title: AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity.
abstract: Naturally occurring glutamate analogs, such as kainate and domoate, which cause excitotoxic shellfish poisoning, induce nondesensitizing responses at neuronal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In addition to acting on AMPA receptors, kainate and domoate also activate high-affinity kainate-type glutamate receptors. The receptor type that mediates their neurotoxicity remains uncertain. Here, we show that the transmembrane AMPA receptor-associated protein (TARP) gamma-2 (or stargazin) and the related TARP gamma-8 augment responses to kainate and domoate by making these neurotoxins more potent and more efficacious AMPA receptor agonists. Genetic deletion of hippocampal enriched gamma-8 selectively abolishes sustained depolarizations in hippocampus mediated by kainate activation of AMPA receptors. gamma-8 knockout mice display typical kainate-induced seizures; however, the associated neuronal cell death in the hippocampus is attenuated in mice lacking gamma-8. This work decisively demonstrates that TARP-associated AMPA receptors mediate kainate neurotoxicity and identifies TARPs as targets for modulating neurotoxic properties of AMPA receptors.
authors.affiliation: Department of Physiology, University of California, San Francisco, CA 94143, USA. susumu.tomita@yale.edu
authors.forename: Susumu
authors.initials: S
authors.lastname: Tomita
authors.forename: R Keith
authors.initials: RK
authors.lastname: Byrd
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouach
authors.forename: Camilla
authors.initials: C
authors.lastname: Bellone
authors.forename: Angela
authors.initials: A
authors.lastname: Venegas
authors.forename: Jessica L
authors.initials: JL
authors.lastname: O'Brien
authors.forename: Kwang S
authors.initials: KS
authors.lastname: Kim
authors.forename: Olav
authors.initials: O
authors.lastname: Olsen
authors.forename: Roger A
authors.initials: RA
authors.lastname: Nicoll
authors.forename: David S
authors.initials: DS
authors.lastname: Bredt
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D051379:Mice; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D018091:Receptors, AMPA; C012301:domoic acid; D007608:Kainic Acid