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• W2054661844 abstract "NMDA 1The abbreviations used are: NMDA, N-methyl-d-aspartate; NMDAR, NMDA receptor; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; ER, endoplasmic reticulum; AMPAR, AMPA receptor; MAGUK, membrane-associated guanylate kinase; PSD, postsynaptic density; PKC, protein kinase C. receptors (NMDARs) are members of the glutamate receptor family of ion channels, which also includes the AMPA, kainate, and delta subtypes of receptors. NMDARs are present at excitatory synapses in the mammalian central nervous system and have specialized characteristics, including voltage-dependent block by magnesium, calcium permeability, and slow deactivation kinetics (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). Biophysical studies of NMDARs outline a complex pharmacology with multiple modulatory sites (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). Calcium entry through the NMDAR regulates numerous downstream signaling pathways leading to both short term and long term neuronal changes (recently reviewed in Ref. 2Hardingham G.E. Bading H. Trends Neurosci. 2003; 26: 81-89Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar). This calcium flux is also necessary for inducing long term potentiation, a molecular model of memory (3Nicoll R.A. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003; 358: 721-726Crossref PubMed Scopus (160) Google Scholar), suggesting that NMDARs are key players in memory formation and synaptic plasticity. In addition, NMDAR dysfunction is implicated in numerous neurologic and psychiatric disorders, and therapeutic agents that target NMDARs have been studied. The present review will focus on the subunit assembly and trafficking of NMDA receptors, areas of significant progress in recent years. The NMDAR family is made up of NR1, NR2, and NR3 subunits. Functional NMDARs are heteromeric complexes containing both NR1 and NR2 subunits (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). NR3 subunits can assemble with NR1-NR2 complexes to depress NMDAR responses and can also assemble with NR1 alone to form a glycine receptor, with the role of this receptor in the central nervous system still unclear (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). The structure of the NMDAR is outlined in Fig. 1. There is a single NR1 subunit that can exist in eight different variants generated by alternative splicing at three sites within the protein, one in the N terminus and two in the C terminus (4Carroll R.C. Zukin R.S. Trends Neurosci. 2002; 25: 571-577Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar). The N-terminal cassette (the N1 cassette or exon 5) is extracellular and affects regulation of the channel with modulators like protons and spermine (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar), whereas the C-terminal cassettes are mediators of protein interactions (4Carroll R.C. Zukin R.S. Trends Neurosci. 2002; 25: 571-577Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar). Splicing in the C terminus regulates expression of three different cassettes, the C1, C2, and C2′ cassettes (as shown in Fig. 1). NR1 subunits can be formed either containing or lacking the C1 cassette. If the C2 cassette is absent, the first stop codon is lost and the separate C2′ cassette is expressed in the subunit instead. Therefore, all NR1 contains either the C2 or C2′ cassette. The C1 cassette contains an endoplasmic reticulum (ER) retention signal, which can be overcome by expression of the C2′ cassette, suggesting that splicing of the C-terminal tail of NR1 may regulate receptor trafficking (as reviewed in Refs. 4Carroll R.C. Zukin R.S. Trends Neurosci. 2002; 25: 571-577Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar and 5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar). Alternatively spliced forms of NR1 have different regional and developmental expression profiles (6Zukin R.S. Bennett M.V.L. Trends Neurosci. 1995; 18: 306-313Abstract Full Text PDF PubMed Scopus (403) Google Scholar) and are regulated by neuronal activity (7Mu Y. Otsuka T. Horton A.C. Scott D.B. Ehlers M.D. Neuron. 2003; 40: 581-594Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar), generating a large degree of channel diversity. NR2 subunits contain the glutamate-binding site, and four genes encoding NR2 subunits (NR2A–D) have been cloned. The specific NR2 subunits within the receptor complex regulate NMDAR properties in heterologous cells (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar, 5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar, 8Stephenson F.A. Curr. Drug Targets. 2001; 2: 233-239Crossref PubMed Scopus (74) Google Scholar). NR2A and NR2B (which form high conductance channels) are highly expressed in the mammalian forebrain (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). NR2B subunit expression predominates early in development, whereas NR2A expression increases with development (8Stephenson F.A. Curr. Drug Targets. 2001; 2: 233-239Crossref PubMed Scopus (74) Google Scholar). As the NR2A subunit produces NMDARs with the fastest kinetics, the increasing speed of NMDAR current decay kinetics over development is likely because of its increased expression (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). The NR2C subunit expression is confined mainly to the mature cerebellum, whereas the NR2D subunit is most highly expressed in the young thalamus (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). Regional and developmental regulation of NR2 subunit expression underlies much of the diversity of NMDAR responses in the central nervous system (5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar, 8Stephenson F.A. Curr. Drug Targets. 2001; 2: 233-239Crossref PubMed Scopus (74) Google Scholar). Functional NMDA receptors contain at least 2 glutamate-binding sites and 2 glycine-binding sites, implying a minimum of 4 subunits within the functional channel (1Cull-Candy S. Brickley S. Farrant M. Curr. Opin. Neurobiol. 2001; 11: 327-335Crossref PubMed Scopus (1414) Google Scholar). NMDARs can also assemble with 2 different NR1 splice isoforms and 2 different NR2 subunits (5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar). Studies on the AMPA receptor (AMPAR), another member of the ionotropic glutamate receptor family, give insights into the structure of the NMDA receptor. Crystallographic analysis coupled with electrophysiologic studies indicates a tetrameric structure of the AMPARs formed by GluR2 composed of a dimer of dimers (9Sun Y. Olson R. Horning M. Armstrong N. Mayer M. Gouaux E. Nature. 2002; 417: 245-253Crossref PubMed Scopus (599) Google Scholar). In the NMDAR, regions of NR2 and NR1 subunits necessary for transmitting allosteric signals between the glutamate and glycine-binding sites are analogous to the areas of dimer interactions in AMPARs (10Regalado M.P. Villarroel A. Lerma J. Neuron. 2001; 32: 1085-1096Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar), suggesting that NMDARs have a similar dimerdimer interaction. The properties of NMDAR tandems (with a fusion of NR1 and NR2 subunits) also support the idea of the channel being formed of a dimer of dimers (an NR1 dimer and an NR2 dimer) (11Schorge S. Colquhoun D. J. Neurosci. 2003; 23: 1151-1158Crossref PubMed Google Scholar). Therefore, the preponderance of evidence now indicates that functional NMDAR complexes are tetramers of 2 NR1 and 2 NR2 subunits, with an evolutionary link between glutamate receptors and K+ channels (12Kuner T. Seeburg P.H. Guy H.R. Trends Neurosci. 2003; 26: 27-32Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). The actual process of assembly of the individual subunits into the functional channel is not yet well characterized; however, critical residues are known to be located in the N terminus of the receptor (13McIlhinney R.A. Philipps E. Le Bourdelles B. Grimwood S. Wafford K. Sandhu S. Whiting P. Biochem. Soc. Trans. 2003; 31: 865-868Crossref PubMed Scopus (38) Google Scholar). Retention in the ER is a common quality control mechanism to block surface delivery of proteins that are not properly assembled or folded. When expressed alone in heterologous systems, NR2 subunits are retained in the ER (14McIlhinney R.A. Le Bourdelles B. Molnar E. Tricaud N. Streit P. Whiting P.J. Neuropharmacology. 1998; 37: 1355-1367Crossref PubMed Scopus (134) Google Scholar). The ER retention of NR1 subunits is dependent upon splicing, with only the NR1–1 splice variant (which contains the C1 and C2 cassettes) being ER retained. The C1 cassette of NR1 contains an RRR sequence, resulting in retention of unassembled NR1–1 (15Scott D.B. Blanpied T.A. Swanson G.T. Zhang C. Ehlers M.D. J. Neurosci. 2001; 21: 3063-3072Crossref PubMed Google Scholar, 16Standley S. Roche K.W. McCallum J. Sans N. Wenthold R.J. Neuron. 2000; 28: 887-898Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, 17Xia H. Hornby Z.D. Malenka R.C. Neuropharmacology. 2001; 41: 714-723Crossref PubMed Scopus (103) Google Scholar). NR1–3 (which contains the C1 and C2′ cassettes) is not retained because the presence of the C2′ cassette overcomes the ER retention of the C1 cassette. The PDZ-binding domain of the C2′ cassette (-STVV) (15Scott D.B. Blanpied T.A. Swanson G.T. Zhang C. Ehlers M.D. J. Neurosci. 2001; 21: 3063-3072Crossref PubMed Google Scholar, 16Standley S. Roche K.W. McCallum J. Sans N. Wenthold R.J. Neuron. 2000; 28: 887-898Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, 17Xia H. Hornby Z.D. Malenka R.C. Neuropharmacology. 2001; 41: 714-723Crossref PubMed Scopus (103) Google Scholar) is required for overcoming ER retention of C1, suggesting that a PDZ protein may interact with the NR1 subunit while it is in the ER and promote exit from the ER. Neurons have a large pool of unassembled, intracellular NR1 subunits, whereas most NR2 subunits are assembled with NR1 and are present on the cell surface (5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar). Overexpression of NR2 subunits by transfection increases the number of surface NMDA channels in cerebellar granule cells (18Prybylowski K. Fu Z. Losi G. Hawkins L.M. Luo J. Chang K. Wenthold R.J. Vicini S. J. Neurosci. 2002; 22: 8902-8910Crossref PubMed Google Scholar), suggesting that the production of functional NMDA receptors is limited, at least in part, by the availability of NR2 subunits. Functional NMDARs formed with NR1 splice variants that lack ER retention motifs are more readily expressed on the cell surface (19Okabe S. Miwa A. Okado H. J. Neurosci. 1999; 19: 7781-7792Crossref PubMed Google Scholar), and long term potentiation in older animals may be dependent upon changes in trafficking of NMDARs containing the C2 cassette (20Grosshans D.R. Clayton D.A. Coultrap S.J. Browning M.D. Nat. Neurosci. 2002; 5: 27-33Crossref PubMed Scopus (303) Google Scholar). Recent work also suggests activity-dependent changes in NR1 splicing at the C2/C2′ site, with the switch to forms containing C2′ increasing the speed of exit of assembled complexes out of the ER (7Mu Y. Otsuka T. Horton A.C. Scott D.B. Ehlers M.D. Neuron. 2003; 40: 581-594Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). An understanding of trafficking of proteins in neurons, however, is complicated by the possibility of local protein synthesis in the dendrite (21Steward O. Schuman E.M. Neuron. 2003; 40: 347-359Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar). Trafficking of proteins produced in this manner has not yet been well characterized. NMDARs interact with numerous proteins, which affect the functional properties, trafficking, and synaptic organization of the receptor. One of the most highly studied interactions of the NMDAR is with membrane-associated guanylate kinases (MAGUKs) (reviewed in Refs. 22Hung A.Y. Sheng M. J. Biol. Chem. 2002; 277: 5699-5702Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar and 23McGee A.W. Bredt D.S. Curr. Opin. Neurobiol. 2003; 13: 111-118Crossref PubMed Scopus (83) Google Scholar). MAGUKs are a family of proteins (including SAP102, SAP97, PSD-93, and PSD-95) that are highly expressed in neurons, contain multiple protein-protein interacting domains, and appear to play a role in scaffolding of the postsynaptic density (PSD) (22Hung A.Y. Sheng M. J. Biol. Chem. 2002; 277: 5699-5702Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar, 23McGee A.W. Bredt D.S. Curr. Opin. Neurobiol. 2003; 13: 111-118Crossref PubMed Scopus (83) Google Scholar). The NMDAR/MAGUK interaction is mediated by the PDZ-binding domain of the NR2 subunit (-ESDV, which is found on the extreme distal region of NR2A and NR2B, or -ESEV on NR2C and NR2D) and the first and second PDZ domains of MAGUKS (22Hung A.Y. Sheng M. J. Biol. Chem. 2002; 277: 5699-5702Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar, 23McGee A.W. Bredt D.S. Curr. Opin. Neurobiol. 2003; 13: 111-118Crossref PubMed Scopus (83) Google Scholar). Although the NR2A and NR2B subunits contain identical PDZ-binding domains, there are indications of preferences for MAGUK interactions between NR2A and NR2B (24Townsend M. Yoshii A. Mishina M. Constantine-Paton M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 1340-1345Crossref PubMed Scopus (90) Google Scholar). NR2 subunits lacking the PDZ-binding domain show decreased expression at the synapse, suggesting that MAGUKs stabilize NMDARs at the synapse (18Prybylowski K. Fu Z. Losi G. Hawkins L.M. Luo J. Chang K. Wenthold R.J. Vicini S. J. Neurosci. 2002; 22: 8902-8910Crossref PubMed Google Scholar, 25Barria A. Malinow R. Neuron. 2002; 35: 345-353Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). Although they are concentrated at the PSD and are generally thought to anchor NMDARs, there is increasing evidence that MAGUKs are also involved in earlier trafficking of NMDARs. PSD-95 associates directly with the kinesin KIF1B and may be involved in NMDAR trafficking (26Mok H. Shin H. Kim S. Lee J.R. Yoon J. Kim E. J. Neurosci. 2002; 22: 5253-5258Crossref PubMed Google Scholar). mLin10 (a PDZ-containing protein) works as a scaffold linking the NR2B subunit with KIF17, another kinesin motor, through a multiprotein complex critical for NR2B delivery to the synapse (27Guillaud L. Setou M. Hirokawa N. J. Neurosci. 2003; 23: 131-140Crossref PubMed Google Scholar). MAGUKs also interact with Sec8, a protein of the exocyst complex, through a PDZ interaction (28Sans N. Prybylowski K. Petralia R.S. Chang K. Wang Y.X. Racca C. Vicini S. Wenthold R.J. Nat. Cell Biol. 2003; 5: 520-530Crossref PubMed Scopus (265) Google Scholar, 29Riefler G.M. Balasingam G. Lucas K.G. Wang S. Hsu S.C. Firestein B.L. Biochem. J. 2003; 373: 49-55Crossref PubMed Scopus (35) Google Scholar). This interaction, which begins in the ER, is necessary for the delivery of the NMDAR to the synapse and shows that an exocyst-MAGUK-NMDAR complex forms early in the delivery of NMDARs (28Sans N. Prybylowski K. Petralia R.S. Chang K. Wang Y.X. Racca C. Vicini S. Wenthold R.J. Nat. Cell Biol. 2003; 5: 520-530Crossref PubMed Scopus (265) Google Scholar). Recent work has also implicated MAGUKs (including PSD-95) as molecular adaptors to bring NMDAR modulators into close proximity with the channel; for example, the kinase Pyk2 binds the SH3 domain of MAGUKs (30Seabold G.K. Burette A. Lim I.A. Weinberg R.J. Hell J.W. J. Biol. Chem. 2003; 278: 15040-15048Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). PSD-95 also links the protein huntingtin to the NMDAR, an interaction that may underlie the excitotoxicity seen in Huntington's disease models (31Zeron M.M. Hansson O. Chen N. Wellington C.L. Leavitt B.R. Brundin P. Hayden M.R. Raymond L.A. Neuron. 2002; 33: 849-860Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar). Interfering with the association of PSD-95 and the NMDAR can reduce ischemic brain damage (32Aarts M. Liu Y. Liu L. Besshoh S. Arundine M. Gurd J.W. Wang Y.T. Salter M.W. Tymianski M. Science. 2002; 298: 846-850Crossref PubMed Scopus (840) Google Scholar), indicating that studies of MAGUK/NMDAR interactions may yield novel approaches to the design of therapeutic drugs for modulating NMDAR function. Numerous other proteins interact with NMDARs (as reviewed recently in Ref. 5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar). Of particular interest is CaMKII, which has characteristics consistent with a molecule critical for memory formation in its ability to modulate AMPARs and organize the synapse (33Lisman J. Schulman H. Cline H. Nat. Rev. Neurosci. 2002; 3: 175-190Crossref PubMed Scopus (1493) Google Scholar). CaMKII, a serine/threonine kinase that is necessary for long term potentiation induction, is activated by NMDAR-mediated calcium influx (33Lisman J. Schulman H. Cline H. Nat. Rev. Neurosci. 2002; 3: 175-190Crossref PubMed Scopus (1493) Google Scholar), and an interaction with the NR2B subunit appears to stabilize CaMKII in an active conformation (34Bayer K.U. De Koninck P. Leonard A.S. Hell J.W. Schulman H. Nature. 2001; 411: 801-805Crossref PubMed Scopus (578) Google Scholar). The protein RACK1 is another critical interactor with the NR2B subunit that controls ethanol and Fyn kinase modulation of the NMDAR (35Yaka R. Phamluong K. Ron D. J. Neurosci. 2003; 23: 3623-3632Crossref PubMed Google Scholar). The functional significance of these interactions and the interplay of multiple binding partners at a single site on the NMDAR remain active areas of research. Although NMDARs are concentrated at the postsynaptic membrane, a second population of receptors, extrasynaptic NMDARs, has been identified and may have important functional roles distinct from those of synaptic receptors. For example, extrasynaptic receptors are important mediators of excitotoxicity, whereas synaptic NMDAR activation appears neuroprotective (2Hardingham G.E. Bading H. Trends Neurosci. 2003; 26: 81-89Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar, 36Sattler R. Tymianski M. Mol. Neurobiol. 2001; 24: 107-129Crossref PubMed Scopus (467) Google Scholar). Synaptic and extrasynaptic receptors are also differentially regulated in response to phosphorylation changes (37Li B. Chen N. Luo T. Otsu Y. Murphy T.H. Raymond L.A. Nat. Neurosci. 2002; 5: 833-834Crossref PubMed Scopus (137) Google Scholar), but the relationship between synaptic and extra-synaptic receptors remains unclear. Synaptic receptors can be replaced rapidly through lateral diffusion in the plasma membrane, presumably from extrasynaptic receptors (38Tovar K.R. Westbrook G.L. Neuron. 2002; 34: 255-264Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar). On the other hand, synaptic and extrasynaptic NMDARs differ in their subunit compositions, with extrasynaptic receptors being mainly NR2B-containing whereas synaptic receptors are mainly NR2A-containing at ages when both subunits are expressed (see Fig. 2) (39Rumbaugh G. Vicini S. J. Neurosci. 1999; 19: 10603-10610Crossref PubMed Google Scholar, 40Tovar K.R. Westbrook G.L. J. Neurosci. 1999; 19: 4180-4188Crossref PubMed Google Scholar). The rules governing receptor localization at the synapse are still unclear. Compared with AMPA receptors, NMDARs are stable components of the synapse and are not readily changed in number. NMDARs also appear to be present at immature synapses before AMPARs (41Petralia R.S. Esteban J.A. Wang Y.X. Partridge J.G. Zhao H.M. Wenthold R.J. Malinow R. Nat. Neurosci. 1999; 2: 31-36Crossref PubMed Scopus (419) Google Scholar), producing “silent synapses” that are inactive in the absence of sufficient depolarization to remove the magnesium block of the NMDAR. However, a number of manipulations have been shown to alter the number of surface NMDARs (Table I), suggesting that surface expression of NMDARs in vivo is plastic and subject to changes in the neuronal environment. Specific changes in the synaptic NMDAR population may be due to several mechanisms, including differences in NMDAR delivery, internalization, and movement between synaptic and extrasynaptic regions (as recently reviewed in Refs. 5Wenthold R.J. Prybylowski K. Standley S. Sans N. Petralia R.S. Annu. Rev. Pharmacol. Toxicol. 2003; 43: 335-358Crossref PubMed Scopus (293) Google Scholar and 42Choquet D. Triller A. Nat. Rev. Neurosci. 2003; 4: 251-265Crossref PubMed Scopus (338) Google Scholar). Fig. 2 summarizes our present understanding of the role of subunit composition in NMDAR trafficking. Synaptic insertion of NR2A/NR1 receptors is dependent upon glutamate binding, although insertion of NR2B/NR1 receptors is not (25Barria A. Malinow R. Neuron. 2002; 35: 345-353Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). In addition, integrin signaling is critical for changes in subunit composition of synaptic NMDARs over maturation, which appears to be coordinated with decreases in presynaptic release probability (43Chavis P. Westbrook G. Nature. 2001; 411: 317-321Crossref PubMed Scopus (277) Google Scholar). Decreasing the number of synaptic NR2B subunits increases the number of synaptic NR2A subunits (27Guillaud L. Setou M. Hirokawa N. J. Neurosci. 2003; 23: 131-140Crossref PubMed Google Scholar). There is also evidence that NR2A subunits can replace NR2B subunits at the synapse, but not vice versa (25Barria A. Malinow R. Neuron. 2002; 35: 345-353Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar), although studies differ on this (18Prybylowski K. Fu Z. Losi G. Hawkins L.M. Luo J. Chang K. Wenthold R.J. Vicini S. J. Neurosci. 2002; 22: 8902-8910Crossref PubMed Google Scholar). Interestingly, the type of presynaptic neuron is a critical determinant of the subunit composition of NMDARs expressed at the synapse (44Gottmann K. Mehrle A. Gisselmann G. Hatt H. J. Neurosci. 1997; 17: 2766-2774Crossref PubMed Google Scholar). The presence of individual NMDARs containing multiple NR2 subunits (most likely NR1/NR2A/NR2B) raises interesting questions of how they are trafficked in neurons, with physiological (39Rumbaugh G. Vicini S. J. Neurosci. 1999; 19: 10603-10610Crossref PubMed Google Scholar, 40Tovar K.R. Westbrook G.L. J. Neurosci. 1999; 19: 4180-4188Crossref PubMed Google Scholar) and biochemical (45Dunah A.W. Standaert D.G. J. Neurochem. 2003; 85: 935-943Crossref PubMed Scopus (76) Google Scholar) suggestions that they might be preferentially stabilized in the synaptic pool.Table IModulators of NMDAR localizationActivityBlocking synaptic activity increases NMDAR number at the synapse (49Watt A.J. van Rossum M.C. MacLeod K.M. Nelson S.B. Turrigiano G.G. Neuron. 2000; 26: 659-670Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar)LTP in mature rats increases surface NMDAR number (20Grosshans D.R. Clayton D.A. Coultrap S.J. Browning M.D. Nat. Neurosci. 2002; 5: 27-33Crossref PubMed Scopus (303) Google Scholar)Agonist bindingGlutamate or glycine antagonists inhibit synaptic NR1/NR2A delivery (25Barria A. Malinow R. Neuron. 2002; 35: 345-353Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar)Glycine primes NMDARs for internalization (50Nong Y. Huang Y.Q. Ju W. Kalia L.V. Ahmadian G. Wang Y.T. Salter M.W. Nature. 2003; 422: 302-307Crossref PubMed Scopus (357) Google Scholar)InsulinInsulin increases surface expression of NMDARs in oocytes (51Skeberdis V.A. Lan J. Zheng X. Zukin R.S. Bennett M.V.L. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3561-3566Crossref PubMed Scopus (268) Google Scholar)PSD-95 coexpression eliminates insulin potentiation of NR1/NR2A (52Liao G.Y. Kreitzer M.A. Sweetman B.J. Leonard J.P. J. Neurochem. 2000; 75: 282-287Crossref PubMed Scopus (45) Google Scholar)Metabotropic glutamate receptors (mGluRs)Group I mGluR stimulation internalizes NMDARs in neurons (53Snyder E.M. Philpot B.D. Huber K.M. Dong X. Fallon J.R. Bear M.F. Nat. Neurosci. 2001; 4: 1079-1085Crossref PubMed Scopus (460) Google Scholar)Group I mGluR stimulation increases surface NMDARs in oocytes (54Lan J.Y. Skeberdis V.A. Jover T. Zheng X. Bennett M.V. Zukin R.S. J. Neurosci. 2001; 21: 6058-6068Crossref PubMed Google Scholar)PKCPKC potentiates NMDA currents but with complex effects (55Lan J.Y. Skeberdis V.A. Jover T. Grooms S.Y. Lin Y. Araneda R.C. Zheng X. Bennett M.V.L. Zukin R.S. Nat. Neurosci. 2001; 4: 382-390Crossref PubMed Scopus (369) Google Scholar) (reviewed in Ref. 56MacDonald J.F. Kotecha S.A. Lu W.Y. Jackson M.F. Curr. Drug Targets. 2001; 2: 299-312Crossref PubMed Scopus (92) Google Scholar)PKC phosphorylation in the C1 cassette increases surface NR1 constructs (15Scott D.B. Blanpied T.A. Swanson G.T. Zhang C. Ehlers M.D. J. Neurosci. 2001; 21: 3063-3072Crossref PubMed Google Scholar)PKC moves NMDAR from synaptic to extrasynaptic sites in neurons (57Fong D.K. Rao A. Crump F.T. Craig A.M. J. Neurosci. 2002; 22: 2153-2164Crossref PubMed Google Scholar)PSD-95 attenuates PKC effects in oocytes (58Yamada Y. Chochi Y. Takamiya K. Sobue K. Inui M. J. Biol. Chem. 1999; 274: 6647-6652Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar)Tyrosine phosphorylationMultiple effects of Src kinase on NMDARs have been recently reviewed (59Ali D.W. Salter M.W. Curr. Opin. Neurobiol. 2001; 11: 336-342Crossref PubMed Scopus (278) Google Scholar)In striatum, tyrosine phosphorylation moves NMDARs into synaptosomes (60Dunah A.W. Standaert D.G. J. Neurosci. 2001; 21: 5546-5558Crossref PubMed Google Scholar)Dephosphorylation of Tyr-842 in NR2A promotes NMDAR rundown (47Vissel B. Krupp J.J. Heinemann S.F. Westbrook G.L. Nat. Neurosci. 2001; 4: 587-596Crossref PubMed Scopus (217) Google Scholar)Tyrosine dephosphorylation causes extrasynaptic NMDAR rundown (37Li B. Chen N. Luo T. Otsu Y. Murphy T.H. Raymond L.A. Nat. Neurosci. 2002; 5: 833-834Crossref PubMed Scopus (137) Google Scholar) Open table in a new tab Whether there is a specific mechanism for delivering NMDARs to the synapse is still not clear. The recent discovery that the NMDAR is associated with the exocyst complex (as discussed above) and that interfering with this interaction decreases synaptic NMDAR responses (28Sans N. Prybylowski K. Petralia R.S. Chang K. Wang Y.X. Racca C. Vicini S. Wenthold R.J. Nat. Cell Biol. 2003; 5: 520-530Crossref PubMed Scopus (265) Google Scholar) may outline a process of regulated delivery to the synapse. In addition, binding of the motor protein KIF17 to a multiprotein complex containing the NR2B subunit is critical for delivery of NR2B-containing receptors to the dendrite, although KIF17 may only regulate delivery of NMDARs to the periphery of the synapse (27Guillaud L. Setou M. Hirokawa N. J. Neurosci. 2003; 23: 131-140Crossref PubMed Google Scholar). Interestingly, the interaction of NMDARs with both the exocyst and KIF17 has been shown for the NR2B subunit, so the questions of whether NR2A trafficking is similar to that of NR2B and how individual NMDARs with multiple NR2 subunits traffic remain unanswered. Introduction of light stimuli to dark-reared animals quickly changes synaptic subunit composition in rats, indicating a process allowing for very rapid movement of NR2A-containing receptors into the synapse (46Philpot B.D. Sekhar A.K. Shouval H.Z. Bear M.F. Neuron. 2001; 29: 157-169Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar). The mechanism of how neurons differentially traffic NR2A- and NR2B-containing NMDARs remains a basic question of critical importance in shaping the synaptic response. Endocytosis is a common mechanism used to regulate the number of ion channels that are present on the plasma membrane. Two sites have been implicated in the clathrin-mediated internalization of NR2 subunits. The first is in the C terminus close to the last transmembrane domain (Tyr-842 in NR2A) with a similar motif present in all NR2 subunits as well as NR1. Dephosphorylation of this tyrosine leads to AP-2 binding and clathrin-mediated endocytosis (47Vissel B. Krupp J.J. Heinemann S.F. Westbrook G.L. Nat. Neurosci. 2001; 4: 587-596Crossref PubMed Scopus (217) Google Scholar). The second site is near the distal C terminus (Tyr-1472 of NR2B, with a similar motif present in NR2A). Constructs containing the NR2B C terminus are stabilized on the cell surface by loss of Tyr-1472, implying that an interaction with AP-2 is involved in receptor internalization (48Roche K.W. Standley S. McCallum J. Ly D.C. Ehlers M.D. Wenthold R.J. Nat. Neurosci. 2001; 4: 794-802Crossref PubMed Scopus (440) Google Scholar). Interaction of the NR2 C terminus with PSD-95 also decreases internalization suggesting that stabilization of the receptor on the cell surface is another important function of the NMDAR/MAGUK interaction (48Roche K.W. Standley S. McCallum J. Ly D.C. Ehlers M.D. Wenthold R.J. Nat. Neurosci. 2001; 4: 794-802Crossref PubMed Scopus (440) Google Scholar). The importance of the NMDAR to synaptic function has been recognized for more than two decades but only recently have the tools been available to investigate the mechanisms that regulate the expression of functional receptors at the synapse. Events that appear distant from the ultimate function at the synapse, such as the assembly of subunits in the ER, are critical because the properties of the receptor are determined by the subunit composition. The trafficking of the receptors to the synapse and their organization at the synapse appear to depend on two major factors, phosphorylation of the receptor and its interaction with other proteins. As expected for a molecule playing a key role at the synapse, multiple interacting proteins are emerging, and the determination of how the various interactions with these proteins are coordinated lies ahead." @default.
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• W2054661844 title "N-Methyl-D-aspartate Receptors: Subunit Assembly and Trafficking to the Synapse" @default.
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