title: EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia.
abstract: EAAC1 is a neuronal glutamate and cysteine transporter. EAAC1 uptake of cysteine provides substrate for neuronal glutathione synthesis, which plays a key role in both antioxidant defenses and intracellular zinc binding. Here we evaluated the role of EAAC1 in neuronal resistance to ischemia. EAAC1(-/-) mice subjected to transient cerebral ischemia exhibited twice as much hippocampal neuronal death as wild-type mice and a corresponding increase in microglial activation. EAAC1(-/-) mice also had elevated vesicular and cytosolic zinc concentrations in hippocampal CA1 neurons and an increased zinc translocation to postsynaptic neurons after ischemia. Treatment of the EAAC1(-/-) mice with N-acetyl cysteine restored neuronal glutathione concentrations and normalized basal zinc levels in the EAAC1(-/-) mice. Treatment of the EAAC1(-/-) mice with either N-acetyl cysteine or with zinc chelators reduced ischemia-induced zinc translocation, superoxide production, and neuron death. These findings suggest that cysteine uptake by EAAC1 is important for zinc homeostasis and neuronal antioxidant function under ischemic conditions.
authors.affiliation: Department of Neurology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA.
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.forename: Byung Hoon
authors.initials: BH
authors.lastname: Yoo
authors.forename: Angela M
authors.initials: AM
authors.lastname: Brennan
authors.forename: Byung Seop
authors.initials: BS
authors.lastname: Shin
authors.forename: Tiina M
authors.initials: TM
authors.lastname: Kauppinen
authors.forename: Ari E
authors.initials: AE
authors.lastname: Berman
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Swanson
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Suh
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D018450:Disease Progression; D050580:Excitatory Amino Acid Transporter 3 / Q000172:deficiency / Q000235:genetics*; D017353:Gene Deletion; D006706:Homeostasis / Q000235:genetics*; D002546:Ischemic Attack, Transient / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology*; D015032:Zinc / Q000502:physiology*
chemical_list: D050580:Excitatory Amino Acid Transporter 3; C493399:Slc1a1 protein, mouse; D015032:Zinc; D000111:Acetylcysteine