Neurexins and neuroligins (Homo sapiens)

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3, 12, 19, 20, 221, 142, 15, 16115-10, 13, 17...251, 1411Presynaptic cellcytosolPostsynaptic cellcytosolSynaptic cleftDLG2 EPB41L2 GRIN2C NRXN3 SHANK2 SHARPINSYT2 NRXN2 NRXN2 APBA1 NRXN1 NLGN2 SYT1 NRXN1 NLGN3 NRXN1 NRXN2 SHANK3 EPB41L5 DLG3 DLGAP4 SHANK1 NRXN1 SHANK1 EPB41L2 SYT9 NLGN4X NLGN1 CASK HOMER1 NRXN3 CASK:Protein 4.1DLG2 GRIN2A NRXN1 NRXN2 GRM5 DLG3 APBA1 NLGN4X SYT2 NRXNs:NLGNdimer:PSD-95:GKAP1-4:SHANK1,2,3APBA3 NLGN dimersNLGN3 NRXNs:STX1A:MUNC18:MINT1,2,(3)GRIN2D NRXN2 SYT10 SPAR NLGN4X DLGAP1 NLGN2 DLGAP3 NLGN4X APBA3 NRXN1 APBA1 LRRTMsHOMER1 APBA2 DLGAP3 DBNL NRXN1 NRXN3 NLGN1 DLGAP1 DLG2 NLGN4Y NRXNs:NLGNdimer:PSD-95:GKAP1-4:SHANK1,2,3:DBNLGRIN2D NMDAreceptorcomplex:DLG2,DLG3,DLG4:SPAR:PDLIM5NLGN3 DLG3 DLG4 DLG4 NRXN3 HOMER1 DLG4 NRXNs:NLGNdimers:CASK:Protein4.1NRXN1 NLGN4X HOMER3 SYT1 CASKHOMER3 EPB41L3 NMDAreceptorcomplex:DLG2,DLG3,DLG4:SPARDLGAP2 NRXN2 NMDAreceptorcomplex:DLG2,DLG3,DLG4NRXN1 DLG4 NRXN1 NRXN1 HOMER1,2,3:GRM1,GRM5NLGN2 LIN7:CASK:APBA1PDLIM5 EPB41L5 NMDA receptorcomplexDLGAP4 EPB41 LRRTM2 GRIN2A NRXN3 APBA2 NRXN2 NRXNs:NLGNdimers:PSD-95membersLIN7B GKAP1-4STX1A NMDAreceptorcomplex:PSD-95:BEGAINDLGAP1 DLG3 GRIN2C LIN7C NRXN3 NRXN3 NRXN1 GRIN1 HOMER3 NLGN2 NRXN3 SYT10 LRRTM2 NLGN4Y NLGN4Y EPB41L1 LIN7A GRM1 GRIN2B HOMER2 GRIN1 NLGN3 GRIN1 NRXN3 DLG4 NRXNs:LRRTMsGRIN1 EPB41L3 NRXN3 SHANK1 NLGN4X NLGN1 DLG3 SYT9 NRXN3 DLGAP4 GRM1 HOMER1,2,3SPARSYT12 LIN7A GRIN2A NRXN2 DLG4 HOMER2 EPB41L1 NRXN3 2xHOMER1,2,3:GRM1,GRM5GRM5 DLG2 NRXN2 HOMER2 NRXN3 NRXN2 NRXN2 LRRTM4 EPB41L2 NRXN3 SHANK3 NRXN1 GRM1 SHARPIN:SHANK1,2,3GRM1,GRM5GRIN2B NRXN3 NRXNs:SYTDLG2, DLG3, DLG4NRXNs:LIN7:CASK:APBA1DLG3 NRXN3 GRIN2D DLGAP4 EPB41 HOMER1 LIN7B EPB41L1 DLGAP2 DLGAP3 DLG2 NLGN1 DLG3 NRXN1 NLGN1 SHANK3 DLGAP2 STXBP1 GRM5 SHANK2 SHANK2 GRIN2D NRXN3 SYT7 NRXNs:NLGNdimer:PSD-95:GKAP1-4NLGN4Y DLG2 EPB41L3 SHANK1 NRXN2 LRRTM3 GRM1 NLGN3 NRXN1 PDLIM5CASK NLGN4Y NRXN1 SHANK1 NRXNsDLG2 NRXN3 NRXN2 DLGAP1 GRIN2C NRXN2 DLGAP2 NRXN1 DLGAP1 SYTSHARPIN GRIN2A STX1A NLGN2 LRRTM1 NLGN3 EPB41 DLG3 SYT7 NLGN1 NRXN3 GRIN2C NRXN3 NRXN1 NRXN3 STX1A:MUNC18:MINT1,2,(3)DLGAP4 NRXN2 NLGN4Y NRXN2 DLG3 LRRTM3 EPB41L5 GRIN2B NRXN1 DLG4 NLGN2 NRXN2 DLG2 DLG2 NRXNs:NLGN dimersNRXN3 DLGAP2 NRXN2 NLGN2 APBA1 NRXN2 SPAR NRXN2 SHANK2 NLGN4X SHANK2 SHANK1,2,3BEGAIN STXBP1 DLG3 NLGN3 BEGAINGRIN1 DLGAP3 HOMER2 DBNLNLGN4Y NLGN4X NLGN1 NRXNs:NLGNdimer:PSD-95:GKAP1-4:SHANK1,2,3:2xHOMER1,2,3:GRM1,5NLGN3 SHANK3 NRXN1 Protein 4.1NRXN1 LRRTM1 GRM5 NRXN2 DLG4 CASK CASK DLG4 SHANK3 HOMER3 GRIN2D DLG4 GRIN2B NRXN2 SYT12 GRIN2C DLG2 NLGN2 LIN7C NRXN3 NLGN4Y LRRTM4 NLGN1 NRXN1 NRXN3 NRXN2 GRIN2B NRXN2 NRXN1 DLGAP3 GRIN2A NRXN1 4


Description

Neurexins (NRXNs) and neuroligins (NLGNs) are best characterized synaptic cell-adhesion molecules. They are part of excitatory glutamatergic and inhibitory GABAergic synapses in mammalian brain, mediate trans-synaptic signaling, and shape neural network properties by specifying synaptic functions. As cell-adhesion molecules, NRXNs and NLGNs probably function by binding to each other and by interacting with intracellular PDZ-domain proteins, but the precise mechanisms involved and their relation to synaptic transmission remain unclear. The binding of NRXNs and NLGNs to their partners, helps to align the pre-synaptic release machinery and post-synaptic receptors. The importance of neurexins and neuroligins for synaptic function is evident from the dramatic deficits in synaptic transmission in mice lacking Nrxns or Nlgns. In humans, alterations in NRXNs or NLGNs genes are implicated in autism and other cognitive diseases, connecting synaptic cell adhesion to cognition and its disorders (Sudhof 2008, Craig et al. 2006, Craig & Kang 2007). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 6794361
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114945view16:46, 25 January 2021ReactomeTeamReactome version 75
113389view11:46, 2 November 2020ReactomeTeamReactome version 74
112594view15:56, 9 October 2020ReactomeTeamReactome version 73
101510view11:37, 1 November 2018ReactomeTeamreactome version 66
101046view21:19, 31 October 2018ReactomeTeamreactome version 65
100577view19:52, 31 October 2018ReactomeTeamreactome version 64
100126view16:37, 31 October 2018ReactomeTeamreactome version 63
99676view15:07, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94050view13:54, 16 August 2017ReactomeTeamreactome version 61
93738view13:25, 16 August 2017ReactomeTeamreactome version 61
93732view12:48, 16 August 2017ReactomeTeamreactome version 61
93677view11:30, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xHOMER1,2,3:GRM1,GRM5ComplexR-HSA-6794288 (Reactome)
APBA1 ProteinQ02410 (Uniprot-TrEMBL)
APBA2 ProteinQ99767 (Uniprot-TrEMBL)
APBA3 ProteinO96018 (Uniprot-TrEMBL)
BEGAIN ProteinQ9BUH8 (Uniprot-TrEMBL)
BEGAINProteinQ9BUH8 (Uniprot-TrEMBL)
CASK ProteinO14936 (Uniprot-TrEMBL)
CASK:Protein 4.1ComplexR-HSA-6797558 (Reactome)
CASKProteinO14936 (Uniprot-TrEMBL)
DBNL ProteinQ9UJU6 (Uniprot-TrEMBL)
DBNLProteinQ9UJU6 (Uniprot-TrEMBL)
DLG2 ProteinQ15700 (Uniprot-TrEMBL)
DLG2, DLG3, DLG4ComplexR-HSA-6794325 (Reactome)
DLG3 ProteinQ92796 (Uniprot-TrEMBL)
DLG4 ProteinP78352 (Uniprot-TrEMBL)
DLGAP1 ProteinO14490 (Uniprot-TrEMBL)
DLGAP2 ProteinQ9P1A6 (Uniprot-TrEMBL)
DLGAP3 ProteinO95886 (Uniprot-TrEMBL)
DLGAP4 ProteinQ9Y2H0 (Uniprot-TrEMBL)
EPB41 ProteinP11171 (Uniprot-TrEMBL)
EPB41L1 ProteinQ9H4G0 (Uniprot-TrEMBL)
EPB41L2 ProteinO43491 (Uniprot-TrEMBL)
EPB41L3 ProteinQ9Y2J2 (Uniprot-TrEMBL)
EPB41L5 ProteinQ9HCM4 (Uniprot-TrEMBL)
GKAP1-4ComplexR-HSA-6794312 (Reactome)
GRIN1 ProteinQ05586 (Uniprot-TrEMBL)
GRIN2A ProteinQ12879 (Uniprot-TrEMBL)
GRIN2B ProteinQ13224 (Uniprot-TrEMBL)
GRIN2C ProteinQ14957 (Uniprot-TrEMBL)
GRIN2D ProteinO15399 (Uniprot-TrEMBL)
GRM1 ProteinQ13255 (Uniprot-TrEMBL)
GRM1,GRM5ComplexR-HSA-6794289 (Reactome)
GRM5 ProteinP41594 (Uniprot-TrEMBL)
HOMER1 ProteinQ86YM7 (Uniprot-TrEMBL)
HOMER1,2,3:GRM1,GRM5ComplexR-HSA-6794305 (Reactome)
HOMER1,2,3ComplexR-HSA-6794285 (Reactome)
HOMER2 ProteinQ9NSB8 (Uniprot-TrEMBL)
HOMER3 ProteinQ9NSC5 (Uniprot-TrEMBL)
LIN7:CASK:APBA1ComplexR-HSA-6794330 (Reactome)
LIN7A ProteinO14910 (Uniprot-TrEMBL)
LIN7B ProteinQ9HAP6 (Uniprot-TrEMBL)
LIN7C ProteinQ9NUP9 (Uniprot-TrEMBL)
LRRTM1 ProteinQ86UE6 (Uniprot-TrEMBL)
LRRTM2 ProteinO43300 (Uniprot-TrEMBL)
LRRTM3 ProteinQ86VH5 (Uniprot-TrEMBL)
LRRTM4 ProteinQ86VH4 (Uniprot-TrEMBL)
LRRTMsComplexR-HSA-6797965 (Reactome)
NLGN dimersComplexR-HSA-6794303 (Reactome)
NLGN1 ProteinQ8N2Q7 (Uniprot-TrEMBL)
NLGN2 ProteinQ8NFZ4 (Uniprot-TrEMBL)
NLGN3 ProteinQ9NZ94 (Uniprot-TrEMBL)
NLGN4X ProteinQ8N0W4 (Uniprot-TrEMBL)
NLGN4Y ProteinQ8NFZ3 (Uniprot-TrEMBL)
NMDA

receptor

complex:DLG2,DLG3,DLG4:SPAR:PDLIM5
ComplexR-HSA-6794310 (Reactome)
NMDA

receptor

complex:DLG2,DLG3,DLG4:SPAR
ComplexR-HSA-6794327 (Reactome)
NMDA

receptor

complex:DLG2,DLG3,DLG4
ComplexR-HSA-6794302 (Reactome)
NMDA

receptor

complex:PSD-95:BEGAIN
ComplexR-HSA-6794309 (Reactome)
NMDA receptor complexComplexR-HSA-6794308 (Reactome) NMDAR complex consists of two NR1 subunits and two NR2 subunits. Each subunit has extensive C terminal tail that is modified by series of protein kinases and protein phosphatases. The NR1 subunits binds co-agonist glycine while the NR2 subunit binds glutamate. Hence the activation of NR1/NR2 containing NMDA receptor complexes are activated upon depolarization of the membrane and binding of both glycine and glutamate. The dual requirement of membrane depolarization and agonist binding facilitate coincidence detection by NMDA receptors that ensures activation of both pre-synaptic and post-synaptic cell. NR1/NR2 containing NMDA receptors are highly Ca2+ permeable and subjected to a voltage dependent Mg2+ block.
NRXN1 ProteinP58400 (Uniprot-TrEMBL)
NRXN1 ProteinQ9ULB1 (Uniprot-TrEMBL)
NRXN2 ProteinP58401 (Uniprot-TrEMBL)
NRXN2 ProteinQ9P2S2 (Uniprot-TrEMBL)
NRXN3 ProteinQ9HDB5 (Uniprot-TrEMBL)
NRXN3 ProteinQ9Y4C0 (Uniprot-TrEMBL)
NRXNs:LIN7:CASK:APBA1ComplexR-HSA-6794319 (Reactome)
NRXNs:LRRTMsComplexR-HSA-6797968 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4:SHANK1,2,3:2xHOMER1,2,3:GRM1,5ComplexR-HSA-6794286 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4:SHANK1,2,3:DBNLComplexR-HSA-6797565 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4:SHANK1,2,3ComplexR-HSA-6794299 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4ComplexR-HSA-6794296 (Reactome)
NRXNs:NLGN

dimers:CASK:Protein

4.1
ComplexR-HSA-6797545 (Reactome)
NRXNs:NLGN

dimers:PSD-95

members
ComplexR-HSA-6797306 (Reactome)
NRXNs:NLGN dimersComplexR-HSA-6794314 (Reactome)
NRXNs:STX1A:MUNC18:MINT1,2,(3)ComplexR-HSA-6794333 (Reactome)
NRXNs:SYTComplexR-HSA-6794320 (Reactome)
NRXNsComplexR-HSA-6794323 (Reactome)
PDLIM5 ProteinQ96HC4 (Uniprot-TrEMBL)
PDLIM5ProteinQ96HC4 (Uniprot-TrEMBL)
Protein 4.1ComplexR-HSA-6797561 (Reactome)
SHANK1 ProteinQ9Y566 (Uniprot-TrEMBL)
SHANK1,2,3ComplexR-HSA-6794282 (Reactome)
SHANK2 ProteinQ9UPX8 (Uniprot-TrEMBL)
SHANK3 ProteinQ9BYB0 (Uniprot-TrEMBL)
SHARPIN ProteinQ9H0F6 (Uniprot-TrEMBL)
SHARPIN:SHANK1,2,3ComplexR-HSA-6794315 (Reactome)
SHARPINProteinQ9H0F6 (Uniprot-TrEMBL)
SPAR ProteinO43166 (Uniprot-TrEMBL)
SPARProteinO43166 (Uniprot-TrEMBL)
STX1A ProteinQ16623 (Uniprot-TrEMBL)
STX1A:MUNC18:MINT1,2,(3)ComplexR-HSA-6794307 (Reactome)
STXBP1 ProteinP61764 (Uniprot-TrEMBL)
SYT1 ProteinP21579 (Uniprot-TrEMBL)
SYT10 ProteinQ6XYQ8 (Uniprot-TrEMBL)
SYT12 ProteinQ8IV01 (Uniprot-TrEMBL)
SYT2 ProteinQ8N9I0 (Uniprot-TrEMBL)
SYT7 ProteinO43581 (Uniprot-TrEMBL)
SYT9 ProteinQ86SS6 (Uniprot-TrEMBL)
SYTComplexR-HSA-6794313 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2xHOMER1,2,3:GRM1,GRM5ArrowR-HSA-6794347 (Reactome)
2xHOMER1,2,3:GRM1,GRM5R-HSA-6794344 (Reactome)
BEGAINR-HSA-6794356 (Reactome)
CASK:Protein 4.1ArrowR-HSA-6797553 (Reactome)
CASK:Protein 4.1R-HSA-6797568 (Reactome)
CASKR-HSA-6797553 (Reactome)
DBNLR-HSA-6797554 (Reactome)
DLG2, DLG3, DLG4R-HSA-6794336 (Reactome)
DLG2, DLG3, DLG4R-HSA-6794345 (Reactome)
GKAP1-4R-HSA-6794338 (Reactome)
GRM1,GRM5R-HSA-6794355 (Reactome)
HOMER1,2,3:GRM1,GRM5ArrowR-HSA-6794355 (Reactome)
HOMER1,2,3:GRM1,GRM5R-HSA-6794347 (Reactome)
HOMER1,2,3R-HSA-6794347 (Reactome)
HOMER1,2,3R-HSA-6794355 (Reactome)
LIN7:CASK:APBA1R-HSA-6794352 (Reactome)
LRRTMsR-HSA-6797974 (Reactome)
NLGN dimersR-HSA-6794346 (Reactome)
NMDA

receptor

complex:DLG2,DLG3,DLG4:SPAR:PDLIM5
ArrowR-HSA-6794354 (Reactome)
NMDA

receptor

complex:DLG2,DLG3,DLG4:SPAR
ArrowR-HSA-6794349 (Reactome)
NMDA

receptor

complex:DLG2,DLG3,DLG4:SPAR
R-HSA-6794354 (Reactome)
NMDA

receptor

complex:DLG2,DLG3,DLG4
ArrowR-HSA-6794336 (Reactome)
NMDA

receptor

complex:DLG2,DLG3,DLG4
R-HSA-6794349 (Reactome)
NMDA

receptor

complex:DLG2,DLG3,DLG4
R-HSA-6794356 (Reactome)
NMDA

receptor

complex:PSD-95:BEGAIN
ArrowR-HSA-6794356 (Reactome)
NMDA receptor complexR-HSA-6794336 (Reactome)
NRXNs:LIN7:CASK:APBA1ArrowR-HSA-6794352 (Reactome)
NRXNs:LRRTMsArrowR-HSA-6797974 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4:SHANK1,2,3:2xHOMER1,2,3:GRM1,5ArrowR-HSA-6794344 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4:SHANK1,2,3:DBNLArrowR-HSA-6797554 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4:SHANK1,2,3ArrowR-HSA-6794357 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4:SHANK1,2,3R-HSA-6794344 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4:SHANK1,2,3R-HSA-6797554 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4ArrowR-HSA-6794338 (Reactome)
NRXNs:NLGN dimer:PSD-95:GKAP1-4R-HSA-6794357 (Reactome)
NRXNs:NLGN

dimers:CASK:Protein

4.1
ArrowR-HSA-6797568 (Reactome)
NRXNs:NLGN

dimers:PSD-95

members
ArrowR-HSA-6794345 (Reactome)
NRXNs:NLGN

dimers:PSD-95

members
R-HSA-6794338 (Reactome)
NRXNs:NLGN dimersArrowR-HSA-6794346 (Reactome)
NRXNs:NLGN dimersR-HSA-6794345 (Reactome)
NRXNs:NLGN dimersR-HSA-6797568 (Reactome)
NRXNs:STX1A:MUNC18:MINT1,2,(3)ArrowR-HSA-6794353 (Reactome)
NRXNs:SYTArrowR-HSA-6794348 (Reactome)
NRXNsR-HSA-6794346 (Reactome)
NRXNsR-HSA-6794348 (Reactome)
NRXNsR-HSA-6794352 (Reactome)
NRXNsR-HSA-6794353 (Reactome)
NRXNsR-HSA-6797974 (Reactome)
PDLIM5R-HSA-6794354 (Reactome)
Protein 4.1R-HSA-6797553 (Reactome)
R-HSA-6794336 (Reactome) NMDA receptors are multimeric glutamate-gated cation channels, which are major constituents of the postsynaptic density (PSD). PSD-95/SAP90 protein is a member of the membrane-associated guanylate kinase (MAGUK) family and a prominant component of the PSD and associates with NMDA receptors. The interaction is mediated by binding of the C-terminus of the NMDA receptor subunits to the first two PDZ (also known as GLGF or DHR) domains of PSD-95 (Kornau et al. 1995, Niethammer et al. 1996). PSD-95 acts as a scaffolding protein in NMDA receptor signalling by bringing together NMDA receptor and various proteins like enzyme neuronal nitric oxide synthase (nNOS) (Brenman et al. 1996), SynGAP (Kim et al. 1998), GKAP (Kim et al. 1997), SHANK (Naisbitt et al. 1999) and multiple non-receptor tyrosine kinases (Sala & Sheng 1999). In this way, the multidomain PSD-95 molecule connects NMDA receptors to a variety of intracellular signaling proteins and anchors the whole complex to the postsynaptic density. PSD-95 subfamily includes other three more members: PSD-93/chapsyn-110, SAP97/hDlg, and SAP102. All except SAP97 appear to be components of the PSD and associated with NMDA receptors.
R-HSA-6794338 (Reactome) Guanylate kinase-associated protein (GKAP; also known as synapse-associated 42 protein 90-postsynaptic density-95-associated protein (SAPAP) and Discs-large-associated 43 protein (DAP) family proteins) a synaptic protein is one of the major constituent of the postsynaptic density (PSD). GKAP binds directly to the GK (guanylate kinase-like) domain of the four known members of the PSD-95 (postsynaptic density protein 95) family (Kim et al. 1997, Naisbitt et al. 1997, Takeuchi et al. 1997). GKAP is therefore one of the major scaffold proteins organizing glutamate receptors in the PSD.
R-HSA-6794344 (Reactome) Homer with its EVH1 domain binds to proline-rich motif of Shank family members. Shank and Homer coimmunoprecipitate from brain and colocalize at postsynaptic densities. Shank uses distinct domains to bind to GKAP and Homer, thus it can bridge between these two proteins. Thus, Shank may cross-link Homer and PSD-95 complexes in the PSD and play a role in the signaling mechanisms of both mGluRs and NMDA receptors (Tu et al. 1999).
R-HSA-6794345 (Reactome) Neuroligins (NLGNs) bind to the third PDZ domain of postsynaptic density (PSD)-95 whereas NMDA receptor and K+ channels interact with the first and the second PDZ domains. The cytoplasmic domains of all three neuroligins interacts with the NH2-terminus of PSD-95 and its homologs PSD-93 and SAP102, which contains the three PDZ domains (Irie et al. 1997).
R-HSA-6794346 (Reactome) The mammalian genome contains three NRXN genes (NRXN1, NRXN2 and NRXN3), each of which produce from independent promoters a longer alpha- and a shorter beta neurexin isoform. Furthermore, extensive alternative splicing at five canonical positions generates thousands of NRXN isoforms. In situ hybridizations showed that different alpha and beta-NRXNs are co-expressed in the same class of neurons, but that each type of NRXN is differentially distributed among different classes of neurons (Ullirich et al. 1995, Sudhof 2009, Missler et al. 2012).
Neuroligins (NLGNs) are endogenous NRXN ligands. NLGNs are expressed from four genes in vertebrates (NLGN-1 to -4). All NLGNs are alternatively spliced at a single canonical position (referred to as SS A) (Boucard et al. 2005, Ichtchenko et al. 1996). In contrast to neurexins, neuroligins are specifically localized to particular synapses. NLGN1 is only present at excitatory synapses (Song et al. 1999), NLGN2 and NLGN4 at inhibitory synapses (Varoqueaux et al. 2004, Hoon et al. 2011), whereas NLGN3 is present at both excitatory and inhibitory synapses (Budreck and Scheiffele 2007). alpha- and beta-neurexins both bind to all neuroligins to form cell adhesion complexes (Boucard et al. 2005). alpha-NRXNs with thier sixth LNS (laminin, neurexin and sex hormone-binding globulin-like) domain and beta-NRXNs with their single LNS domain bind to the lateral sides of the NLGNs esterase-homology domain (Fabrichny et al. 2007, Arac et al. 2007, Chen et al. 2008, Boucard et al. 2005, Reissner et al. 2008).
R-HSA-6794347 (Reactome) Homer dimerizes via the coiled-coil domains to form a rod with EVH1 domains on either end. It could interact with mGluRs on one end and with the other EVH1 domain can bind to Shank proteins linking the two receptors together (Hayashi et al. 2009).
R-HSA-6794348 (Reactome) Synaptotagmins (SYTs) are transmembrane proteins involved in membrane trafficking and calcium-dependent exocytosis of synaptic vesicles at the synapse. SYTs may mediate this by binding to presynaptic proteins, the neurexins (NRXNs) (Perin 1994, Hata et al. 1993, Petrenko et al. 1991). The interaction between these two proteins may mediate part of the recognition of presynaptic active sites by synaptic vesicles or may regulate neurotransmitter release (Perin 1996).
R-HSA-6794349 (Reactome) Spine-Associated RapGAP (SPAR) is a postsynaptic Rap-specific GTPase-activating protein (RapGAP) that reorganizes actin cytoskeleton and drives dentritic spine head growth. SPAR interacts with the guanylate kinase-like (GK) domain of Disks large homolog proteins (DSGs) forming a complex with NMDA receptors in brain (Pak et al. 2001).
R-HSA-6794351 (Reactome) SHANK with its ankyrin repeats has been found to bind SHARPIN a molecule that can form homomers. SHARPIN is another PSD protein enriched at synaptic sites in mature neurons and may be involved in the formation and maintenance of excitatory synaptic structures (Lim et al. 2001).
R-HSA-6794352 (Reactome) CASK (Calcium/calmodulin-dependent serine protein kinase) a multidomain synaptic scafolding protein binds to the extreme C terminus of neurexins (Hata et al. 1996). In brain, CASK binds to MINT1 with its CaM kinase domain, and all three Velis with the region between the CaM kinase and PDZ domains to form a tight tripartite complex (Butz et al. 1998). This tripartite complex may serve as nucleation site for the assembly of synaptic plasma membrane proteins. Recruitment of this tripartite complex to the plasma membrane by binding to neurexins may be involved in synaptic vesicle traffic.
R-HSA-6794353 (Reactome) The cytoplasmic PDZ (PSD-95, Dlg, and ZO-1/2 domain) domain of Neurexin interacts with the intracellular vesicle trafficking protein MUNC18/STXB1 (syntaxin binding peotein) via a multiprotein complex that involves MINT1 and MINT2. MUNC18, a sec1-like protein that is essential for neurotransmitter release exists in complex with Syntaxin (STX1A) and MINT1 and MINT2 in the nervous system (Okamoto & Sudhof 1997, Biederer & Sudhof 2000).
R-HSA-6794354 (Reactome) Spine-Associated RapGAP (SPAR) interacts with a PDZ-LIM domain family protein called PDZ and LIM domain 5 (PDLIM5), formerly known as Enigma Homolog (ENH). PDLIM5 is expressed postsynaptically in excitatory pyramidal neurons of the hippocampus and associates with SPAR protein in the brain. In hippocampal neurons, PDLIM5 promotes decreased dendritic spine size, opposite to the effect of SPAR overexpression that causes spine head enlargement.
Single nucleotide polymorphisms in PDLIM5 have been associated with schizophrenia, depression, and bipolar disorder (Kato et al. 2005, Li et al. 2008, Liu et al. 2008), although the physiological functions of PDLIM5 are not well understood.
R-HSA-6794355 (Reactome) Homer proteins are closely related neuronal scaffolding molecules that selectively binds the C-terminus of group 1 metabotropic or heterotrimeric GTP-binding protein-linked glutamate receptors (mGluR1a and mGluR5) and are enriched at excitatory synapses (Brakeman et al. 1997, Xiao et al. 1998). Homer proteins contain an amino-terminal EVH1 domain followed by a rod-shaped coiled-coil domain. The EVH1 domain of Homer can bind the proline rich motifs in mGluRs and the inositol 1,4,5-trisphosphate (IP3) receptors, thereby linking these receptors in a signalling complex (Tu et al. 1998, 1999).
R-HSA-6794356 (Reactome) Disks large homolog proteins (DLGs, Post synaptic density proteins) 2, 3 and 4 interact with BEGAIN (Brain-enriched Guanylate Kinase-associated Protein) via their guanylate kinase-like (GK) domain. BEGAIN is specifically expressed in brain and enriched in the PSD fraction and may be involved in the organization of the components of synaptic junctions (Deguchi et al. 2001).
R-HSA-6794357 (Reactome) PSD-95 interacts with GKAP through its GK domain (Kim et al. 1997). In turn, the C-terminus of GKAP binds to the Shank family of PDZ-containing scaffold proteins. The Shank family of proteins is highly enriched in the postsynaptic density (PSD) of excitatory synapses in brain. There are three known SHANK proteins: SHANK1, SHANK2, and SHANK3. SHANK contains multiple domains for protein-protein interactions, including ankyrin repeats, SH3 domain, PDZ domain, SAM domain, and an extensive proline-rich region (Sheng & Kim 2000). Shank may function as a scaffold protein in the PSD, potentially cross-linking NMDA receptor or Neuroligin:PSD-95 complexes and coupling them to regulators of the actin cytoskeleton (Naisbitt et al.1999).
R-HSA-6797553 (Reactome) The protein 4.1 family includes four well-defined members: erythroid protein 4.1 (4.1R), the bestknown and characterized member, 4.1G (general), 4.1N (neuronal), and 4.1 B (brain). Protein 4.1N is a neuronal homologue of erythrocyte membrane cytoskeletal protein 4.1 (4.1R). Protein 4.1N can stabilize the plasticity of the neuronal membrane via interactions with the spectrin-actin-based skeleton, integral membrane channels and receptors, and membrane-associated guanylate kinases (Diakowski et al. 2006). This brain-specific protein 4.1N isoform intercts with CASK and recruits actin and spectrin (Biederer & Sudhof 2001).
R-HSA-6797554 (Reactome) At the PSD (postsynaptic density), activity-dependent reorganizations of the cortical actin cytoskeleton are hypothesized to play a role in synaptic plasticity. Drebrin-like protein (DBNL) (also referred as Filamentous actin (F-actin)-binding protein 1 (ABP1)), which controls Arp2/3 complex-mediated actin nucleation binds to postsynaptic scaffold proteins of the ProSAP (proline-rich synapse-associated protein 1)/Shank family. This DBNL–ProSAP/Shank complexes serve to connect synaptic signal reception to postsynaptic structural plasticity via rearrangements of the actin cytoskeleton in spines (Haeckel et al. 2008).
R-HSA-6797568 (Reactome) In neurons, CASK forms a stable tripartite complex with brain-enriched Veli proteins and brain-specific Mint1 and anchors this complex to neurexins (Butz et al. 1998). CASK also binds to a brain-enriched isoform of protein 4.1, and nucleates local assembly of actin/spectrin filaments. Neurexins are recruited together with CASK and protein 4.1 into these actin filaments and thus intercellular junctions initiated by neurexins with neuroligins are at least partially coupled to the actin cytoskeleton (Biederer & Sudhof 2001).
R-HSA-6797974 (Reactome) The LRRTM (leucine-rich repeat (LRR) transmembrane neuronal) are a small family of paralogous LRR containing cell surface receptors. This family has four members (LRRTM 1-4) that share similar domain structure with an extracellular domain containing ten extracellular leucine-rich repeats that mediate protein-protein interactions, followed by a single transmembrane domain and a short c-terminal sequence containing a class I PDZ-domain-binding motif. LRRTMs are predominantely expressed in the nervous system. All four LRRTMs family members are post-synaptic localized and bind specifically to presynaptic alpha and beta-Neurexins (NRXNs) lacking an insert at splice site S4 (Siddiqui et al. 2010). Neuroligins bind NRXN containing or lacking an insert in S4, LRRTMs bind only NRXNs lacking an insert in this splicing site (de Wit et al. 2009, Ko et al. 2009).
SHANK1,2,3R-HSA-6794351 (Reactome)
SHANK1,2,3R-HSA-6794357 (Reactome)
SHARPIN:SHANK1,2,3ArrowR-HSA-6794351 (Reactome)
SHARPINR-HSA-6794351 (Reactome)
SPARR-HSA-6794349 (Reactome)
STX1A:MUNC18:MINT1,2,(3)R-HSA-6794353 (Reactome)
SYTR-HSA-6794348 (Reactome)
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