AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity.
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.
Tomita
Susumu
S
Department of Physiology, University of California, San Francisco, CA 94143, USA. susumu.tomita@yale.edu
Byrd
R Keith
RK
Rouach
Nathalie
N
Bellone
Camilla
C
Venegas
Angela
A
O'Brien
Jessica L
JL
Kim
Kwang S
KS
Olsen
Olav
O
Nicoll
Roger A
RA
Bredt
David S
DS
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
C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D018091:Receptors, AMPA; C012301:domoic acid; D007608:Kainic Acid