Assembly and cell surface presentation of NMDA receptors (Homo sapiens)

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1, 3-12, 14...16422416endoplasmic reticulum membranecytosoltransport vesicle membraneCASK CAMK2G GRIN1 DLG4 GRIN1:GRIN3Bdi-heterotetramerGRIN2B ACTN2 DLG3 APBA1 GRIN2A DLG1 GRIN2B GRIN2B GRIN2A NEFLGRIN1DLG2 ADPGRIN2A ACTN2 NBEAGRIN1:GRIN2A:GRIN2Ctri-heterotetramerGRIN1:GRIN2Bdi-heterotetramerGRIN2B GRIN3A GRIN1:GRIN2 NMDAreceptorsLRRC7NBEA:DLG3GRIN2A GRIN2C GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers GRIN2CCASK GRIN1 DLG2 DLG4 GRIN3B GRIN3AGRIN1 DLG3GRIN2A GRIN1:GRIN2A,C,Ddi-heteromers,GRIN1:GRIN2tri-heteromersLIN7C DLG1 GRIN1 CAMK2D GRIN2A LIN7:CASK:APBA1ATPDLG1 GRIN3BGRIN2D LRRC7 GRIN1:GRIN2Bdi-heterotetramerGRIN1:GRIN2NMDAreceptors:DLG4:DLG1,DLG2,DLG3,DLG4GRIN2A GRIN1 DLG3 GRIN1 GRIN2A GRIN1 DLG3 GRIN3A GRIN1 GRIN2A GRIN2B CAMK2B GRIN1 GRIN1 GRIN2D GRIN1 GRIN2B GRIN3B DLG1 GRIN1:GRIN2A:GRIN2Dtri-heterotetramerGRIN2D ACTN2 CAMK2A GRIN1 KIF17 dimerMicrotubule protofilament GRIN1 GRIN2B GRIN1:GRIN2A:GRIN3Atri-heterotetramerDLG1 GRIN1:GRIN2A:GRIN2Btri-heterotetramerGRIN2B DLG1,DLG2,DLG3,DLG4PiGRIN3A GRIN2B MicrotubuleGRIN1:GRIN3di-heteromers,(GRIN1:GRIN2:GRIN3 tri-heteromers)Microtubule protofilament Activation of NMDAreceptors andpostsynaptic eventsNEFL NBEA DLG3 LIN7A LIN7A GRIN1:GRIN2Cdi-heterotetramerGRIN1 GRIN2A GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers GRIN1 DLG4 CAMK2G GRIN1 GRIN1:GRIN2NMDAreceptors:DLG4:DLG1,DLG2,DLG3,DLG4:NEFL:ACTN2GRIN1 GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers GRIN2B GRIN1 DLG2 GRIN2B GRIN1 DLG1 homotetramerGRIN2B LIN7B GRIN2C GRIN1:GRIN2B:GRIN2Dtri-heterotetramerGRIN1:GRIN2 NMDAreceptors:PSDproteinsDLG3 GRIN2C KIF17 LIN7C GRIN1:GRIN2B:GRIN3Btri-heterotetramerGRIN2ANEFL GRIN3A DLG4GRIN1 NEFL GRIN1:GRIN2Ddi-heterotetramerGRIN1:GRIN2NMDAreceptors:DLG4:DLG1,DLG2,DLG3,DLG4:NEFLDLG1 homotetramerAPBA1 GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers GRIN1:GRIN3Adi-heterotetramerCAMK2D CAMK2B GRIN2D GRIN1 GRIN1 DLG1 ACTN2 homodimerGRIN1:GRIN2A,C,Ddi-heteromers,GRIN1:GRIN2 tri-heteromersGRIN2BGRIN3B DLG3 GRIN1 GRIN1:GRIN2B:GRIN3Atri-heterotetramerGRIN2D GRIN1:GRIN2Adi-heterotetramerCAMK2A DLG1 DLG2 GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers GRIN2DKIF17 GRIN3A GRIN1 CaMKII dodecamerDLG1 GRIN1:GRIN3di-heteromers,(GRIN1:GRIN2:GRIN3 tri-heteromers)GRIN2B GRIN2C GRIN2B GRIN2B DLG4 GRIN1:GRIN2A:GRIN3Btri-heterotetramerLIN7B GRIN3B GRIN1:GRIN2Bdi-heterotetramer:LIN7:CASK:APBA1:DLG1:KIF17:MicrotubuleGRIN1 DLG4 DLG2 GRIN2B GRIN3B 1717210, 13, 14, 20


Description

N-methyl-D-aspartate receptors (NMDARs) are tetramers that consist of two GluN1 (GRIN1) subunits and two subunits that belong to either the GluN2 (GRIN2) subfamily (GluN2A, GluN2B, GluN2C and GluN2D) or the GluN3 (GRIN3) subfamily (GluN3A and GluN3B). The GluN2/GluN3 subunits in the NMDA tetramer can either be identical, constituting an NMDA di-heteromer (di-heterotetramer), which consists of two subunit types, GluN1 and one of GluN2s/GluN3s, or they can be two different GluN2/GluN3 proteins, constituting an NMDA tri-heteromer (tri-heterotetramer), which consists of three subunit types, GluN1 and two of GluN2s/GluN3s (Monyer et al. 1992, Wafford et al. 1993, Sheng et al. 1994, Dunah et al. 1998, Perez-Otano et al. 2001, Chatterton et al. 2002, Matsuda et al. 2002, Yamakura et al. 2005, Nilsson et al. 2007, Hansen et al. 2014, Kaiser et al. 2018, Bhattacharya et al. 2018, Bhattacharya and Traynelis 2018).
NMDA tetramers assemble in the endoplasmic reticulum and traffic to the plasma membrane as part of transport vesicles (McIlhinney et al. 1998, Perez-Otano et al. 2001). NMDA receptor subunits undergo N-glycosylation, which impacts their trafficking from the endoplasmic reticulum to the plasma membrane. Trafficking efficiency may vary among different subunits of NMDARs (Lichnereva et al. 2015). Mechanistic details, such as glycosyl transferases involved and the type of sugar side chains added, are not known.
As there are eight splicing isoforms of GluN1, four different GluN2 and two different GluN3 proteins, many different combinations of NMDAR subunits are possible, but only a handful of distinct NMDAR receptors have been experimentally confirmed and functionally studied. The composition of NMDARs affects trafficking, spatial (including synaptic) localization, ligand preference, channel conductivity and downstream signal transmission. Prevalent NMDARs differ at different stages of neuronal development, in different regions of the central nervous system, and at different levels of neuronal activity. For review, please refer to Lau and Zukin 2007, Traynelis et al. 2010, Paoletti et al. 2013, Pérez-Otaño et al. 2016, Iacobucci and Popescu 2017. View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9609736
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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  1. Wafford KA, Bain CJ, Le Bourdelles B, Whiting PJ, Kemp JA.; ''Preferential co-assembly of recombinant NMDA receptors composed of three different subunits.''; PubMed Europe PMC Scholia
  2. Djinović-Carugo K, Young P, Gautel M, Saraste M.; ''Structure of the alpha-actinin rod: molecular basis for cross-linking of actin filaments.''; PubMed Europe PMC Scholia
  3. Dunah AW, Luo J, Wang YH, Yasuda RP, Wolfe BB.; ''Subunit composition of N-methyl-D-aspartate receptors in the central nervous system that contain the NR2D subunit.''; PubMed Europe PMC Scholia
  4. Nilsson A, Eriksson M, Muly EC, Akesson E, Samuelsson EB, Bogdanovic N, Benedikz E, Sundström E.; ''Analysis of NR3A receptor subunits in human native NMDA receptors.''; PubMed Europe PMC Scholia
  5. Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D.; ''Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.''; PubMed Europe PMC Scholia
  6. McIlhinney RA, Le Bourdellès B, Molnár E, Tricaud N, Streit P, Whiting PJ.; ''Assembly intracellular targeting and cell surface expression of the human N-methyl-D-aspartate receptor subunits NR1a and NR2A in transfected cells.''; PubMed Europe PMC Scholia
  7. Matsuda K, Kamiya Y, Matsuda S, Yuzaki M.; ''Cloning and characterization of a novel NMDA receptor subunit NR3B: a dominant subunit that reduces calcium permeability.''; PubMed Europe PMC Scholia
  8. Yamakura T, Askalany AR, Petrenko AB, Kohno T, Baba H, Sakimura K.; ''The NR3B subunit does not alter the anesthetic sensitivities of recombinant N-methyl-D-aspartate receptors.''; PubMed Europe PMC Scholia
  9. Sheng M, Cummings J, Roldan LA, Jan YN, Jan LY.; ''Changing subunit composition of heteromeric NMDA receptors during development of rat cortex.''; PubMed Europe PMC Scholia
  10. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R.; ''Glutamate receptor ion channels: structure, regulation, and function.''; PubMed Europe PMC Scholia
  11. Bhattacharya S, Khatri A, Swanger SA, DiRaddo JO, Yi F, Hansen KB, Yuan H, Traynelis SF.; ''Triheteromeric GluN1/GluN2A/GluN2C NMDARs with Unique Single-Channel Properties Are the Dominant Receptor Population in Cerebellar Granule Cells.''; PubMed Europe PMC Scholia
  12. Kaiser TM, Kell SA, Kusumoto H, Shaulsky G, Bhattacharya S, Epplin MP, Strong KL, Miller EJ, Cox BD, Menaldino DS, Liotta DC, Traynelis SF, Burger PB.; ''The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor.''; PubMed Europe PMC Scholia
  13. Hardingham GE, Bading H.; ''Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders.''; PubMed Europe PMC Scholia
  14. Paoletti P, Bellone C, Zhou Q.; ''NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.''; PubMed Europe PMC Scholia
  15. Perez-Otano I, Schulteis CT, Contractor A, Lipton SA, Trimmer JS, Sucher NJ, Heinemann SF.; ''Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors.''; PubMed Europe PMC Scholia
  16. Cui H, Hayashi A, Sun HS, Belmares MP, Cobey C, Phan T, Schweizer J, Salter MW, Wang YT, Tasker RA, Garman D, Rabinowitz J, Lu PS, Tymianski M.; ''PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors.''; PubMed Europe PMC Scholia
  17. Marfatia SM, Byron O, Campbell G, Liu SC, Chishti AH.; ''Human homologue of the Drosophila discs large tumor suppressor protein forms an oligomer in solution. Identification of the self-association site.''; PubMed Europe PMC Scholia
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  19. Hansen KB, Ogden KK, Yuan H, Traynelis SF.; ''Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors.''; PubMed Europe PMC Scholia
  20. Cohen S, Greenberg ME.; ''Communication between the synapse and the nucleus in neuronal development, plasticity, and disease.''; PubMed Europe PMC Scholia
  21. Lau CG, Zukin RS.; ''NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders.''; PubMed Europe PMC Scholia
  22. Zhang JB, Chang S, Xu P, Miao M, Wu H, Zhang Y, Zhang T, Wang H, Zhang J, Xie C, Song N, Luo C, Zhang X, Zhu S.; ''Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors.''; PubMed Europe PMC Scholia
  23. Bhattacharya S, Traynelis SF.; ''Unique Biology and Single-Channel Properties of GluN2A- and GluN2C-Containing Triheteromeric N-Methyl-D-Aspartate Receptors.''; PubMed Europe PMC Scholia
  24. Lichnerova K, Kaniakova M, Park SP, Skrenkova K, Wang YX, Petralia RS, Suh YH, Horak M.; ''Two N-glycosylation Sites in the GluN1 Subunit Are Essential for Releasing N-methyl-d-aspartate (NMDA) Receptors from the Endoplasmic Reticulum.''; PubMed Europe PMC Scholia
  25. Pérez-Otaño I, Larsen RS, Wesseling JF.; ''Emerging roles of GluN3-containing NMDA receptors in the CNS.''; PubMed Europe PMC Scholia
  26. Iacobucci GJ, Popescu GK.; ''NMDA receptors: linking physiological output to biophysical operation.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114995view16:52, 25 January 2021ReactomeTeamReactome version 75
113439view11:51, 2 November 2020ReactomeTeamReactome version 74
112891view14:12, 16 October 2020DeSlOntology Term : 'glutamate signaling pathway via NMDA receptor' added !
112826view18:31, 9 October 2020DeSlOntology Term : 'transport pathway' added !
112773view16:17, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ACTN2 ProteinP35609 (Uniprot-TrEMBL)
ACTN2 homodimerComplexR-HSA-9610932 (Reactome)
ADPMetaboliteCHEBI:456216 (ChEBI)
APBA1 ProteinQ02410 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
Activation of NMDA

receptors and

postsynaptic events		PathwayR-HSA-442755 (Reactome) NMDA receptors are a subtype of ionotropic glutamate receptors that are specifically activated by a glutamate agonist N-methyl-D-aspartate (NMDA). Activation of NMDA receptors involves opening of the ion channel that allows the influx of Ca2+. NMDA receptors are central to activity dependent changes in synaptic strength and are predominantly involved in the synaptic plasticity that pertains to learning and memory. A unique feature of NMDA receptors, unlike other glutamate receptors, is the requirement for dual activation, both voltage-dependent and ligand-dependent activation. The ligand-dependent activation of NMDA receptors requires co-activation by two ligands, glutamate and glycine. However, at resting membrane potential, the pore of ligand-bound NMDA receptors is blocked by Mg2+. The voltage dependent Mg2+ block is relieved upon depolarization of the post-synaptic membrane. NMDA receptors are coincidence detectors, and are activated only if there is a simultaneous activation of both pre- and post-synaptic cell. Upon activation, NMDA receptors allow the influx of Ca2+ that initiates various molecular signaling cascades involved in the processes of learning and memory. For review, please refer to Cohen and Greenberg 2008, Hardingham and Bading 2010, Traynelis et al. 2010, and Paoletti et al. 2013.
CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
CAMK2B ProteinQ13554 (Uniprot-TrEMBL)
CAMK2D ProteinQ13557 (Uniprot-TrEMBL)
CAMK2G ProteinQ13555 (Uniprot-TrEMBL)
CASK ProteinO14936 (Uniprot-TrEMBL)
CaMKII dodecamerComplexR-HSA-9611355 (Reactome) CaMKII is composed of a homo or hetero dodecamer of four subunits apha, beta, delta and gamma. In a heteromultimer the ratio of alpha to beta may vary from 6;1, 3:1 or 1:1.
DLG1 ProteinQ12959 (Uniprot-TrEMBL)
DLG1 homotetramerComplexR-HSA-9610596 (Reactome)
DLG1 homotetramerComplexR-HSA-9610630 (Reactome)
DLG1,DLG2,DLG3,DLG4ComplexR-HSA-9610652 (Reactome)
DLG2 ProteinQ15700 (Uniprot-TrEMBL)
DLG3 ProteinQ92796 (Uniprot-TrEMBL)
DLG3ProteinQ92796 (Uniprot-TrEMBL)
DLG4 ProteinP78352 (Uniprot-TrEMBL)
DLG4ProteinP78352 (Uniprot-TrEMBL)
GRIN1 ProteinQ05586 (Uniprot-TrEMBL)
GRIN1:GRIN2

NMDA

receptors:DLG4:DLG1,DLG2,DLG3,DLG4:NEFL:ACTN2		ComplexR-HSA-9611031 (Reactome)
GRIN1:GRIN2

NMDA

receptors:DLG4:DLG1,DLG2,DLG3,DLG4:NEFL		ComplexR-HSA-9610878 (Reactome)
GRIN1:GRIN2

NMDA

receptors:DLG4:DLG1,DLG2,DLG3,DLG4		ComplexR-HSA-9610654 (Reactome)
GRIN1:GRIN2 NMDA

receptors:PSD

proteins		ComplexR-HSA-9611369 (Reactome)
GRIN1:GRIN2 NMDA receptorsComplexR-HSA-9610678 (Reactome)
GRIN1:GRIN2A di-heterotetramerComplexR-HSA-9609783 (Reactome)
GRIN1:GRIN2A,C,D

di-heteromers, GRIN1:GRIN2

tri-heteromers		ComplexR-HSA-9610757 (Reactome)
GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromersComplexR-HSA-9610756 (Reactome)
GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers R-HSA-9610756 (Reactome)
GRIN1:GRIN2A:GRIN2B tri-heterotetramerComplexR-HSA-9609782 (Reactome)
GRIN1:GRIN2A:GRIN2C tri-heterotetramerComplexR-HSA-9609776 (Reactome)
GRIN1:GRIN2A:GRIN2D tri-heterotetramerComplexR-HSA-9610194 (Reactome)
GRIN1:GRIN2A:GRIN3A tri-heterotetramerComplexR-HSA-9610268 (Reactome)
GRIN1:GRIN2A:GRIN3B tri-heterotetramerComplexR-HSA-9610323 (Reactome)
GRIN1:GRIN2B di-heterotetramer:LIN7:CASK:APBA1:DLG1:KIF17:MicrotubuleComplexR-HSA-9610410 (Reactome)
GRIN1:GRIN2B di-heterotetramerComplexR-HSA-3928507 (Reactome)
GRIN1:GRIN2B di-heterotetramerComplexR-HSA-9609778 (Reactome)
GRIN1:GRIN2B:GRIN2D tri-heterotetramerComplexR-HSA-9609780 (Reactome)
GRIN1:GRIN2B:GRIN3A tri-heterotetramerComplexR-HSA-9609781 (Reactome)
GRIN1:GRIN2B:GRIN3B tri-heterotetramerComplexR-HSA-9609785 (Reactome)
GRIN1:GRIN2C di-heterotetramerComplexR-HSA-9609784 (Reactome)
GRIN1:GRIN2D di-heterotetramerComplexR-HSA-9609779 (Reactome)
GRIN1:GRIN3 di-heteromers,(GRIN1:GRIN2:GRIN3 tri-heteromers)ComplexR-HSA-9610777 (Reactome)
GRIN1:GRIN3 di-heteromers,(GRIN1:GRIN2:GRIN3 tri-heteromers)ComplexR-HSA-9610778 (Reactome)
GRIN1:GRIN3A di-heterotetramerComplexR-HSA-9609786 (Reactome)
GRIN1:GRIN3B di-heterotetramerComplexR-HSA-9609777 (Reactome)
GRIN1ProteinQ05586 (Uniprot-TrEMBL)
GRIN2A ProteinQ12879 (Uniprot-TrEMBL)
GRIN2AProteinQ12879 (Uniprot-TrEMBL)
GRIN2B ProteinQ13224 (Uniprot-TrEMBL)
GRIN2BProteinQ13224 (Uniprot-TrEMBL)
GRIN2C ProteinQ14957 (Uniprot-TrEMBL)
GRIN2CProteinQ14957 (Uniprot-TrEMBL)
GRIN2D ProteinO15399 (Uniprot-TrEMBL)
GRIN2DProteinO15399 (Uniprot-TrEMBL)
GRIN3A ProteinQ8TCU5 (Uniprot-TrEMBL)
GRIN3AProteinQ8TCU5 (Uniprot-TrEMBL)
GRIN3B ProteinO60391 (Uniprot-TrEMBL)
GRIN3BProteinO60391 (Uniprot-TrEMBL)
KIF17 ProteinQ9P2E2 (Uniprot-TrEMBL)
KIF17 dimerComplexR-HSA-5624926 (Reactome)
LIN7:CASK:APBA1ComplexR-HSA-9610409 (Reactome)
LIN7A ProteinO14910 (Uniprot-TrEMBL)
LIN7B ProteinQ9HAP6 (Uniprot-TrEMBL)
LIN7C ProteinQ9NUP9 (Uniprot-TrEMBL)
LRRC7 ProteinQ96NW7 (Uniprot-TrEMBL)
LRRC7ProteinQ96NW7 (Uniprot-TrEMBL)
Microtubule protofilament R-HSA-8982424 (Reactome)
MicrotubuleComplexR-HSA-190599 (Reactome)
NBEA ProteinQ8NFP9 (Uniprot-TrEMBL)
NBEA:DLG3ComplexR-HSA-9668211 (Reactome)
NBEAProteinQ8NFP9 (Uniprot-TrEMBL)
NEFL ProteinP07196 (Uniprot-TrEMBL)
NEFLProteinP07196 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:43474 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ACTN2 homodimerR-HSA-9611030 (Reactome)
ADPArrowR-HSA-9610627 (Reactome)
ATPR-HSA-9610627 (Reactome)
CaMKII dodecamerR-HSA-9611368 (Reactome)
DLG1 homotetramerArrowR-HSA-9610627 (Reactome)
DLG1 homotetramerR-HSA-9610408 (Reactome)
DLG1,DLG2,DLG3,DLG4R-HSA-9610653 (Reactome)
DLG3R-HSA-9668218 (Reactome)
DLG4R-HSA-9610653 (Reactome)
GRIN1:GRIN2

NMDA

receptors:DLG4:DLG1,DLG2,DLG3,DLG4:NEFL:ACTN2		ArrowR-HSA-9611030 (Reactome)
GRIN1:GRIN2

NMDA

receptors:DLG4:DLG1,DLG2,DLG3,DLG4:NEFL:ACTN2		R-HSA-9611368 (Reactome)
GRIN1:GRIN2

NMDA

receptors:DLG4:DLG1,DLG2,DLG3,DLG4:NEFL		ArrowR-HSA-9610879 (Reactome)
GRIN1:GRIN2

NMDA

receptors:DLG4:DLG1,DLG2,DLG3,DLG4:NEFL		R-HSA-9611030 (Reactome)
GRIN1:GRIN2

NMDA

receptors:DLG4:DLG1,DLG2,DLG3,DLG4		ArrowR-HSA-9610653 (Reactome)
GRIN1:GRIN2

NMDA

receptors:DLG4:DLG1,DLG2,DLG3,DLG4		R-HSA-9610879 (Reactome)
GRIN1:GRIN2 NMDA

receptors:PSD

proteins		ArrowR-HSA-9611368 (Reactome)
GRIN1:GRIN2 NMDA receptorsR-HSA-9610653 (Reactome)
GRIN1:GRIN2A di-heterotetramerArrowR-HSA-9609742 (Reactome)
GRIN1:GRIN2A,C,D

di-heteromers, GRIN1:GRIN2

tri-heteromers		R-HSA-9610750 (Reactome)
GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromersArrowR-HSA-9610750 (Reactome)
GRIN1:GRIN2A:GRIN2B tri-heterotetramerArrowR-HSA-9609746 (Reactome)
GRIN1:GRIN2A:GRIN2C tri-heterotetramerArrowR-HSA-9609738 (Reactome)
GRIN1:GRIN2A:GRIN2D tri-heterotetramerArrowR-HSA-9610195 (Reactome)
GRIN1:GRIN2A:GRIN3A tri-heterotetramerArrowR-HSA-9610270 (Reactome)
GRIN1:GRIN2A:GRIN3B tri-heterotetramerArrowR-HSA-9610327 (Reactome)
GRIN1:GRIN2B di-heterotetramer:LIN7:CASK:APBA1:DLG1:KIF17:MicrotubuleArrowR-HSA-9610408 (Reactome)
GRIN1:GRIN2B di-heterotetramer:LIN7:CASK:APBA1:DLG1:KIF17:MicrotubuleR-HSA-9610627 (Reactome)
GRIN1:GRIN2B di-heterotetramer:LIN7:CASK:APBA1:DLG1:KIF17:Microtubulemim-catalysisR-HSA-9610627 (Reactome)
GRIN1:GRIN2B di-heterotetramerArrowR-HSA-9609744 (Reactome)
GRIN1:GRIN2B di-heterotetramerArrowR-HSA-9610627 (Reactome)
GRIN1:GRIN2B di-heterotetramerR-HSA-9610408 (Reactome)
GRIN1:GRIN2B:GRIN2D tri-heterotetramerArrowR-HSA-9609737 (Reactome)
GRIN1:GRIN2B:GRIN3A tri-heterotetramerArrowR-HSA-9609743 (Reactome)
GRIN1:GRIN2B:GRIN3B tri-heterotetramerArrowR-HSA-9609740 (Reactome)
GRIN1:GRIN2C di-heterotetramerArrowR-HSA-9609739 (Reactome)
GRIN1:GRIN2D di-heterotetramerArrowR-HSA-9609741 (Reactome)
GRIN1:GRIN3 di-heteromers,(GRIN1:GRIN2:GRIN3 tri-heteromers)ArrowR-HSA-9610802 (Reactome)
GRIN1:GRIN3 di-heteromers,(GRIN1:GRIN2:GRIN3 tri-heteromers)R-HSA-9610802 (Reactome)
GRIN1:GRIN3A di-heterotetramerArrowR-HSA-9609747 (Reactome)
GRIN1:GRIN3B di-heterotetramerArrowR-HSA-9609728 (Reactome)
GRIN1R-HSA-9609728 (Reactome)
GRIN1R-HSA-9609737 (Reactome)
GRIN1R-HSA-9609738 (Reactome)
GRIN1R-HSA-9609739 (Reactome)
GRIN1R-HSA-9609740 (Reactome)
GRIN1R-HSA-9609741 (Reactome)
GRIN1R-HSA-9609742 (Reactome)
GRIN1R-HSA-9609743 (Reactome)
GRIN1R-HSA-9609744 (Reactome)
GRIN1R-HSA-9609746 (Reactome)
GRIN1R-HSA-9609747 (Reactome)
GRIN1R-HSA-9610195 (Reactome)
GRIN1R-HSA-9610270 (Reactome)
GRIN1R-HSA-9610327 (Reactome)
GRIN2AR-HSA-9609738 (Reactome)
GRIN2AR-HSA-9609742 (Reactome)
GRIN2AR-HSA-9609746 (Reactome)
GRIN2AR-HSA-9610195 (Reactome)
GRIN2AR-HSA-9610270 (Reactome)
GRIN2AR-HSA-9610327 (Reactome)
GRIN2BR-HSA-9609737 (Reactome)
GRIN2BR-HSA-9609740 (Reactome)
GRIN2BR-HSA-9609743 (Reactome)
GRIN2BR-HSA-9609744 (Reactome)
GRIN2BR-HSA-9609746 (Reactome)
GRIN2CR-HSA-9609738 (Reactome)
GRIN2CR-HSA-9609739 (Reactome)
GRIN2DR-HSA-9609737 (Reactome)
GRIN2DR-HSA-9609741 (Reactome)
GRIN2DR-HSA-9610195 (Reactome)
GRIN3AR-HSA-9609743 (Reactome)
GRIN3AR-HSA-9609747 (Reactome)
GRIN3AR-HSA-9610270 (Reactome)
GRIN3BR-HSA-9609728 (Reactome)
GRIN3BR-HSA-9609740 (Reactome)
GRIN3BR-HSA-9610327 (Reactome)
KIF17 dimerArrowR-HSA-9610627 (Reactome)
KIF17 dimerR-HSA-9610408 (Reactome)
LIN7:CASK:APBA1ArrowR-HSA-9610627 (Reactome)
LIN7:CASK:APBA1R-HSA-9610408 (Reactome)
LRRC7R-HSA-9611368 (Reactome)
MicrotubuleArrowR-HSA-9610627 (Reactome)
MicrotubuleR-HSA-9610408 (Reactome)
NBEA:DLG3ArrowR-HSA-9668218 (Reactome)
NBEAR-HSA-9668218 (Reactome)
NEFLR-HSA-9610879 (Reactome)
PiArrowR-HSA-9610627 (Reactome)
R-HSA-9609728 (Reactome) GluN3B (GRIN3B) binds to GluN1 (GRIN1) to form a di-heteromeric NMDA receptor (Chatterton et al. 2002). The tetrameric structure of the GluN1:GluN3B (GRIN1:GRIN3B) di-heteromer is inferred from the tetrameric architecture of all known glutamate receptors (Traynelis et al. 2010). GluN3B expression gradually increases during development and is expressed at highest levels in the adult motor neurons (reviewed by Paoletti et al. 2013). GluN1:GluN3B (GRIN1:GRIN3B) di-heteromers can be activated by glycine in Xenopus oocytes but not in human embryonic kidney cell line HEK293 (Smothers and Woodward 2007).
R-HSA-9609737 (Reactome) GluN1 (GRIN1) binds GluN2B (GRIN2B) and GluN2D (GRIN2D) to form a tri-heteromeric NMDA receptor (Dunah et al. 1998). The tetrameric structure of the GluN1:GluN2B:GluN2D (GRIN1:GRIN2B:GRIN2D) tri-heterotetramer, consisting of two molecules of GluN1 (GRIN1) and one molecule of each GluN2B (GRIN2B) and GluN2D (GRIN2D), is assumed to be similar to the cryo-EM structure of the Xenopus GluN1:GluN2A:GluN2B NMDA receptor (Lu et al. 2017).
R-HSA-9609738 (Reactome) GluN1 (GRIN1) forms a tri-heterotetramer with GluN2A (GRIN2A) and GluN2C (GRIN2C). The tetramer includes two molecules of GluN1, one molecule of GluN2A and one molecule of GluN2C (Wafford et al. 1993). The tetrameric structure of the GluN1:GluN2A:GluN2C (GRIN1:GRIN2A:GRIN2C) tri-heteromer is assumed to be similar to the described structure of the Xenopus GluN1:GluN2A:GluN2B tri-heteromer (Lu et al. 2017). GluN1:GluN2A:GluN2C tri-heteromers are the predominant NMDA receptors in cerebellar granule cells (Bhattacharya et al. 2018, reviewed in Bhattacharya and Traynelis 2018).
R-HSA-9609739 (Reactome) GluN1 (GRIN1) forms a di-heterotetrameric complex with GluN2C (GRIN2C) in heterologous expression systems. The tetramer includes two molecules of GluN1 and two molecules of GluN2C (Monyer et al. 1994). The stoichiometry in neurons remains to be determined. GluN2C expression starts late during embryonic development and is most prominent in cerebellum, olfactory bulb, and glial cells (Karavanova et al. 2007, Ravikrishnan et al. 2018, reviewed by Traynelis et al. 2010, Paoletti et al. 2013).
R-HSA-9609740 (Reactome) GluN1 (GRIN1) binds to GluN2B (GRIN2B) and GluN3B (GRIN3B) to form a tri-heteromeric NMDA receptor GluN1:GluN2B:GluN3B (GRIN1:GRIN2B:GRIN3B) (Yamakura et al. 2005).
R-HSA-9609741 (Reactome) GluN1 (GRIN1) forms a di-heterotetramer with GluN2D (GRIN2D) in heterologous expression systems, although stoichiometry is unclear in neurons. The tetramer includes two molecules of GluN1 and two molecules of GluN2D (Dunah et al. 1998). GluN2D is expressed in the brain during embryonic development. In adult brain, GluN2D expression is low and mostly restricted to diencephalon and mesencephalon, as well as GABAergic interneurons (von Engelhardt et al. 2015, Perszyk et al. 2016, reviewed by Paoletti et al. 2013). The ligand binding domain of GluN2D interacts with agonists in a similar fashion to other GluN2 subunits (Vance et al. 2011, Hansen et al. 2013).
R-HSA-9609742 (Reactome) GluN2A (GRIN2A) forms a di-heterotetramer with GluN1 (GRIN1). Based on the crystal structure of the rat GluN1:GluN2A (Grin1:Grin2a) NMDA receptor (Furukawa et al. 2005) and the Cryo-EM structure of the human GluN1:GluN2A (GRIN1:GRIN2A) NMDA receptor (Zhang et al. 2018), the tetramer includes 2 molecules of GluN1 and two molecules of GluN2A. GluN2A expression starts postnatally and GluN2A is highly expressed in adult brain (Monyer et al. 1992, Sheng et al. 1994).
R-HSA-9609743 (Reactome) GluN1 (GRIN1) binds to GluN2B (GRIN2B) and GluN3A (GRIN3A) to form a tri-heteromeric NMDA receptor GluN1:GluN2B:GluN3A (GRIN1:GRIN2B:GRIN3A) (Das et al. 1998, Al-Hallaq et al. 2002, Nilsson et al. 2007).
R-HSA-9609744 (Reactome) GluN2B (GRIN2B) forms a di-heterotetramer with GluN1 (GRIN1). The tetramer includes two molecules of GluN1 and two molecules of GluN2B. GluN2B expression starts during embryonic development and continues in adult brain (Monyer et al. 1992, Sheng et al. 1994). The tetrameric structure is deduced from the crystal structure of the rat GluN1:GluN2B (Grin1:Grin2b) NMDA receptor (Karakas and Furukawa 2014) and the Xenopus GluN1:GluN2B NMDA receptor (Lee et al. 2014).
R-HSA-9609746 (Reactome) GluN1 (GRIN1) forms a tri-heterotetramer with GluN2A (GRIN2A) and GluN2B (GRIN2B). The tetramer includes two molecules of GluN1, one molecule of GluN2A and one molecule of GluN2B (Sheng et al. 1994). The tetrameric structure of the GluN1:GluN2A:GluN2B (GRIN1:GRIN2A:GRIN2B) triheteromeric NMDA receptor was demonstrated on the cryo-EM structure of the Xenopus orthologue (Lu et al. 2017). The majority of native NMDA receptors in adult forebrain are GluN1:GluN2A:GluN2B tri-heteromers, and their pharmacological properties are distinct from the properties of GluN1:GluN2A and GluN1:GluN2B di-heteromers (Hansen et al. 2014).
R-HSA-9609747 (Reactome) GluN3A (GRIN3A) interacts with GluN1 (GRIN1) to form a di-heteromeric NMDA receptor (Perez-Otano et al. 2001, Chatterton et al. 2002). The tetrameric structure of the GluN1:GluN3A (GRIN1:GRIN3A) di-heteromer is inferred from the tetrameric architecture of all known glutamate receptors (Traynelis et al. 2010). GluN3A expression reaches the highest level in early postnatal period and then declines (reviewed by Paoletti et al. 2013). GluN1:GluN3A di-heteromers can be activated by glycine in Xenopus oocytes (Smothers and Woodward 2007), and the action of glycine can be greatly enhanced by diminishing the ability of GluN1 subunit to interact with glycine (Awobuluyi et al. 2007, Kvist et al. 2013, Grand et al. 2018).
R-HSA-9610195 (Reactome) GluN1 (GRIN1) is assumed to form a tri-heterotetramer with GluN2A (GRIN2A) and GluN2D (GRIN2D). The tetramer includes two molecules of GluN1, one molecule of GluN2A and one molecule of GluN2D (Dunah et al. 1998). The tetrameric structure of the GluN1:GluN2A:GluN2D (GRIN1:GRIN2A:GRIN2D) tri-heterotetramer is assumed to follow from the cryo-EM structure of the triheteromeric Xenopus GluN1:GluN2A:GluN2B NMDA receptor (Lu et al. 2017).
R-HSA-9610270 (Reactome) GluN1 (GRIN1) binds to GluN2A (GRIN2A) and GluN3A (GRIN3A) to form a tri-heteromeric GluN1:GluN2A:GluN3A (GRIN1:GRIN2A:GRIN3A) NMDA receptor (Perez-Otano et al. 2001, Nilsson et al. 2007, Tong et al. 2008).
R-HSA-9610327 (Reactome) GluN1 (GRIN1) binds to GluN2B (GRIN2B) and GluN3B (GRIN3B) to form a tri-heteromeric NMDA receptor GluN1:GluN2B:GluN3B (GRIN1:GRIN2B:GRIN3B) (Yamakura et al. 2005).
R-HSA-9610408 (Reactome) GluN1:GluN2B (GRIN1:GRIN2B) di-heteromers are transported to the plasma membrane from the endoplasmic reticulum (ER) via transport vesicles. At the membrane of transport vesicles, GluN1:GluN2B NMDA receptors associate with the complex of LIN7 (LIN7A, LIN7B or LIN7C), CASK and APBA1. The microtubule-associated kinesin motor protein KIF17 binds to the LIN7:CASK:APBA1 complex (Jo et al. 1999, Setou et al. 2000). During transport from ER to the plasma membrane, NMDA receptors are diverted from the somatic Golgi network and go through the dendritic ER subcompartment and dendritic Golgi instead. Besides CASK, interaction with DLG1 (SAP97) is required for GluN1:GluN2B NMDA receptors to go through this transport route (Jeyifous et al. 2009).
R-HSA-9610627 (Reactome) Kinesin KIF17 transports vesicles that contain GluN1:GluN2B (GRIN1:GRIN2B) NMDA receptor to the plasma membrane (Setou et al. 2000).
R-HSA-9610653 (Reactome) All GluN2 (GRIN2) family subunits, GluN2A (GRIN2A), GluN2B (GRIN2B), GluN2C (GRIN2C) and GluN2D (GRIN2D), can bind to any of the PSD-95 protein family members DLG1 (SAP-97), DLG2 (PSD-93), DLG3 (SAP-102) and DLG4 (PSD-95). Binding to different PSD-95 family members does not affect transport of GluN1:GluN2 (GRIN1:GRIN2) NMDA receptors to the plasma membrane, but does affect their positioning and retention at the plasma membrane postsynaptic density, as well as their excitability (Cui et al. 2007, Cousins et al. 2008, Bard et al. 2010). DLG4, the most prominent postsynaptic density protein, can also interact directly with GluN1 isoforms that possess the PDZ-binding domain in their C-terminus (Kornau et al. 1995).
R-HSA-9610750 (Reactome) NMDA receptors composed of GluN1 (GRIN1) and various combinations of GluN2 (GRIN2) subunits (GluN2A, GluN2B, GluN2C and GluN2D) are all delivered to the plasma membrane where they are anchored to postsynaptic density regions via the interaction with the PSD-95 family of proteins (DLG1, DLG2, DLG3 and DLG3) (Cui et al. 2007). Details of trafficking from the endoplasmic reticulum to the plasma membrane for the majority of GluN1:GluN2 di-heteromers and tri-heteromers, except for GluN1:GluN2B NMDA receptors, are not known.
R-HSA-9610802 (Reactome) NMDA receptors that contain GluN3A (GRIN3A) or GluN3B (GRIN3B) subunits, traffic to the plasma membrane to the perisynaptic regions, located at the periphery of the postsynaptic density (PSD). GluN3A and GluN3B do not have PDZ-binding domains and thus do not interact directly with PSD-95 family members. A small fraction of GluN3-containing NMDA receptors that localize to the central region of the PSD may be tri-heteromers with GluN2 (GRIN2) subunits (Perez-Otano et al. 2006, Wee et al. 2016).
R-HSA-9610879 (Reactome) The GluN1 (GRIN1) subunit of NMDA receptors binds to neurofilament light chain (NEFL, also known as NF-L), a type of cytoskeleton interfilaments, at postsynaptic density (PSD). Binding to NEFL may increase the stability of NMDA receptors at the PSD. Different GluN1 splicing isoforms may have different affinity for NEFL (Ehlers et al. 1998, Ratnam and Teichberg 2005). It is uncertain whether NEFL is a part of the core PSD (Dosemeci et al. 2007).
R-HSA-9611030 (Reactome) ACTN2 (alpha-actinin-2) directly binds to GluN1 (GRIN1) subunit of the NMDA receptor, but can also bind to GluN2B (GRIN2B) (Wyszynski et al. 1997). Binding to ACTN2 anchors NMDA receptors to the actin cytoskeleton and is needed for the assembly of the postsynaptic density (Wyszynski et al. 1997, Hodges et al. 2014).
R-HSA-9611368 (Reactome) The calmodulin-dependent kinase, CaMKII, is enriched in postsynaptic density (PSD) and co-localizes with NMDA receptors. CaMKII can independently bind to alpha-actinin-2 (ACTN2), densin-180 (LRRC7) and the NMDA receptor subunit GluN2B (GRIN2B). Any of the four CAMK2 isoforms, CAMK2A, CAMK2B, CAMK2D or CAMK2G, which associate to form homomeric or heteromeric CaMKII dodecamers, can bind to ACTN2 and GluN2B, while LRRC7 shows the highest affinity for CAMK2A. Binding of CaMKII to the NMDA receptor-associated proteins is independent of CaMKII phosphorylation (Robison et al. 2005).
R-HSA-9668218 (Reactome) Based on studies in mouse brain and cultured mouse neurons, NBEA (neurobeachin) forms a complex with DLG3 (SAP-102) (Lauks et al. 2012, Farzana et al. 2016). The PH domain in the C-terminus of NBEA is involved in this interaction (Lauks et al. 2012). Based on UniProt reference protein sequence alignment, human NBEA protein is 97% identical with mouse Nbea, while human DLG3 protein is 95% identical with mouse Dlg3.
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