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J. Biol. Chem., Vol. 281, Issue 52, 40164-40173, December 29, 2006

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Actinfilin Is a Cul3 Substrate Adaptor, Linking GluR6 Kainate Receptor Subunits to the Ubiquitin-Proteasome Pathway^*

Gregory D. Salinas, Leslie A. C. Blair, Leigh A. Needleman, Justina D. Gonzales, Ying Chen^¶, Min Li^¶, Jeffrey D. Singer, and John Marshall¹

From the Departments of Molecular Pharmacology, Physiology, and Biotechnology and Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912 and the ^¶Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205

Kainate receptors have been implicated in excitotoxic neuronal death induced by diseases such as epilepsy and stroke. Actinfilin, a synaptic member of the BTB-Kelch protein family, is known to bind to the actin cytoskeleton. However, little is understood about its function at the synapse. Here, we report that actinfilin is able to bind to GluR6, a kainate-type glutamate receptor subunit, and target GluR6 for degradation. Like many members of its protein family, actinfilin acts as a substrate adaptor, binding Cullin 3 (Cul3) and linking GluR6 to the E3 ubiquitin-ligase complex. We map this interaction to the Kelch repeat domain of actinfilin and the GluR6 C terminus. Co-immunoprecipitation and immunofluorescence studies show that GluR6 is ubiquitinated, and that GluR6 levels are decreased by actinfilin overexpression but increased when actinfilin levels are reduced by specific RNA interference. Furthermore, actinfilin-Cul3 interactions appear to be important for regulating surface GluR6 expression. Synaptic GluR6 levels are elevated in mice with lowered neuronal Cul3 expression and when dominant-negative forms of Cul3 are transfected into hippocampal neurons. Together our data demonstrate that actinfilin acts as a scaffold, linking GluR6 to the Cul3 ubiquitin ligase to provide a novel mechanism for kainate receptor degradation.

Received for publication, August 25, 2006 , and in revised form, October 10, 2006.

^* This work was supported by National Institutes of Health Grants RO1 NS39063 and NS39309 and the DEARS Foundation (to J. M), the Emerald Foundation and COBRE (to J. D. S), and National Institutes of Health Grant GM070959 (to M. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 401-863-2574; Fax: 401-863-1595; E-mail: John_Marshall{at}brown.edu.

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