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. 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. Ionotropic glutamate receptors mediate fast excitatory neurotransmission in the mammalian brain and, based on agonist sensitivity, are subdivided into the N-methyl-d-aspartic acid (NMDA), 2The abbreviations used are: NMDA, N-methyl-d-aspartic acid; KAR, kainate receptors; TRITC, tetramethylrhodamine isothiocyanate; RNAi, RNA interference; GFP, green fluorescent protein; HA, hemagglutinin; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; SM, starting material; AF, actinfilin. 2The abbreviations used are: NMDA, N-methyl-d-aspartic acid; KAR, kainate receptors; TRITC, tetramethylrhodamine isothiocyanate; RNAi, RNA interference; GFP, green fluorescent protein; HA, hemagglutinin; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; SM, starting material; AF, actinfilin. α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainate receptor families. Kainate receptors (KARs) consist of tetrameric assembly of five subunits, GluR5-7 and KA1-2, to control intrinsic excitability, regulate transmitter release and are implicated in epileptiform activity (1Lerma J. Curr. Opin. Pharmacol. 2006; 6: 89-97Crossref PubMed Scopus (150) Google Scholar, 2Pinheiro P. Mulle C. Cell Tissue Res. 2006; 326: 457-482Crossref PubMed Scopus (185) Google Scholar). GluR5-7 can form functional homomeric or heteromeric receptors, whereas KA1 and KA2 assembly with GluR5-7 subunits is necessary for their intracellular trafficking and formation of functional receptors (3Nasu-Nishimura Y. Hurtado D. Braud S. Tang T.T. Isaac J.T. Roche K.W. J. Neurosci. 2006; 26: 7014-7021Crossref PubMed Scopus (58) Google Scholar, 4Ren Z. Riley N.J. Garcia E.P. Sanders J.M. Swanson G.T. Marshall J. J. Neurosci. 2003; 23: 6608-6616Crossref PubMed Google Scholar, 5Ren Z. Riley N.J. Needleman L.A. Sanders J.M. Swanson G.T. Marshall J. J. Biol. 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Neuron. 2003; 37: 625-638Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 9Jaskolski F. Coussen F. Nagarajan N. Normand E. Rosenmund C. Mulle C. J. Neurosci. 2004; 24: 2506-2515Crossref PubMed Scopus (83) Google Scholar, 10Mehta S. Wu H. Garner C.C. Marshall J. J. Biol. Chem. 2001; 276: 16092-16099Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 11Yan S. Sanders J.M. Xu J. Zhu Y. Contractor A. Swanson G.T. J. Neurosci. 2004; 24: 679-691Crossref PubMed Scopus (50) Google Scholar). Presynaptically, KARs modulate transmitter release at both excitatory and inhibitory synapses and may be involved in long-term synaptic plasticity via PDZ domain interactions (1Lerma J. Curr. Opin. Pharmacol. 2006; 6: 89-97Crossref PubMed Scopus (150) Google Scholar, 2Pinheiro P. Mulle C. Cell Tissue Res. 2006; 326: 457-482Crossref PubMed Scopus (185) Google Scholar). In hippocampal neurons, postsynaptic GluR6-containing KARs mediate a slow excitatory synaptic current (6Ruiz A. Sachidhanandam S. Utvik J.K. Coussen F. Mulle C. J. Neurosci. 2005; 25: 11710-11718Crossref PubMed Scopus (120) Google Scholar, 12Castillo P.E. Malenka R.C. Nicoll R.A. Nature. 1997; 388: 182-186Crossref PubMed Scopus (434) Google Scholar, 13Contractor A. Swanson G. Heinemann S.F. Neuron. 2001; 29: 209-216Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 14Mulle C. Sailer A. Perez-Otano I. Dickinson-Anson H. Castillo P.E. Bureau I. Maron C. Gage F.H. Mann J.R. Bettler B. Heinemann S.F. Nature. 1998; 392: 601-605Crossref PubMed Scopus (402) Google Scholar, 15Vignes M. Collingridge G.L. Nature. 1997; 388: 179-182Crossref PubMed Scopus (364) Google Scholar), and can also enhance excitability through a metabotropic inhibition of a calcium-activated potassium channel (IsAHP) via G-protein and protein kinase C activation (6Ruiz A. Sachidhanandam S. Utvik J.K. Coussen F. Mulle C. J. Neurosci. 2005; 25: 11710-11718Crossref PubMed Scopus (120) Google Scholar, 16Fisahn A. Contractor A. Traub R.D. Buhl E.H. Heinemann S.F. McBain C.J. J. Neurosci. 2004; 24: 9658-9668Crossref PubMed Scopus (174) Google Scholar, 17Fisahn A. Heinemann S.F. McBain C.J. J. Physiol. 2005; 562: 199-203Crossref PubMed Scopus (73) Google Scholar, 18Melyan Z. Lancaster B. Wheal H.V. J. Neurosci. 2004; 24: 4530-4534Crossref PubMed Scopus (82) Google Scholar). Using KAR knock-out mice the metabotropic inhibition of IsAHP was found to be dependent on the KA2 subunit, which interacts with Gq/11 proteins known to be involved in this modulation (6Ruiz A. Sachidhanandam S. Utvik J.K. Coussen F. Mulle C. J. Neurosci. 2005; 25: 11710-11718Crossref PubMed Scopus (120) Google Scholar). KAR degradation is known to involve activity-dependent endocytosis, in which GluR6-containing receptors are sorted for recycling or degradation (19Martin S. Henley J.M. EMBO J. 2004; 23: 4749-4759Crossref PubMed Scopus (89) Google Scholar). Ubiquitination plays an important role in regulating the abundance of many synaptic proteins and destabilizing receptors within the postsynaptic density (20Pak D.T. Sheng M. Science. 2003; 302: 1368-1373Crossref PubMed Scopus (261) Google Scholar, 21Bingol B. Schuman E.M. Nature. 2006; 441: 1144-1148Crossref PubMed Scopus (264) Google Scholar, 22Ehlers M.D. Nat. Neurosci. 2003; 6: 231-242Crossref PubMed Scopus (817) Google Scholar). The selection of substrates for ubiquitination is accomplished by an E3 ligase that consists of a complex of proteins that act together to transfer ubiquitin to the substrate at specific lysine residues. This results in the attachment of a polyubiquitin tag that targets the substrate for proteasomal degradation (23Petroski M.D. Deshaies R.J. Nat. Rev. Mol. Cell. Biol. 2005; 6: 9-20Crossref PubMed Scopus (1661) Google Scholar). Two major families of E3 ligases have been described: the HECT domain family and the RING family, which includes the closely related Cullin proteins, Cul1 and Cul3 (23Petroski M.D. Deshaies R.J. Nat. Rev. Mol. Cell. Biol. 2005; 6: 9-20Crossref PubMed Scopus (1661) Google Scholar). Cullin-based E3 ligases function as large protein complexes. One of the best characterized is the Skp1-Cul1-F box-Roc1 complex, in which Cul1 binds an adaptor molecule, Skp1, via an N-terminal domain, and a small RING finger protein, RBX1/Roc1, via a C-terminal domain (23Petroski M.D. Deshaies R.J. Nat. Rev. Mol. Cell. Biol. 2005; 6: 9-20Crossref PubMed Scopus (1661) Google Scholar). Through Skp1, Cul1 associates with an F-box protein that in turn binds a phosphorylated substrate to target it for degradation. Recent studies show that Cul3 associates with substrate-specific adaptors consisting of an N-terminal BTB motif (from bric a brac, and and a of C-terminal Kelch A. M. EMBO J. 2004; 23: PubMed Scopus Google Scholar, S. Curr. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Actinfilin, an protein of a BTB domain, Kelch domain and a C-terminal PDZ binding motif Y. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. 2005; PubMed Scopus Google Scholar). Using a with the GluR6 C as we actinfilin as a binding Here, we show that actinfilin binds GluR6 and its degradation via the and and used at for The for and The and for The was The was The was and used at The was as an a that was to form of an in the GluR6 the was and used at The for is in Y. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google The was as Cell. Biol. PubMed Scopus Google and used at for and neuronal was The was The fluorescent was for of in the of with the The C of GluR6 was into the acid to the on and with an hippocampal into on and and and for and was the and into The actinfilin and into the Two actinfilin and The levels of interaction with the GluR6 C by the levels of in of of GluR6 and was Heinemann for was the of The actinfilin and its are in Y. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google was The and of The GluR6 with and Swanson The by with and and into the and of the was the by to and in of The was with a and at to The was in an of and a by through of The was at for and the as the Cell and and and to in with with and a and and in with and G. J. Cell Biol. PubMed Scopus Google Scholar). with the for of and transfected with the or S. with the for to or and with and in of The by and at for to at for to the for and with of at The was with of protein for at The with and proteins by in by or and levels in the by substrate and with with with and binding with or on the of the of surface the was for both surface and intracellular was at with the to and to or was a or a The of GluR6 and their of GluR6 with or was Cul3 and for the Cul3 as in M. B. J.M. PubMed Scopus Google Scholar). and in a and This was at at for of was to this which was and The was and an was for a brain The was at to a of the was with of The was in of via or and of GluR6 in brain of and mice and in at for into and in in ubiquitin and which are of the proteasomal with or to the for at The are to bind substrates in The with and by in levels of GluR6 by to and for the of the GluR6 C as for a we the domain protein, actinfilin. was shown to be to the in the and and is in the postsynaptic density Y. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The protein a by a domain, a domain, Kelch domain and a C-terminal PDZ binding Recent that the role of BTB domain-containing proteins is related to protein Cul3 and the E3 ubiquitin-ligase A. M. EMBO J. 2004; 23: PubMed Scopus Google Scholar, S. Curr. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The of actinfilin in postsynaptic of the that actinfilin may be involved in the degradation of proteins involved in neuronal and the interaction actinfilin and GluR6 be in brain we a We found that actinfilin binds GluR6 and in the but with the potassium channel receptor or the receptor subunits and that actinfilin proteins by a or proteins by its we of actinfilin with postsynaptic receptors and proteins in shown in actinfilin binds to GluR6 and but to and the region of actinfilin for the binding to GluR6, we the binding or of the to the activation domain with the C of the domain We that actinfilin and the Kelch the GluR6 C but the domain to However, actinfilin many the Kelch region on that it a The binding data by to the A. N. Nicoll R.A. S. A. 2005; PubMed Scopus Google Scholar). that the Kelch is able to bind GluR6, whereas the and Cul3 actinfilin is a member of the protein family involved in protein it be to bind the for the E3 ubiquitin-ligase complex J. Mol. Cell. Biol. 2004; 24: PubMed Scopus Google Scholar, M. Y. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, A. H. M. Y. T. M. Mol. Cell. Biol. 2004; 24: PubMed Scopus Google Scholar). In actinfilin Cul3 Cul3 Y. J. P. M. Nature. 2003; PubMed Scopus Google Scholar), to interaction with BTB proteins was to bind actinfilin a was also to bind actinfilin. when actinfilin is with its expression is whereas the Cul3 Cul1 on actinfilin levels This that the Cul3 ubiquitin-ligase complex may also the adaptor protein actinfilin as as the The actinfilin-Cul3 as for this protein family, within the The the actinfilin whereas the Kelch the BTB GluR6 the of actinfilin on GluR6 or in we actinfilin and into a the However, for GluR6 was that actinfilin degradation of this kainate receptor This was by the of proteasomal and by of dominant-negative to the GluR6 degradation The was by for GluR6 levels We found that the is by with the proteasomal for to and The a and that actinfilin degradation through proteasomal with we found that of the Cul3 that interaction with BTB proteins, but GluR6 degradation and of ubiquitin which the attachment of ubiquitin elevated GluR6 levels and a we actinfilin the expression of the was GluR6 in GluR6 is in we a GluR6 with an the GluR6, and for the The of GluR6 was However, with the proteasomal for to the of GluR6 in the actinfilin can also be on we that actinfilin is as an GluR6 and the ubiquitination of GluR6 and of the on GluR6 that are for the actinfilin we a of C-terminal GluR6 with in that the and the can bind actinfilin We that a region a is for be that levels of with the of actinfilin as both the and GluR6 expression the binding of actinfilin to receptor degradation. results map the in the region that actinfilin we in the which was to degradation of the to the levels of we receptor levels for the starting protein in the be the that actinfilin reduced GluR6 levels we found that with expression levels and interaction with actinfilin The and GluR6 the degradation with the actinfilin acts as an adaptor to GluR6 to the actinfilin be to the ubiquitination of the of actinfilin on GluR6 we or with and and actinfilin in to proteasomal was to Cell with GFP, and for the of We found that ubiquitination of GluR6 in the of but as for the GluR6 that bind is in the ubiquitination of GluR6 with or actinfilin Cul3 GluR6 is in the we a with reduced Cul3 expression levels M. B. J.M. PubMed Scopus Google Scholar). Cul3 knock-out mice are we used knock-out which have decreased Cul3 expression in the brain but D. and J. D. for and and via to in expression GluR6 levels are increased in brain whereas kainate receptor the N-methyl-d-aspartic acid receptor subunits the receptor subunits and actin levels of GluR6 also by the polyubiquitin binding to M.D. Nat. Neurosci. 2003; 6: 231-242Crossref PubMed Scopus (817) Google Scholar). the levels of GluR6 we synaptic GluR6 levels the and and GluR6 was found in mice as with mice for Cul3 results are with Cul3 a role in regulating GluR6 levels at the and Cul3 as a in GluR6 and Cul3 GluR6 in actinfilin the of GluR6 in neurons, we a small inhibitory RNA to actinfilin or the dominant-negative The surface levels and of both GluR6 and transfected GluR6 of synaptic was by for synaptic and We found that actinfilin levels via increased surface GluR6 expression in as and by increased with PSD-95 and and Synaptic GluR6 and the of the GluR6-containing increased control neurons, neurons, the was in actinfilin levels is in and the actinfilin a also in the of of little GluR6 was in the and with synaptic was and of the dominant-negative Cul3 and our results that degradation may provide an important mechanism for regulating neuronal GluR6 surface expression and, in for regulating GluR6 levels at synapses is for the role of ubiquitination in regulating the number of glutamate receptors and and proteins (20Pak D.T. 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Full Text Full Text PDF PubMed Scopus Google Scholar, I. J. Neurosci. 1998; PubMed Google Scholar). We that actinfilin both the synaptic and the of synaptic GluR6-containing kainate receptor in hippocampal neurons. In the of levels of synaptic GluR6 was However, actinfilin via a specific increased both the synaptic and the of synaptic GluR6-containing kainate receptor as expression of a dominant-negative Recent studies demonstrate that ubiquitination can modulate assembly to control the number of receptors on the J.C. EMBO J. 2004; 23: PubMed Scopus Google Scholar). actinfilin function to regulate assembly of kainate receptors by receptor ubiquitination as of the degradation Cell. Biol. 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However, in the we that the BTB domain and the of the domain, a region that the BTB and Kelch to the domain been to be involved in substrate of this region may the of the Kelch repeat to with GluR6 2004; 29: Full Text Full Text PDF PubMed Scopus Google Scholar). the actinfilin BTB domain may as a domain for substrate binding N. M. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). The function of actinfilin in ubiquitination is with studies that proteins can function as Cul3 adaptors A. M. EMBO J. 2004; 23: PubMed Scopus Google Scholar, M. Y. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, Y. J. P. M. Nature. 2003; PubMed Scopus Google Scholar, S. S. J. Mol. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, Z. M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). which acid to acts as a Cul3 adaptor, for degradation S. C.J. N. Nat. Cell. Biol. 2006; PubMed Scopus Google Scholar), as which targets the J. Mol. 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Shang J. Fukushima T. Fallon J.R. Garner C.C. Marshall J. Neuron. 1998; 21: 727-739Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). are the C-terminal of the GluR6 protein may on to binding to actinfilin. In GluR6 may with PDZ domain proteins to actinfilin binding E.P. Mehta S. Blair L.A.C. Wells D.G. Shang J. Fukushima T. Fallon J.R. Garner C.C. Marshall J. Neuron. 1998; 21: 727-739Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 10Mehta S. Wu H. Garner C.C. Marshall J. J. Biol. Chem. 2001; 276: 16092-16099Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). binding is of an to a acid or of the results in of However, this is in which we can also bind actinfilin. This that the is a of actinfilin it may the binding it may the C-terminal through an interaction of this domain with the The is to a trafficking domain and that includes of such in the GluR6 C known to be S. A. PubMed Scopus Google Scholar). at an the and of of with C. H. M. 2001; PubMed Scopus Google Scholar, A. J. PubMed Google Scholar). the function in GluR6 to the C in a of actinfilin results that in actinfilin is and that its protein levels are by of Cul3 actinfilin whereas of a Cul3 or Cul1 such that actinfilin be with its and F-box and adaptor proteins appear to be by degradation in a Z. M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Here, we of inhibition on actinfilin levels in We also that actinfilin levels in that degradation may provide a for regulating the that Cul3 is reduced but may be a We that KA2 levels in the Cul3 our and others have shown that GluR6 knock-out results in the reduced KA2 to signals that surface expression of KA2 in the of subunits (3Nasu-Nishimura Y. Hurtado D. Braud S. Tang T.T. Isaac J.T. Roche K.W. J. Neurosci. 2006; 26: 7014-7021Crossref PubMed Scopus (58) Google Scholar, 4Ren Z. Riley N.J. Garcia E.P. Sanders J.M. Swanson G.T. Marshall J. J. Neurosci. 2003; 23: 6608-6616Crossref PubMed Google Scholar, J.K. S. J. J. Neurosci. 2004; 24: PubMed Scopus Google Scholar), the of of KA2 levels in the mice the that in actinfilin may the proteasomal degradation of homomeric and BTB-Kelch proteins, such as have been shown to with the actin and interactions with actin are necessary for to regulate levels of A. N. M. S. A. 2004; PubMed Scopus Google Scholar). synaptic activity is known to the of to via an with actin B. Schuman E.M. Nature. 2006; 441: 1144-1148Crossref PubMed Scopus (264) Google Scholar). the actin proteins may regulate actinfilin One may be protein a protein with PDZ and Y. M. 2005; PubMed Scopus Google Scholar, S. H. M. Cell. Full Text Full Text PDF PubMed Scopus Google have shown that binds to the actinfilin C-terminal is also with the density proteins synaptic and for proteins in regulating kainate binding or the trafficking of GluR6 to the degradation in demonstrate that postsynaptic kainate receptors can a metabotropic role and, in neuronal the of kainate excitatory (1Lerma J. Curr. Opin. Pharmacol. 2006; 6: 89-97Crossref PubMed Scopus (150) Google Scholar, 2Pinheiro P. Mulle C. Cell Tissue Res. 2006; 326: 457-482Crossref PubMed Scopus (185) Google Scholar). GluR6 been implicated in excitotoxic neuronal death via activation of a kinase and N-terminal kinase A. Garcia E.P. D. Marshall J. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), and in with with and our data that actinfilin may provide an important for the of GluR6 surface expression. In studies have to GluR6 to kainate death J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, A. T. Marshall J. Chem. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), and that actinfilin may to be a target to control synaptic We Riley in the of this and in the GluR6 that was used to the GluR6 We also and for of Kelch
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