New transmembrane AMPA receptor regulatory protein isoform, gamma-7, differentially regulates AMPA receptors.
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.
Kato
Akihiko S
AS
Neuroscience Discovery, Lilly Research Laboratories, University of California, San Francisco, San Francisco, California 94143, USA.
Zhou
Wei
W
Milstein
Aaron D
AD
Knierman
Mike D
MD
Siuda
Edward R
ER
Dotzlaf
Joe E
JE
Yu
Hong
H
Hale
John E
JE
Nisenbaum
Eric S
ES
Nicoll
Roger A
RA
Bredt
David S
DS
D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism* / Q000502:physiology
D008565:Membrane Proteins; D020033:Protein Isoforms; D021122:Protein Subunits; D018091:Receptors, AMPA; C519955:TARP gamma-7 protein, mouse