Year: 2004
Type: review
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 Google Scholar, G. Wang S. Biochem. J. 2003; PubMed Scopus Google Scholar). This which in the ER, is necessary for the delivery of the NMDAR to the synapse and that an 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 Google Scholar). Recent work has also implicated MAGUKs (including PSD-95) as molecular to NMDAR modulators into with the for the kinase the domain of MAGUKs A. R.J. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). PSD-95 also the protein to the NMDAR, an interaction that may the in O. N. P. Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). with the of PSD-95 and the NMDAR can M. Y. L. S. M. Wang M. 2002; PubMed Scopus Google Scholar), that studies of interactions may to the of therapeutic for NMDAR proteins interact with NMDARs (as reviewed 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). is which has with a critical for memory formation in its to AMPARs and the synapse J. H. H. Nat. Rev. Neurosci. 2002; PubMed Scopus Google Scholar). a kinase that is necessary for long term potentiation is by calcium J. H. H. Nat. Rev. Neurosci. 2002; PubMed Scopus Google Scholar), and an interaction with the NR2B subunit to stabilize in an P. H. Nature. 2001; PubMed Scopus Google Scholar). The protein is another critical with the NR2B subunit that and kinase of the NMDAR R. K. D. J. Neurosci. 2003; 23: PubMed Google Scholar). The functional of interactions and the of multiple at a single on the NMDAR areas of Although NMDARs are concentrated at the postsynaptic a second of receptors, NMDARs, has been and may have functional from of synaptic receptors. receptors are mediators of whereas synaptic NMDAR G.E. Bading H. Trends Neurosci. 2003; 26: 81-89Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar, R. M. Neurobiol. 2001; PubMed Scopus Google Scholar). and receptors are also regulated in to changes B. N. Luo T. Y. Nat. Neurosci. 2002; 5: PubMed Scopus Google Scholar), the between synaptic and receptors receptors can be through in the from receptors Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). the synaptic and NMDARs in subunit with receptors being mainly whereas synaptic receptors are mainly at both subunits are expressed Fig. G. Vicini S. J. Neurosci. 1999; 19: PubMed Google Scholar, J. Neurosci. 1999; 19: PubMed Google Scholar). The receptor at the synapse are still with AMPA receptors, NMDARs are of the synapse and are not readily in NMDARs also appear to be present at synapses AMPARs R.S. Wang Y.X. Wenthold R.J. Malinow R. Nat. Neurosci. 1999; 2: PubMed Scopus Google Scholar), that are in the of to the block of the a number of have been shown to the number of surface NMDARs suggesting that surface expression of NMDARs in is and to changes in the neuronal changes in the synaptic NMDAR may be to including in NMDAR and between synaptic and regions (as 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 D. A. Nat. Rev. Neurosci. 2003; PubMed Scopus Google Scholar). Fig. 2 present understanding of the role of subunit in NMDAR of receptors is dependent upon glutamate of receptors is not A. Malinow R. Neuron. 2002; 35: 345-353Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). In addition, signaling is critical for changes in subunit of synaptic NMDARs over which to be with in P. G. Nature. 2001; PubMed Scopus Google Scholar). 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 NR2B subunits at the synapse, not A. Malinow R. Neuron. 2002; 35: 345-353Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar), studies 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). the of is a critical of the subunit of NMDARs expressed at the synapse K. A. G. H. J. Neurosci. PubMed Google Scholar). The presence of individual NMDARs containing multiple NR2 subunits likely of they are in neurons, with G. Vicini S. J. Neurosci. 1999; 19: PubMed Google Scholar, J. Neurosci. 1999; 19: PubMed Google Scholar) and A.W. J. 2003; PubMed Scopus Google Scholar) that they be in the synaptic of NMDAR synaptic activity increases NMDAR number at the synapse Neuron. 2000; 26: Full Text Full Text PDF PubMed Scopus Google in mature 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 or glycine synaptic delivery A. Malinow R. Neuron. 2002; 35: 345-353Abstract Full Text Full Text PDF PubMed Scopus (413) Google NMDARs for Y. G. Wang Nature. 2003; PubMed Scopus Google increases surface expression of NMDARs in J. Zukin R.S. Bennett M.V.L. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google potentiation of J. 2000; PubMed Scopus Google glutamate receptors NMDARs in E.M. J.R. Nat. Neurosci. 2001; PubMed Scopus Google increases surface NMDARs in T. Bennett Zukin R.S. J. Neurosci. 2001; 21: PubMed Google NMDA with complex T. Y. R.C. Bennett M.V.L. Zukin R.S. Nat. Neurosci. 2001; PubMed Scopus Google Scholar) (reviewed in Ref. Curr. Drug Targets. 2001; 2: PubMed Scopus Google in the C1 cassette increases surface NR1 (15Scott D.B. Blanpied T.A. Swanson G.T. Zhang C. Ehlers M.D. J. Neurosci. 2001; 21: 3063-3072Crossref PubMed Google NMDAR from synaptic to sites in A. J. Neurosci. 2002; 22: PubMed Google in Y. Y. K. K. M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (74) Google of kinase on NMDARs have been reviewed Curr. Opin. Neurobiol. 2001; 11: PubMed Scopus Google NMDARs into A.W. J. Neurosci. 2001; 21: PubMed Google of in NR2A NMDAR B. Nat. Neurosci. 2001; PubMed Scopus Google NMDAR B. N. Luo T. Y. Nat. Neurosci. 2002; 5: PubMed Scopus Google Scholar) in a there is a specific mechanism for NMDARs to the synapse is still not The recent that the NMDAR is with the exocyst complex (as and that with this interaction 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 Google Scholar) may outline a process of regulated delivery to the In addition, of the protein to a multiprotein complex containing the NR2B subunit is critical for delivery of receptors to the may only regulate delivery of NMDARs to the of the synapse (27Guillaud L. Setou M. Hirokawa N. J. Neurosci. 2003; 23: 131-140Crossref PubMed Google Scholar). the interaction of NMDARs with both the exocyst and has been shown for the NR2B the of NR2A trafficking is similar to that of NR2B and individual NMDARs with multiple NR2 subunits of to animals changes synaptic subunit in a process for of receptors into the synapse Neuron. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The mechanism of and NMDARs a of critical in the synaptic is a common mechanism used to regulate the number of ion channels that are present on the sites have been implicated in the of NR2 subunits. The first is in the C terminus to the domain in with a similar present in all NR2 subunits as well as of this to and B. Nat. Neurosci. 2001; PubMed Scopus Google Scholar). The second is the distal C terminus of NR2B, with a similar present in containing the NR2B C terminus are on the cell surface by of implying that an interaction with is involved in receptor K.W. Standley S. McCallum J. Ehlers M.D. Wenthold R.J. Nat. Neurosci. 2001; PubMed Scopus Google Scholar). of the NR2 C terminus with PSD-95 also suggesting that of the receptor on the cell surface is another of the NMDAR/MAGUK interaction K.W. Standley S. McCallum J. Ehlers M.D. Wenthold R.J. Nat. Neurosci. 2001; PubMed Scopus Google Scholar). The of the NMDAR to synaptic has been for more two only have the been to the that regulate the expression of functional receptors at the that appear from the at the synapse, as the assembly of subunits in the ER, are critical because the properties of the receptor are by the subunit The trafficking of the receptors to the synapse and organization at the synapse appear to on two of the receptor and its interaction with As for a a key role at the synapse, multiple interacting proteins are and the of the interactions with proteins are
Source: Journal of Biological Chemistry
Authors: Kate Prybylowski, Robert J. Wenthold
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2054661844