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The Journal of Neuroscience, May 2, 2007, 27(18):4969-4977; doi:10.1523/JNEUROSCI.5561-06.2007

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Cellular/Molecular
New Transmembrane AMPA Receptor Regulatory Protein Isoform, {gamma}-7, Differentially Regulates AMPA Receptors

Akihiko S. Kato,1 Wei Zhou,3 Aaron D. Milstein,3 Mike D. Knierman,2 Edward R. Siuda,1 Joe E. Dotzlaf,2 Hong Yu,1 John E. Hale,2 Eric S. Nisenbaum,1 Roger A. Nicoll,3 and David S. Bredt1,2

1Neuroscience Discovery and 2Integrated Biology, Lilly Research Laboratories, 3Departments of Physiology, and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94143

Correspondence should be addressed to David S. Bredt, Integrative Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0510. Email: bredt{at}lilly.com

AMPA-type glutamate receptors (GluRs) mediate most excitatory signaling in the brain and are composed of GluR principal subunits and transmembrane AMPA receptor regulatory protein (TARP) auxiliary subunits. Previous studies identified four mammalian TARPs, {gamma}-2 (or stargazin), {gamma}-3, {gamma}-4, and {gamma}-8, that control AMPA receptor trafficking, gating, and pharmacology. Here, we explore roles for the homologous {gamma}-5 and {gamma}-7 proteins, which were previously suggested not to serve as TARPs. Western blotting reveals high levels of {gamma}-5 and {gamma}-7 in the cerebellum, where {gamma}-7 is enriched in Purkinje neurons in the molecular layer and glomerular synapses in the granule cell layer. Immunoprecipitation proteomics shows that cerebellar {gamma}-7 avidly and selectively binds to AMPA receptor GluR subunits and also binds to the AMPA receptor clustering protein, postsynaptic density-95 (PSD-95). Furthermore, {gamma}-7 occurs together with PSD-95 and AMPA receptor subunits in purified postsynaptic densities. In heterologous cells, {gamma}-7 but not {gamma}-5 greatly enhances AMPA receptor glutamate-evoked currents and modulates channel gating. In granule cells from stargazer mice, transfection of {gamma}-7 but not {gamma}-5 increases AMPA receptor-mediated currents. Compared with stargazin, {gamma}-7 differentially modulates AMPA receptor glutamate affinity and kainate efficacy. These studies define {gamma}-7 as a new member of the TARP family that can differentially influence AMPA receptors in cerebellar neurons.

Key words: glutamate receptor; mass spectroscopy; auxiliary subunit; ion channel; cerebellum; excitatory amino acid

Received Dec. 21, 2006; revised March 7, 2007; accepted March 29, 2007.

Correspondence should be addressed to David S. Bredt, Integrative Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0510. Email: bredt{at}lilly.com




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S. Tomita, R. K. Byrd, N. Rouach, C. Bellone, A. Venegas, J. L. O'Brien, K. S. Kim, O. Olsen, R. A. Nicoll, and D. S. Bredt
AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity
PNAS, November 20, 2007; 104(47): 18784 - 18788.
[Abstract] [Full Text] [PDF]


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