Glutamate binding, activation of AMPA receptors and synaptic plasticity (Homo sapiens)

From WikiPathways

Jump to: navigation, search
6, 7, 9462135, 85, 822cytosolendocytic vesicleAP2 complexGRIA3 Activatedconventionalprotein kinase Cp-S880-GRIA2 GRIA1 NSFGRIA4 GRIA1 ATPCa impermeable AMPAreceptors (withphospho GluR2 S880)CACNG8 GRIA3 EPB41L1GRIA2 AP2A1 AP2A2-3 GRIP1 TARP-PSD95-Mdm2GRIP2 GRIA2 p-T287-CAMK2G ADPADPp-T287-CAMK2B p-T286-CAMK2A L-Glu L-Glup-T287-CAMK2D GRIA3 Ca2+ CACNG4 ADPCACNG4 PRKCG Ca permeable AMPAreceptorsGRIA3 GRIP1/GRIP2GRIA2 GRIA1 PiGRIA4 DLG4 GRIA4 Ca permeable AMPAreceptor ligandcomplexCACNG3 AP2S1-1 PiCa2+Ca impermeable AMPAreceptorsDLG1L-Glu ATPGRIA4 GRIA1 PRKCB Ca impermeable AMPAreceptor ligandcomplexCa2+GRIA3 CACNG3 AP2AMDM2 AP2A2-3 GRIA1 AP2B1-1 PICK1GRIA1 PS MYO6GRIA3 TSPAN7:PICK1DLG1CACNG8 Ca impermeable AMPAreceptorsGRIP2 PICK1 CACNG2 DLG4 PICK1Na+Ca permeable AMPAreceptorsPRKCA GRIA3 AP2A1 Na+AKAP5MYO6GRIA4 ATPGRIP1 CACNG2 ATPCaMKIIGRIP1/GRIP2DAG TSPAN7 TARP-PSD95-Mdm2MDM2 EPB41L1PiAP2M1-2 ADPAKAP5GRIA4 GRIA4 PiGRIA1


Description

Excitatory synaptic transmission in the brain is carried out by glutamate receptors through the activation of both ionotropic and metabotropic receptors. Ionotropic glutamate receptors are of three subtypes based on distinct physiologic properties and their differential binding of exogenous ligands namely NMDA (N-methyl D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and Kainate . The ionotropic receptors are glutamate gated ion channels that initiate signaling by influx of ions, and are comprised of subunits with distinct structures and distinguished based on their agonist binding. Even though all three types of receptors are found at the glutamatergic synapses yet they exhibit great diversity in the synaptic distribution. The metabotropic glutamate receptors are a family of G-protein coupled receptors that are slow acting. Fast excitatory synaptic transmission is carried out through AMPA receptors. Post-synaptic transmission involves binding of the ligand such as glutamate/AMPA to the AMPA receptor resulting in the Na influx which causes depolarization of the membrane. NMDA receptors are blocked by Mg at resting membrane potential. NMDA receptors are activated upon coincident depolarization and glutamate binding are activated following AMPA receptor activation.NMDA receptors are blocked by Mg at resting
membrane potential. NMDA receptors are Ca permeable and their activity leads to increase in Ca which, leads to upregulation of AMPA receptors at the synapse which causes the long lasting excitatory post-synaptic potential (EPSP) which forms the basis of long term potentiation (LTP). LTP is one form of synaptic plasticity wherein the strength of the synapses is enhanced by either change in the number, increase in the efficacy by phosphorylation or change in the type of receptors. Phosphorylation of AMPA receptors changes the localization of the receptors, increases the single channel conductance, and increases the probability of open channel. GluR1 has four phosphorylation sites; serine 818 (S818) is phosphorylated by PKC and is necessary for LTP, serine 831 (S831) is phosphorylated by CaMKII that increases the delivery of receptors to the synapse and also increased their single channel conductance, threonine (T840) is implicated in LTP. Serine 845 (S845) is phosphorylated by PKA which regulates open channel probability. Long term depression is another form of plasticity wherein the number of AMPA receptors is diminished by either phosphorylation of GluR2 at Ser880 or dephosphorylation of GluR1 by protein phosphatase1, protein phosphatase 2A and protein phosphatase 2B (calcineurin). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 399721
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Mahajan, SS

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Kott S, Werner M, Körber C, Hollmann M.; ''Electrophysiological properties of AMPA receptors are differentially modulated depending on the associated member of the TARP family.''; PubMed Europe PMC
  2. Lu W, Ziff EB.; ''PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking.''; PubMed Europe PMC
  3. Ishiuchi S, Tsuzuki K, Yoshida Y, Yamada N, Hagimura N, Okado H, Miwa A, Kurihara H, Nakazato Y, Tamura M, Sasaki T, Ozawa S.; ''Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells.''; PubMed Europe PMC
  4. Correia SS, Bassani S, Brown TC, Lisé MF, Backos DS, El-Husseini A, Passafaro M, Esteban JA.; ''Motor protein-dependent transport of AMPA receptors into spines during long-term potentiation.''; PubMed Europe PMC
  5. Li G, Pei W, Niu L.; ''Channel-opening kinetics of GluR2Q(flip) AMPA receptor: a laser-pulse photolysis study.''; PubMed Europe PMC
  6. Kessels HW, Malinow R.; ''Synaptic AMPA receptor plasticity and behavior.''; PubMed Europe PMC
  7. Cull-Candy S, Kelly L, Farrant M.; ''Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond.''; PubMed Europe PMC
  8. Coleman SK, Möykkynen T, Jouppila A, Koskelainen S, Rivera C, Korpi ER, Keinänen K.; ''Agonist occupancy is essential for forward trafficking of AMPA receptors.''; PubMed Europe PMC
  9. Lee HK.; ''Synaptic plasticity and phosphorylation.''; PubMed Europe PMC

History

CompareRevisionActionTimeUserComment
101666view13:46, 1 November 2018DeSlOntology Term : 'glutamate signaling pathway via AMPA receptor' added !
101660view11:51, 1 November 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AKAP5ProteinP24588 (Uniprot-TrEMBL)
AP2 complexComplexR-HSA-416629 (Reactome)
AP2A1 ProteinO95782 (Uniprot-TrEMBL)
AP2A2-3 ProteinO94973-3 (Uniprot-TrEMBL)
AP2AComplexR-HSA-416640 (Reactome)
AP2B1-1 ProteinP63010-1 (Uniprot-TrEMBL)
AP2M1-2 ProteinQ96CW1-2 (Uniprot-TrEMBL)
AP2S1-1 ProteinP53680-1 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated

conventional

protein kinase C
ComplexR-HSA-139830 (Reactome)
CACNG2 ProteinQ9Y698 (Uniprot-TrEMBL)
CACNG3 ProteinO60359 (Uniprot-TrEMBL)
CACNG4 ProteinQ9UBN1 (Uniprot-TrEMBL)
CACNG8 ProteinQ8WXS5 (Uniprot-TrEMBL)
Ca impermeable AMPA

receptor ligand

complex
ComplexR-HSA-420974 (Reactome)
Ca impermeable AMPA

receptors (with

phospho GluR2 S880)
ComplexR-HSA-421001 (Reactome)
Ca impermeable AMPA receptorsComplexR-HSA-399713 (Reactome)
Ca impermeable AMPA receptorsComplexR-HSA-416323 (Reactome)
Ca permeable AMPA

receptor ligand

complex
ComplexR-HSA-420976 (Reactome)
Ca permeable AMPA receptorsComplexR-HSA-399714 (Reactome)
Ca permeable AMPA receptorsComplexR-HSA-416325 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CaMKIIComplexR-HSA-417004 (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.
DAG MetaboliteCHEBI:17815 (ChEBI)
DLG1ProteinQ12959 (Uniprot-TrEMBL)
DLG4 ProteinP78352 (Uniprot-TrEMBL)
EPB41L1ProteinQ9H4G0 (Uniprot-TrEMBL)
GRIA1 ProteinP42261 (Uniprot-TrEMBL)
GRIA2 ProteinP42262 (Uniprot-TrEMBL)
GRIA3 ProteinP42263 (Uniprot-TrEMBL)
GRIA4 ProteinP48058 (Uniprot-TrEMBL)
GRIP1 ProteinQ9Y3R0 (Uniprot-TrEMBL)
GRIP1/GRIP2ComplexR-HSA-416631 (Reactome)
GRIP1/GRIP2ComplexR-HSA-416636 (Reactome)
GRIP2 ProteinQ9C0E4 (Uniprot-TrEMBL)
L-Glu MetaboliteCHEBI:29985 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
MDM2 ProteinQ00987 (Uniprot-TrEMBL)
MYO6ProteinQ9UM54 (Uniprot-TrEMBL)
NSFProteinP46459 (Uniprot-TrEMBL)
Na+MetaboliteCHEBI:29101 (ChEBI)
PICK1 ProteinQ9NRD5 (Uniprot-TrEMBL)
PICK1ProteinQ9NRD5 (Uniprot-TrEMBL)
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCB ProteinP05771 (Uniprot-TrEMBL)
PRKCG ProteinP05129 (Uniprot-TrEMBL)
PS MetaboliteCHEBI:18303 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
TARP-PSD95-Mdm2ComplexR-HSA-416329 (Reactome)
TARP-PSD95-Mdm2ComplexR-HSA-416851 (Reactome)
TSPAN7 ProteinP41732 (Uniprot-TrEMBL)
TSPAN7:PICK1ComplexR-HSA-8858433 (Reactome)
p-S880-GRIA2 ProteinP42262 (Uniprot-TrEMBL)
p-T286-CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
p-T287-CAMK2B ProteinQ13554 (Uniprot-TrEMBL)
p-T287-CAMK2D ProteinQ13557 (Uniprot-TrEMBL)
p-T287-CAMK2G ProteinQ13555 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-416320 (Reactome)
ADPArrowR-HSA-416639 (Reactome)
ADPArrowR-HSA-416985 (Reactome)
ADPArrowR-HSA-421007 (Reactome)
AKAP5ArrowR-HSA-416320 (Reactome)
AKAP5R-HSA-416320 (Reactome)
AP2 complexArrowR-HSA-416639 (Reactome)
AP2 complexR-HSA-416639 (Reactome)
AP2AArrowR-HSA-421007 (Reactome)
AP2AR-HSA-421007 (Reactome)
ATPR-HSA-416320 (Reactome)
ATPR-HSA-416639 (Reactome)
ATPR-HSA-416985 (Reactome)
ATPR-HSA-421007 (Reactome)
Activated

conventional

protein kinase C
mim-catalysisR-HSA-416639 (Reactome)
Activated

conventional

protein kinase C
mim-catalysisR-HSA-421007 (Reactome)
Ca impermeable AMPA

receptor ligand

complex
ArrowR-HSA-420975 (Reactome)
Ca impermeable AMPA

receptor ligand

complex
mim-catalysisR-HSA-399711 (Reactome)
Ca impermeable AMPA

receptors (with

phospho GluR2 S880)
R-HSA-421007 (Reactome)
Ca impermeable AMPA receptorsArrowR-HSA-416639 (Reactome)
Ca impermeable AMPA receptorsArrowR-HSA-416985 (Reactome)
Ca impermeable AMPA receptorsArrowR-HSA-421007 (Reactome)
Ca impermeable AMPA receptorsR-HSA-416639 (Reactome)
Ca impermeable AMPA receptorsR-HSA-416985 (Reactome)
Ca impermeable AMPA receptorsR-HSA-420975 (Reactome)
Ca permeable AMPA

receptor ligand

complex
ArrowR-HSA-420977 (Reactome)
Ca permeable AMPA

receptor ligand

complex
mim-catalysisR-HSA-399712 (Reactome)
Ca permeable AMPA

receptor ligand

complex
mim-catalysisR-HSA-420980 (Reactome)
Ca permeable AMPA receptorsArrowR-HSA-416320 (Reactome)
Ca permeable AMPA receptorsR-HSA-416320 (Reactome)
Ca permeable AMPA receptorsR-HSA-420977 (Reactome)
Ca2+ArrowR-HSA-399712 (Reactome)
Ca2+R-HSA-399712 (Reactome)
CaMKIImim-catalysisR-HSA-416320 (Reactome)
DLG1ArrowR-HSA-416320 (Reactome)
DLG1R-HSA-416320 (Reactome)
EPB41L1ArrowR-HSA-416320 (Reactome)
EPB41L1R-HSA-416320 (Reactome)
GRIP1/GRIP2ArrowR-HSA-416639 (Reactome)
GRIP1/GRIP2ArrowR-HSA-416985 (Reactome)
GRIP1/GRIP2ArrowR-HSA-421007 (Reactome)
GRIP1/GRIP2R-HSA-416639 (Reactome)
GRIP1/GRIP2R-HSA-416985 (Reactome)
GRIP1/GRIP2R-HSA-421007 (Reactome)
L-GluR-HSA-420975 (Reactome)
L-GluR-HSA-420977 (Reactome)
MYO6ArrowR-HSA-416320 (Reactome)
MYO6R-HSA-416320 (Reactome)
NSFmim-catalysisR-HSA-416985 (Reactome)
Na+ArrowR-HSA-399711 (Reactome)
Na+ArrowR-HSA-420980 (Reactome)
Na+R-HSA-399711 (Reactome)
Na+R-HSA-420980 (Reactome)
PICK1ArrowR-HSA-416639 (Reactome)
PICK1ArrowR-HSA-416985 (Reactome)
PICK1ArrowR-HSA-421007 (Reactome)
PICK1R-HSA-416639 (Reactome)
PICK1R-HSA-416985 (Reactome)
PICK1R-HSA-421007 (Reactome)
PiArrowR-HSA-416320 (Reactome)
PiArrowR-HSA-416639 (Reactome)
PiArrowR-HSA-421007 (Reactome)
PiR-HSA-416985 (Reactome)
R-HSA-399711 (Reactome) Each AMPA receptor subunit binds one glutamate molecule in the ligand binding site in the N terminus. Each receptor is capable of binding four glutamate molecules however, channel opens when two sites are occupied by the ligand and the current increases with increased ligand binding. Ca impermeable AMPA receptors containing GluR2 subunit conduct Na currents upon activation by either glutamate binding or agonist, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding. The Na currents mainly lead to depolarization of the membrane leading to activation of voltage gated channels such as NMDA receptors that require both agonist binding and depolarization for their activation.
R-HSA-399712 (Reactome) Each AMPA receptor subunit binds one glutamate molecule in the ligand binding site in the N terminus. Each receptor is capable of binding four glutamate molecule, however, channel opens when two sites are occupied by the ligand and the current increases with increased ligand binding. Ca permeable AMPA receptors containing homomers of GluR1 or heteromers containing GluR1, GluR3 and GluR4 conduct Ca upon glutamate or agonist namely AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding. Calcium permeable AMPA receptors conduct Ca and other cations such as Na. The inonic flux leads to Ca or Na currents that leads to either increase in the intracellular Ca concentration leading to further Ca-dependent signaling or increase in depolarization that opens voltage gated channels such as NMDA receptors that require both membrane depolarization and glutamate binding for activation.
R-HSA-416320 (Reactome) GluR1-containing AMPA receptors are delivered to the synapses in an activity dependent manner. GluR1 trafficking is controlled by protein- protein interactions with 4.1N/G protein, SAP97 and by intricate regulation of phosphorylation of GluR1 at several phosphorylation sites in the C tail. GluR1 has four phosphorylation sites; serine 818 (S818) is phosphorylated by PKC, necessary for LTP, serine 831 (S831) is phosphorylated by CaMKII and increases the delivery of receptors to the synapse and also increases their single channel conductance, Threonine (T840) is implicated in LTP and serine 845 (S845) phosphorylated by PKA regulates open channel probability and also by cGKII, a cyclic GMP activated kinase, that increases the surface expression of GluR1. GluR1 insertion into synapse by CaMKII may induce LTP. CaMKII is a Ca/calmodulin dependent kinase that is activated upon increases in the Ca ion concentration during postsynaptic activity through NMDA receptors. The increase in GluR1-containing AMPA receptor population at the synapse results in enhancement of excitatory post synaptic potential (EPSC) which forms the basis of Long term potentiation (LTP). LTP is one form of synaptic plasticity that is involved in memory and learning. The increase in the GluR1 containing AMPA receptors and their activity leads to rise in intracellular Ca which induces signaling pathways that in turn promote switch in the type of AMPA receptors (Ca impermeable) thereby limiting the Ca increase and preventing cell death.
R-HSA-416639 (Reactome) GluR2 containing AMPA receptors are trafficked to the plasmamembrane by the activation of Ca activated PKC that binds PICK.The PICK interaction delivers GluR2 containing AMPA receptors to the Plasmamembrane. This reaction is a part of constitutive recycling of AMPA receptor that delivers the AMPA receptors from the endosome to the plasmamembrane and back to endosome from the plasmamembrane.
R-HSA-416985 (Reactome) Constitutively recycling GluR2 containing AMPA receptors in the plasma membrane are stabilized by the action of NSF ATPase activity which disassociates PICK from GluR2 thereby retaining AMPA receptors in the plasma membrane.
R-HSA-420975 (Reactome) AMPA receptors bind glutamate, released in the synaptic cleft by the presynaptic cell, in the ligand binding region in the N terminal domain.
R-HSA-420977 (Reactome) AMPA receptors bind glutamate, released in the synaptic cleft by the presynaptic cell, in the ligand binding region in the N terminal domain.
R-HSA-420980 (Reactome) Each AMPA receptor subunit binds one glutamate molecule in the ligand binding site in the N terminus. Each receptor is capable of binding four glutamate molecule, however, channel opens when two sites are occupied by the ligand and the current increases with increased ligand binding. Ca permeable AMPA receptors containing homomers of GluR1 or heteromers containing GluR1, GluR3 and GluR4 conduct Ca upon glutamate or agonist namely AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding. Calcium permeable AMPA receptors conduct Ca and other cations such as Na. The inonic flux leads to Ca or Na currents that leads to either increase in the intracellular Ca concentration leading to further Ca-dependent signaling or increase in depolarization that opens voltage gated channels such as NMDA receptors that require both membrane depolarization and glutamate binding for activation.
R-HSA-421007 (Reactome) GluR2 containing AMPA receptors are constitutively recycled between the endosome membrane and the plasma membrane. GRIP and PICK compete for the binding to the C tail of GluR2. Once the GluR2 containing AMPA receptors are in the plasmamembrane, phosphorylation of GluR2 at S880 by PKC causes disruption of GRIP interaction, but not PICK interaction which facilitates internalization of GluR2 containing AMPA receptors into endosomes.
TARP-PSD95-Mdm2ArrowR-HSA-416320 (Reactome)
TARP-PSD95-Mdm2R-HSA-416320 (Reactome)
TSPAN7:PICK1TBarR-HSA-416985 (Reactome)
Personal tools