative stress in the neurons of Parkinson’s Disease patients is currently not understood. Previous studies in my lab have shown that the metabolite, H2O2, acutely regulates the activity of System xc- in glioma and dopaminergic cells by triggering the trafficking of the transporter to the plasma membrane. This trafficking event directly results in the rapid recovery of cellular glutathione levels within the cell. Thus, the oxidant-regulated trafficking of System xc- is likely to play a key role in the defense against oxidative stress immediately following an oxidative insult. We are currently using biochemical and cell biological techniques 1) to describe the cellular signaling pathways that control constitutive (basal) and H2O2-regulated activity of system xc- in cultured glioma cells and dopaminergic cells and 2) to determine if the upregulation of transporter activity decreases sensitivity oxidative cell death. Each student in the Chase lab has their own independent research project that fits into the overall research aims of the lab. Students will assist in formulating testable hypotheses and construct appropriate experimental design to test their hypotheses.

Representative Publications:

  • Chase, L.A, N. L. Peterson, and J. F. Koerner. 2007. Lathyrus toxin, ß-N-oxalyl-L-a,ß-diaminoproprionic acid (ODAP), and homocysteic acid sensitize CA1 pyramidal neurons to cystine and L-2-amino-6-phosphonohexanoic acid. Toxicology and Applied Pharmacology 219(1):1-9.
  • Goltz, A.*, N. Costa*, and L. A. Chase. 2007. Hydrogen peroxide regulates the trafficking of System xc- in a dopaminergic cell line. FASEB J. 21:489.10
  • Sierzant, C.G.*, B. Lewis* and L. A. Chase. 2007. System xc- is an electrogenic cystine/glutamate exchanger. FASEB J. 21:489.9.
  • Sheldon, N.*, M. VerHeulen*, M. DeYoung*, and L. Chase 2006. Peroxide triggers the translocation of the transporter, system xC- to the plasma membrane in cultured human glioma cells. FASEB J. 20(5): A1366.
  • Chase, L.A., J. Stewart, and C. C. Barney. 2006. Cultivation of an Interdisciplinary, Research-Based Neuroscience Minor at Hope College. Journal of Undergraduate Neuroscience 5(1):A6-A13.
  • Coleman, R. R.*, M. J. Teusink*, J. Andersen, J., and L. A. Chase. 2004. Role of Cl- in System xc- transport. Benzon Symposium #51.
  • Chase, L. A., L. Wellman, A. J. Beitz, R. J. Roon, and J. F. Koerner. 2001. L-Quisqualic acid transport into hippocampal neurons by a L-cystine-sensitive carrier is required for the induction of L-quisqualate sensitization. Neuroscience 106 (2): 287-301
  • Littman, L., L. A. Chase, M. Renzi, A. B. Garlin, J. F. Koerner, R. L. Johnson, R.L. and M. B. Robinson. 1995. Effects of quisqualic acid analogs on metabotropic glutamate receptors coupled to phosphoinositide hydrolysis in rat hippocampus. Neuropharmacology 34: 829-841.

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