Activation of NMDA receptors and postsynaptic events (Homo sapiens)

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14, 19, 3020515829234, 12, 13, 25, 2824316226217, 27, 311117, 3224926nucleoplasmcytosolCAMK2B ADCY3 ACTN2 p-T286-CAMK2A CALM1:4xCa2+HRAS:GTPGly:L-Glu:GRIN1:GRIN2 NMDA receptorsL-GluNa+p-T287-CAMK2D p-T185,Y187-MAPK1LRRC7 ATPPRKACA,(PRKACB,PRKACG,PRKX)p-S363,S380,T573-RPS6KA1 p-S338-BRAF Mg2+phospho-CaMKIV:CalmodulinCALM1 NEFL ADCY1 CaMKIIDLG2 RASGRF2 GRIN1 CAMK2G GRIN1:GRIN2 NMDAreceptors:PSDproteinsCAMK2D CAMK2B GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers Ca2+GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers RPS6KA3 DLG2 CAMK4 RasGTP-B raf compexRASGRF1 GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers ADPCAMK2 heteromerCa2+ PDPK1HRAS p-T286-CAMK2A ACTN2 RRAS RasGRFPPip-T287-CAMK2B Gly GRIN2B CAMK2D Phospho(S363,S380,T573)-ribosomal S6 kinaseGRIN1 Glutamate binding,activation of AMPAreceptors andsynaptic plasticityp-S227,S369,S386,T573-RPS6KA3 GTP GRIA1 L-Glu p-T286-CAMK2A L-Glu CAMK2B ATPGRIA4 p-T287-CAMK2G LRRC7 GRIN2B GRIN1 LRRC7 DLG4 NEFL GRIN2B CAMK2G ACTN2 Activated B-rafcomplexCALM1 GRIN2B HRAS p-S133-CREB1CAMK2D CAMK4 DLG1 CaMKIIp-S221,S363,S380,T573-RPS6KA1 p-T287-CAMK2D p-S369,S386,T573-RPS6KA3 DLG1 DLG3 CAMK2D Phospho(S221,S363,S380,T573)-ribosomal S6 kinaseATPRASGRF2 CREB1DLG3 Phospho(S363,S380,T573)- ribosomal S6 kinaseCAMK2D Ca2+CAMK4p-S372,S389,T581-RPS6KA6 HRAS:GDPGRIN1 GRIA3 GTP GRIN1:GRIN2 NMDAreceptors:PSDproteins:Mg2+NEFL PRKACB GRIA2 ATPCalmodulin:CaMK IVCalmodulin:CaMK IVcAMPADPPRKACG RPS6KA6 DLG3 CAMK2G MAPK1CAMK2A DLG3 ADPGly CALM1 CAMK2B RASGRF1 GlyGRIN1 ADCY8 p-S360,S377,T570-RPS6KA2 RPS6KA1 Mg2+ L-Glu CALM1 CAMKK1NEFL p-S12,S13-CAMK4 p-S372,S389,T581-RPS6KA6 GDP Ca2+ p-T287-CAMK2D CALM1CAMK2G Gly:L-Glu:GRIN1:GRIN2 NMDA receptors:PSD proteins:Mg2+Ca2+ p-S360,S377,T570-RPS6KA2 Ca2+ p-T286-CAMK2A ATPCAMK2G NEFL DLG2 CAMK2B ATPp-CAMKK1DLG2 GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers ATPp-S338-RAF1L-Glu Gly CAMK2A RPS6KA2 p-T287-CAMK2G ACTN2 ADPp-S218,S360,S377,T570-RPS6KA2 p-T287-CAMK2B Ca impermeable AMPAreceptor ligandcomplexADPCALM1 CALM1 ADP p-T287-CAMK2G DLG1 CAMK2heteromer:CALM:4xCa2+CAMK2A GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers LRRC7 RRAS DLG3 Ca/calmodulinactivated AdenylateCyclasePRKACA LRRC7 DLG4 p-S369,S386,T573-RPS6KA3 RasGRF:Ca/calmodulinDLG4 Ca2+ p-T287-CAMK2B GTP BRAF DLG1 ADPADPACTN2 p-T287-CAMK2D p-S363,S380,T573-RPS6KA1 Ribosomal S6 kinasePRKX DLG4 Mg2+ Ca2+ ADP ATPNa+p-T287-CAMK2G DLG2 p-S232,S372,S389,T581-RPS6KA6 CAMK2A DLG4 CAMK2A GRIN2B p-T287-CAMK2B DLG1 1, 2, 102318


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, and Paoletti et al. 2013. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 442755
Reactome version: 66
Reactome Author 
Reactome Author: Mahajan, SS

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Ontology Terms



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  1. Kessels HW, Malinow R.; ''Synaptic AMPA receptor plasticity and behavior.''; PubMed Europe PMC
  2. Lee HK.; ''Synaptic plasticity and phosphorylation.''; PubMed Europe PMC
  3. García S, López E, López-Colomé AM.; ''Glutamate accelerates RPE cell proliferation through ERK1/2 activation via distinct receptor-specific mechanisms.''; PubMed Europe PMC
  4. Mei M, Su B, Harrison K, Chao M, Siedlak SL, Previll LA, Jackson L, Cai DX, Zhu X.; ''Distribution, levels and phosphorylation of Raf-1 in Alzheimer's disease.''; PubMed Europe PMC
  5. Bossuyt J, Helmstadter K, Wu X, Clements-Jewery H, Haworth RS, Avkiran M, Martin JL, Pogwizd SM, Bers DM.; ''Ca2+/calmodulin-dependent protein kinase IIdelta and protein kinase D overexpression reinforce the histone deacetylase 5 redistribution in heart failure.''; PubMed Europe PMC
  6. Lemrow SM, Anderson KA, Joseph JD, Ribar TJ, Noeldner PK, Means AR.; ''Catalytic activity is required for calcium/calmodulin-dependent protein kinase IV to enter the nucleus.''; PubMed Europe PMC
  7. Anjum R, Blenis J.; ''The RSK family of kinases: emerging roles in cellular signalling.''; PubMed Europe PMC
  8. Roux PP, Richards SA, Blenis J.; ''Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.''; PubMed Europe PMC
  9. Harum KH, Alemi L, Johnston MV.; ''Cognitive impairment in Coffin-Lowry syndrome correlates with reduced RSK2 activation.''; PubMed Europe PMC
  10. Cull-Candy S, Kelly L, Farrant M.; ''Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond.''; PubMed Europe PMC
  11. Itoh T, Itoh A, Horiuchi K, Pleasure D.; ''AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+.''; PubMed Europe PMC
  12. Gómez-Santos C, Ferrer I, Reiriz J, Viñals F, Barrachina M, Ambrosio S.; ''MPP+ increases alpha-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells.''; PubMed Europe PMC
  13. Salzano M, Rusciano MR, Russo E, Bifulco M, Postiglione L, Vitale M.; ''Calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates Raf-1 at serine 338 and mediates Ras-stimulated Raf-1 activation.''; PubMed Europe PMC
  14. Paoletti P, Bellone C, Zhou Q.; ''NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.''; PubMed Europe PMC
  15. Bilbao A, Parkitna JR, Engblom D, Perreau-Lenz S, Sanchis-Segura C, Schneider M, Konopka W, Westphal M, Breen G, Desrivieres S, Klugmann M, Guindalini C, Vallada H, Laranjeira R, de Fonseca FR, Schumann G, Schütz G, Spanagel R.; ''Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine.''; PubMed Europe PMC
  16. Cairns BE, Svensson P, Wang K, Hupfeld S, Graven-Nielsen T, Sessle BJ, Berde CB, Arendt-Nielsen L.; ''Activation of peripheral NMDA receptors contributes to human pain and rat afferent discharges evoked by injection of glutamate into the masseter muscle.''; PubMed Europe PMC
  17. Jensen CJ, Buch MB, Krag TO, Hemmings BA, Gammeltoft S, Frödin M.; ''90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1.''; PubMed Europe PMC
  18. Chen TY, Illing M, Molday LL, Hsu YT, Yau KW, Molday RS.; ''Subunit 2 (or beta) of retinal rod cGMP-gated cation channel is a component of the 240-kDa channel-associated protein and mediates Ca(2+)-calmodulin modulation.''; PubMed Europe PMC
  19. Cohen S, Greenberg ME.; ''Communication between the synapse and the nucleus in neuronal development, plasticity, and disease.''; PubMed Europe PMC
  20. Yamamori E, Asai M, Yoshida M, Takano K, Itoi K, Oiso Y, Iwasaki Y.; ''Calcium/calmodulin kinase IV pathway is involved in the transcriptional regulation of the corticotropin-releasing hormone gene promoter in neuronal cells.''; PubMed Europe PMC
  21. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C, Ben-Ari Y, Clapham DE, Medina I.; ''The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1.''; PubMed Europe PMC
  22. Wu X, McMurray CT.; ''Calmodulin kinase II attenuation of gene transcription by preventing cAMP response element-binding protein (CREB) dimerization and binding of the CREB-binding protein.''; PubMed Europe PMC
  23. Anborgh PH, Qian X, Papageorge AG, Vass WC, DeClue JE, Lowy DR.; ''Ras-specific exchange factor GRF: oligomerization through its Dbl homology domain and calcium-dependent activation of Raf.''; PubMed Europe PMC
  24. Williams CL, Phelps SH, Porter RA.; ''Expression of Ca2+/calmodulin-dependent protein kinase types II and IV, and reduced DNA synthesis due to the Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 (1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenyl piperazine) in small cell lung carcinoma.''; PubMed Europe PMC
  25. Rajakulendran T, Sahmi M, Lefrançois M, Sicheri F, Therrien M.; ''A dimerization-dependent mechanism drives RAF catalytic activation.''; PubMed Europe PMC
  26. Chatila T, Anderson KA, Ho N, Means AR.; ''A unique phosphorylation-dependent mechanism for the activation of Ca2+/calmodulin-dependent protein kinase type IV/GR.''; PubMed Europe PMC
  27. Richards SA, Dreisbach VC, Murphy LO, Blenis J.; ''Characterization of regulatory events associated with membrane targeting of p90 ribosomal S6 kinase 1.''; PubMed Europe PMC
  28. Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD.; ''Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.''; PubMed Europe PMC
  29. Hellevuo K, Yoshimura M, Kao M, Hoffman PL, Cooper DM, Tabakoff B.; ''A novel adenylyl cyclase sequence cloned from the human erythroleukemia cell line.''; PubMed Europe PMC
  30. Hardingham GE, Bading H.; ''Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders.''; PubMed Europe PMC
  31. Smith JA, Poteet-Smith CE, Malarkey K, Sturgill TW.; ''Identification of an extracellular signal-regulated kinase (ERK) docking site in ribosomal S6 kinase, a sequence critical for activation by ERK in vivo.''; PubMed Europe PMC
  32. Zeniou M, Ding T, Trivier E, Hanauer A.; ''Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning.''; PubMed Europe PMC


101671view13:49, 1 November 2018DeSlOntology Term : 'glutamate signaling pathway via NMDA receptor' added !
101656view11:51, 1 November 2018ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
ACTN2 ProteinP35609 (Uniprot-TrEMBL)
ADCY1 ProteinQ08828 (Uniprot-TrEMBL)
ADCY3 ProteinO60266 (Uniprot-TrEMBL)
ADCY8 ProteinP40145 (Uniprot-TrEMBL)
ADP MetaboliteCHEBI:16761 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated B-raf complexComplexR-HSA-1063697 (Reactome)
BRAF ProteinP15056 (Uniprot-TrEMBL)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:4xCa2+ComplexR-HSA-74294 (Reactome)
CALM1ProteinP0DP23 (Uniprot-TrEMBL)
CAMK2 heteromer:CALM:4xCa2+ComplexR-HSA-444601 (Reactome)
CAMK2 heteromerComplexR-HSA-432792 (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.
CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
CAMK2B ProteinQ13554 (Uniprot-TrEMBL)
CAMK2D ProteinQ13557 (Uniprot-TrEMBL)
CAMK2G ProteinQ13555 (Uniprot-TrEMBL)
CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
CAMK4ProteinQ16566 (Uniprot-TrEMBL)
CAMKK1ProteinQ8N5S9 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
Ca impermeable AMPA

receptor ligand

ComplexR-HSA-420974 (Reactome)

activated Adenylate

ComplexR-HSA-443461 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CaMKIIComplexR-HSA-444796 (Reactome)
CaMKIIComplexR-HSA-445374 (Reactome)
Calmodulin:CaMK IVComplexR-HSA-111900 (Reactome)
Calmodulin:CaMK IVComplexR-HSA-112281 (Reactome)
DLG1 ProteinQ12959 (Uniprot-TrEMBL)
DLG2 ProteinQ15700 (Uniprot-TrEMBL)
DLG3 ProteinQ92796 (Uniprot-TrEMBL)
DLG4 ProteinP78352 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GRIA1 ProteinP42261 (Uniprot-TrEMBL)
GRIA2 ProteinP42262 (Uniprot-TrEMBL)
GRIA3 ProteinP42263 (Uniprot-TrEMBL)
GRIA4 ProteinP48058 (Uniprot-TrEMBL)
GRIN1 ProteinQ05586 (Uniprot-TrEMBL)


ComplexR-HSA-9614184 (Reactome)


ComplexR-HSA-9611369 (Reactome)
GRIN1:GRIN2A,C,D di-heteromers,GRIN1:GRIN2 tri-heteromers R-HSA-9610756 (Reactome)
GRIN2B ProteinQ13224 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
Glutamate binding,

activation of AMPA receptors and

synaptic plasticity
PathwayR-HSA-399721 (Reactome) 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).
Gly MetaboliteCHEBI:57305 (ChEBI)
Gly:L-Glu:GRIN1:GRIN2 NMDA receptors:PSD proteins:Mg2+ComplexR-HSA-9614256 (Reactome)
Gly:L-Glu:GRIN1:GRIN2 NMDA receptorsComplexR-HSA-9614253 (Reactome)
GlyMetaboliteCHEBI:57305 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
HRAS:GDPComplexR-HSA-206896 (Reactome)
HRAS:GTPComplexR-HSA-206946 (Reactome)
L-Glu MetaboliteCHEBI:29985 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
LRRC7 ProteinQ96NW7 (Uniprot-TrEMBL)
MAPK1ProteinP28482 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mg2+MetaboliteCHEBI:18420 (ChEBI)
NEFL ProteinP07196 (Uniprot-TrEMBL)
Na+MetaboliteCHEBI:29101 (ChEBI)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACA,(PRKACB,PRKACG,PRKX)ComplexR-HSA-9615387 (Reactome)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PRKX ProteinP51817 (Uniprot-TrEMBL)
Phospho(S221,S363,S380,T573)-ribosomal S6 kinaseComplexR-HSA-444291 (Reactome)
Phospho(S363,S380,T573)- ribosomal S6 kinaseComplexR-HSA-444261 (Reactome)
Phospho(S363,S380,T573)-ribosomal S6 kinaseComplexR-HSA-445403 (Reactome)
RASGRF1 ProteinQ13972 (Uniprot-TrEMBL)
RASGRF2 ProteinO14827 (Uniprot-TrEMBL)
RPS6KA1 ProteinQ15418 (Uniprot-TrEMBL)
RPS6KA2 ProteinQ15349 (Uniprot-TrEMBL)
RPS6KA3 ProteinP51812 (Uniprot-TrEMBL)
RPS6KA6 ProteinQ9UK32 (Uniprot-TrEMBL)
RRAS ProteinP10301 (Uniprot-TrEMBL)
RasGRF:Ca/calmodulinComplexR-HSA-442735 (Reactome)
RasGRFComplexR-HSA-442734 (Reactome)
RasGTP-B raf compexComplexR-HSA-1063687 (Reactome)
Ribosomal S6 kinaseComplexR-HSA-444247 (Reactome)
cAMPMetaboliteCHEBI:17489 (ChEBI)
p-CAMKK1ProteinQ8N5S9 (Uniprot-TrEMBL)
p-S12,S13-CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S218,S360,S377,T570-RPS6KA2 ProteinQ15349 (Uniprot-TrEMBL)
p-S221,S363,S380,T573-RPS6KA1 ProteinQ15418 (Uniprot-TrEMBL)
p-S227,S369,S386,T573-RPS6KA3 ProteinP51812 (Uniprot-TrEMBL)
p-S232,S372,S389,T581-RPS6KA6 ProteinQ9UK32 (Uniprot-TrEMBL)
p-S338-BRAF ProteinP15056 (Uniprot-TrEMBL)
p-S338-RAF1ProteinP04049 (Uniprot-TrEMBL)
p-S360,S377,T570-RPS6KA2 ProteinQ15349 (Uniprot-TrEMBL)
p-S363,S380,T573-RPS6KA1 ProteinQ15418 (Uniprot-TrEMBL)
p-S369,S386,T573-RPS6KA3 ProteinP51812 (Uniprot-TrEMBL)
p-S372,S389,T581-RPS6KA6 ProteinQ9UK32 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1ProteinP28482 (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)
phospho-CaMK IV:CalmodulinComplexR-HSA-111904 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-111912 (Reactome)
ADPArrowR-HSA-111915 (Reactome)
ADPArrowR-HSA-111919 (Reactome)
ADPArrowR-HSA-442724 (Reactome)
ADPArrowR-HSA-442726 (Reactome)
ADPArrowR-HSA-442737 (Reactome)
ADPArrowR-HSA-442739 (Reactome)
ADPArrowR-HSA-442749 (Reactome)
ADPArrowR-HSA-443475 (Reactome)
ADPArrowR-HSA-444253 (Reactome)
ATPR-HSA-111912 (Reactome)
ATPR-HSA-111915 (Reactome)
ATPR-HSA-111919 (Reactome)
ATPR-HSA-442715 (Reactome)
ATPR-HSA-442724 (Reactome)
ATPR-HSA-442726 (Reactome)
ATPR-HSA-442737 (Reactome)
ATPR-HSA-442739 (Reactome)
ATPR-HSA-442749 (Reactome)
ATPR-HSA-443475 (Reactome)
ATPR-HSA-444253 (Reactome)
Activated B-raf complexArrowR-HSA-442726 (Reactome)
CALM1:4xCa2+ArrowR-HSA-74448 (Reactome)
CALM1:4xCa2+R-HSA-111913 (Reactome)
CALM1:4xCa2+R-HSA-442725 (Reactome)
CALM1R-HSA-442760 (Reactome)
CALM1R-HSA-74448 (Reactome)
CAMK2 heteromer:CALM:4xCa2+ArrowR-HSA-442725 (Reactome)
CAMK2 heteromerR-HSA-442725 (Reactome)
CAMK2 heteromerR-HSA-445367 (Reactome)
CAMK4R-HSA-111913 (Reactome)
CAMKK1R-HSA-442749 (Reactome)
CAMKK1mim-catalysisR-HSA-442749 (Reactome)
CREB1R-HSA-111912 (Reactome)
CREB1R-HSA-111919 (Reactome)
CREB1R-HSA-442724 (Reactome)
CREB1R-HSA-443475 (Reactome)
Ca impermeable AMPA

receptor ligand

mim-catalysisR-HSA-432162 (Reactome)
Ca impermeable AMPA

receptor ligand

mim-catalysisR-HSA-438037 (Reactome)

activated Adenylate

mim-catalysisR-HSA-442715 (Reactome)
Ca2+ArrowR-HSA-432164 (Reactome)
Ca2+ArrowR-HSA-442715 (Reactome)
Ca2+R-HSA-432164 (Reactome)
Ca2+R-HSA-442715 (Reactome)
Ca2+R-HSA-442760 (Reactome)
Ca2+R-HSA-74448 (Reactome)
CaMKIIArrowR-HSA-444792 (Reactome)
CaMKIIArrowR-HSA-445367 (Reactome)
CaMKIIR-HSA-444792 (Reactome)
CaMKIImim-catalysisR-HSA-442725 (Reactome)
CaMKIImim-catalysisR-HSA-442726 (Reactome)
CaMKIImim-catalysisR-HSA-443475 (Reactome)
Calmodulin:CaMK IVArrowR-HSA-111913 (Reactome)
Calmodulin:CaMK IVArrowR-HSA-112282 (Reactome)
Calmodulin:CaMK IVR-HSA-111915 (Reactome)
Calmodulin:CaMK IVR-HSA-112282 (Reactome)
Calmodulin:CaMK IVmim-catalysisR-HSA-111915 (Reactome)


ArrowR-HSA-9614185 (Reactome)


R-HSA-432172 (Reactome)


R-HSA-9614185 (Reactome)
Gly:L-Glu:GRIN1:GRIN2 NMDA receptors:PSD proteins:Mg2+ArrowR-HSA-432172 (Reactome)
Gly:L-Glu:GRIN1:GRIN2 NMDA receptors:PSD proteins:Mg2+R-HSA-432162 (Reactome)
Gly:L-Glu:GRIN1:GRIN2 NMDA receptorsArrowR-HSA-432162 (Reactome)
Gly:L-Glu:GRIN1:GRIN2 NMDA receptorsR-HSA-442760 (Reactome)
Gly:L-Glu:GRIN1:GRIN2 NMDA receptorsmim-catalysisR-HSA-432164 (Reactome)
Gly:L-Glu:GRIN1:GRIN2 NMDA receptorsmim-catalysisR-HSA-442760 (Reactome)
Gly:L-Glu:GRIN1:GRIN2 NMDA receptorsmim-catalysisR-HSA-445367 (Reactome)
GlyR-HSA-432172 (Reactome)
HRAS:GDPR-HSA-442732 (Reactome)
HRAS:GTPArrowR-HSA-442732 (Reactome)
L-GluR-HSA-432172 (Reactome)
MAPK1R-HSA-442737 (Reactome)
Mg2+ArrowR-HSA-432162 (Reactome)
Mg2+R-HSA-9614185 (Reactome)
Na+ArrowR-HSA-432162 (Reactome)
Na+ArrowR-HSA-438037 (Reactome)
Na+R-HSA-438037 (Reactome)
PDPK1mim-catalysisR-HSA-442739 (Reactome)
PPiArrowR-HSA-442715 (Reactome)
PRKACA,(PRKACB,PRKACG,PRKX)mim-catalysisR-HSA-111919 (Reactome)
Phospho(S221,S363,S380,T573)-ribosomal S6 kinaseArrowR-HSA-442739 (Reactome)
Phospho(S221,S363,S380,T573)-ribosomal S6 kinasemim-catalysisR-HSA-442724 (Reactome)
Phospho(S363,S380,T573)- ribosomal S6 kinaseArrowR-HSA-9029434 (Reactome)
Phospho(S363,S380,T573)- ribosomal S6 kinaseR-HSA-442739 (Reactome)
Phospho(S363,S380,T573)-ribosomal S6 kinaseArrowR-HSA-444253 (Reactome)
Phospho(S363,S380,T573)-ribosomal S6 kinaseR-HSA-9029434 (Reactome)
R-HSA-111912 (Reactome) The cAMP-responsive element binding protein (CREB), a key regulator of gene expression, is activated by phosphorylation on Ser-133. Several different protein kinases possess the capability of driving this phosphorylation, making it a point of potential convergence for multiple intracellular signaling cascades. Work in neurons has indicated that physiologic synaptic stimulation recruits a fast calmodulin kinase IV (CaMKIV)-dependent pathway that dominates early signaling to CREB. Activated CaMKIV phosphorylates CREB at S133 thereby initiating the transcription of CREB regulated set of genes leading to protein synthesis and long lasting changes that underlie synaptic plasticity.
R-HSA-111913 (Reactome) CaMKIV becomes fully activated after a three-step mechanism: Upon a transient increase in intracellular calcium, calcium-bound calmodulin (Ca2+/CaM) binds to its autoregulatory domain, which relieves intersteric inhibition. An activating protein kinase, calcium/calmodulin-dependent protein kinase kinase (CaMKK), binds to the Ca2+/CaM:CaMKIV complex and phosphorylates CaMKIV on a threonine residue in the activation loop. After full activation by the three-step mechanism mentioned above, the activity of CaMKIV becomes autonomous and no longer requires bound Ca2+/CaM. This activity is required for CaMKIV-mediated transcriptional regulation. The CaMKIV-associated PP2A then dephosphorylates CaMKIV, thereby terminating autonomous activity and CaMKIV-mediated gene transcription.
R-HSA-111915 (Reactome) Autophosphorylation of the N-terminus Ser12-Ser13 is required for full activation after Ca2+/calmodulin binding and phosphorylation of the Ca2+/calmodulin-bound enzyme on Thr200 by a Ca2+/calmodulin-dependent protein kinase kinase.
R-HSA-111919 (Reactome) Protein kinase A (PKA) has two regulatory subunits and two catalytic subunits which are held together to form the holoenzyme and is activated upon binding of cAMP to the regulatory subunits. Once cAMP binds the regulatory subunits, the catalytic subunits are released to carry out phosphorylation of CREB1 at serine residue S133. Only the PKA catalytic subunit alpha, PRKACA, was directly demonstrated to phosphorylate CREB1 at S133, using recombinant mouse and rat proteins, respectively (Gonzalez and Montminy 1989). PKA catalytic subunits beta and gamma (PRKACB and PRKACG) are candidate CREB1 kinases based on indirect evidence and sequence similarity (Nagakura et al. 2002, Liang et al. 2007, James et al. 2009). PRKX is the catalytic subunit of the cAMP dependent protein kinase X, which shares the regulatory subunits and functional properties with the PKA. PRKX is highly expressed in the mouse fetal brain (Li et al. 2005) and is implicated in CREB1 phosphorylation through indirect evidence (Di Pasquale and Stacey 1998, Li et al. 2002).
R-HSA-112282 (Reactome) The calmodulin:CaMK IV complex enters the nucleus.
R-HSA-432162 (Reactome) NMDA receptors are activated in a two step mechanism, first by ligand binding and then by removal of the voltage dependent Mg2+ block. At resting membrane potential NMDA receptors can not be activated by ligand alone due to the presence of Mg2+ ion in the pore of the channel. Due to the activation of other membrane resident channels that allow the influx of Na+ the membrane is depolarized which triggers the removal of Mg2+ form the NMDA receptor pore. Once Mg2+ is expelled, agonist (glutamate) and the co-agonist (glycine) bound NMDA receptors become active (Wollmuth et al. 1998, Clarke et al. 2013)..
R-HSA-432164 (Reactome) NMDA receptors are activated upon binding of two ligands, glutamate and glycine.
The activation leads to Ca2+ influx into the post-synaptic cell. The local rise in the Ca2+ ion concentration further leads to activation of several Ca2+ dependent pathways leading to long term changes in the synapse.
R-HSA-432172 (Reactome) NMDA receptors require binding of two ligands; the agonist, glutamate and co-agonist, glycine. The N-terminal extracellular ligand binding domain in NR1 (GRIN1) subunits binds co-agonist glycine and the N-terminal extracellular ligand binding domain in NR2 (GRIN2) binds glutamate. In total, two molecules of glycine (one per each of the two GRIN1 subunits) and two molecules of glutamate (one per each of the two GRIN2 subunits) are bound per one NMDA receptor (Benveniste and Mayer 1991, Andersen et al. 1995, Furukawa et al. 2005).
R-HSA-438037 (Reactome) Membrane depolarization occurs due to glutamate dependent activation of Ca-impermeable AMPA receptors, which permits the influx of Na+ ions. The depolarization triggers the removal of Mg2+ from the NMDA receptor pore to facilitate its activation. Therefore activation of AMPA receptors by glutamate precedes activation of NMDA receptors.
R-HSA-442715 (Reactome) Ca2+ fluxes through NMDA receptors in the post-synaptic neuron facilitate binding of Ca2+/Calmodulin to adenylate cyclase type 1, 3 or 8, resulting in its activation. Once activated, cAMP is produced which further activates PKA.
R-HSA-442724 (Reactome) CREB is phosphorylated at serine 133 by any of the four isoforms of ribosomal S6 kinase.
R-HSA-442725 (Reactome) CaMKII is fully activated upon Ca2+/Calmodulin binding. In addition to Ca2+/Calmodulin activation, CaMKII undergoes multiple autophosphorylation events leading Ca2+/Calmodulin independent activity of the enzyme.
R-HSA-442726 (Reactome) Raf is a downstream effector of ras. Raf is activated upon phosphorylation at S338, oligomerization and membrane localization. Membrane localization is facilitated by ras. Interaction of ras with raf is a necessary step but not sufficient for raf activation. Other unknown protein partner interactions are required for raf activation. Raf further activates MAP kinase.
R-HSA-442732 (Reactome) Binding of RasGRF to Ca2+/Calmodulin in the presence of high Ca2+ leads to the activation of Ras. Activation of Ras involves the exchange of GDP for GTP.
R-HSA-442737 (Reactome) MAPK/ERK is phosphorylated at threonine 185 and tyrosine 187 by membrane associated activated raf kianse leading to the activation of MAPK/ERK kinase. The activated MAPK/ERK in turn activates ribosomal S6 kinase.
R-HSA-442739 (Reactome) PDK1 activates ribosomal S6 kinase (RSK) by phosphorylating S221. The binding site for PDK1 on RSK is available after RSK phosphorylation by MAPK/ERK. PDK1 is present in the activated form at the plasma membrane where the phosphorylation occurs. The activation of RSK occurs in the cytoplasm, plasma membrane and in the nucleus where it finally activates CREB by phosphorylation.
R-HSA-442749 (Reactome) CaMKK is fully activated upon binding Ca2+/Calmodulin after intracellular Ca2+ levels increase. Once CaMKK binds Ca2+/Calmodulin it autophosphorylates, resulting in activation. CaMKK is negatively regulated by phosphorylation of S74 and T108 by PKA. Once activated CaMKK phosphorylates CaMKIV in a Ca2+/Calmodulin dependent manner.
R-HSA-442760 (Reactome) RASGRF is activated upon binding of Ca2+/Calmodulin after Ca2+ influx through the NMDA receptor.
R-HSA-443475 (Reactome) CaMKII is an important regulator of neuronal plasticity. CaMKII shows distinct subcellular localization and acts quickly in a spatio-temporal manner. CaMKII shows fast synaptic localization upon synaptic activity and also nuclear localization, where it phosphorylates CREB at serine 133 to activate transcription of set of genes that results in long lasting structural changes at the synapse.
R-HSA-444253 (Reactome) Activated MAPK/ERK activates RSK in its C terminal kinase domain by sequentially phosphorylating T573, S363 and 380.
R-HSA-444792 (Reactome) Nuclear targeting of CaMKII depends on several factors including the phosphorylation in the regulatory domain of CaMKII and induction of other signal transduction pathways.
R-HSA-445367 (Reactome) CaMKII gets activated upon Ca2+ influx through the NMDA receptor and moves from plasma membrane to cytoplasm and then nucleus where it phosphorylates CREB at serine 133.
R-HSA-74448 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions.
R-HSA-9029434 (Reactome) Activation of RS6K by MAPK is required for its translocation to the plasma membrane and for subsequent translocation to the nucleus, where it phosphorylates targets such as CREB1 (Richards et al, 2001; Smith et al, 1999; reviewed in Anjum and Blenis, 2012). Whether nuclear translocation precedes or follows RS6K phosphorylation by PDPK1 is unclear.
R-HSA-9614185 (Reactome) The pore of the NMDA receptor is blocked by binding of Mg2+ ions. The strength of the block depends on the composition of the NMDA receptor, as both the GRIN1 (NR1) subunit and GRIN2 (NR2) subunits interact with Mg2+ (Nowak et al. 1984, Mayer et al. 1984, Wollmuth et al. 1998, Vargas-Caballero and Robinson 2004, Siegler Retchless et al. 2012, Schwartz et al. 2012, Clarke et al. 2013, reviewed by Iacobucci and Popescu 2017).
RasGRF:Ca/calmodulinArrowR-HSA-442760 (Reactome)
RasGRF:Ca/calmodulinmim-catalysisR-HSA-442732 (Reactome)
RasGRFR-HSA-442760 (Reactome)
RasGTP-B raf compexR-HSA-442726 (Reactome)
Ribosomal S6 kinaseR-HSA-444253 (Reactome)
cAMPArrowR-HSA-442715 (Reactome)
p-CAMKK1ArrowR-HSA-442749 (Reactome)
p-S133-CREB1ArrowR-HSA-111912 (Reactome)
p-S133-CREB1ArrowR-HSA-111919 (Reactome)
p-S133-CREB1ArrowR-HSA-442724 (Reactome)
p-S133-CREB1ArrowR-HSA-443475 (Reactome)
p-S338-RAF1mim-catalysisR-HSA-442737 (Reactome)
p-T185,Y187-MAPK1ArrowR-HSA-442737 (Reactome)
p-T185,Y187-MAPK1mim-catalysisR-HSA-444253 (Reactome)
phospho-CaMK IV:CalmodulinArrowR-HSA-111915 (Reactome)
phospho-CaMK IV:Calmodulinmim-catalysisR-HSA-111912 (Reactome)
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