AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity

doi:10.1073/pnas.0708970104

AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity

Departments of *Physiology and
^§Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143;
**Department of Integrative Biology, Eli Lilly and Company, Indianapolis, IN 46285; and
^†Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520

Contributed by Roger A. Nicoll, September 20, 2007 (received for review August 20, 2007)

Abstract

Naturally occurring glutamate analogs, such as kainate and domoate, which cause excitotoxic shellfish poisoning, induce nondesensitizing responses at neuronal α-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) γ-2 (or stargazin) and the related TARP γ-8 augment responses to kainate and domoate by making these neurotoxins more potent and more efficacious AMPA receptor agonists. Genetic deletion of hippocampal enriched γ-8 selectively abolishes sustained depolarizations in hippocampus mediated by kainate activation of AMPA receptors. γ-8 knockout mice display typical kainate-induced seizures; however, the associated neuronal cell death in the hippocampus is attenuated in mice lacking γ-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.

Footnotes

^‡To whom correspondence may be addressed at
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520.
E-mail: susumu.tomita{at}yale.edu
^‖To whom correspondence may be addressed. E-mail: nicoll{at}cmp.ucsf.edu or E-mail: bredt{at}lilly.com
Author contributions: S.T., R.A.N., and D.S.B. designed research; S.T., R.K.B., N.R., C.B., A.V., and J.L.O. performed research; S.T., R.K.B., N.R., C.B., A.V., J.L.O., K.S.K., and O.O. analyzed data; and S.T., O.O., R.A.N., and D.S.B. wrote the paper.
↵ ^¶Present address: Unité 840, Institut National de la Santé et de la Recherche Médicale, College de France, Paris 75005, France.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708970104/DC1.
Abbreviations:

AMPA,

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;

CTZ,

cyclothiazide;

TARP,

transmembrane AMPA receptor-associated protein.