DAG and IP3 signaling (Homo sapiens)

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58, 1710114, 211113, 6, 12, 16, 18...4, 24201392, 15, 20nucleoplasmendoplasmic reticulum lumencytosolCa2+ activated PDE1dimersCAMK2A ADPADPCALM1:4xCa2+ITPR1 ADCY3 CAMK2G p-CAMKK1 ITPR1 NBEA:PRKAR2APRKAR1A ITPR2 activated PDE1A IP3 receptorhomotetramerPRKX ADCY6 CALM1 CALM1 NBEA Ca2+ G-betagammaCALM1 PRKCA cAMP:PKA regulatorysubunitNBEAPI(4,5)P2PKA catalyticsubunitADPPRKACA CaMKK:CALM1:4xCa2+PRKAR1A p-T286-CaMKIIdodecamer:CALM1:4xCa2+PRKACG ADCY5 PRKAR2B PRKACA,(PRKACB,PRKACG,PRKX)PRKAR2A CAMK4Ca2+ PRKAR1B Ca2+ ATPADCY7 PRKCG Ca2+p-CAMKK2 p-T287-CAMK2G CALM1 p-T287-CAMK2Gdodecamer:CALM1:4xCa2+PRKACB PDE1C PRKAR1B PRKACA KPNA2Adenylate cyclase(Mg2+ cofactor)AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerPRKAR1B CALM1 GRK2:CALM1:4xCa2+p-S12,S13,T200-CAMK4 CALM1 PDE1 dimerscAMPPRKACB PKC-delta/epsilonCa2+ p-T287-CAMK2Gdodecamer:CALM1:4xCa2+p-T507,S645,S664-PRKCD(1-676) ATPp-S133-CREB1ADCY9 PKA tetramerATPPPip-T566,T710,S729-PRKCE CAMKK1 I(1,4,5)P3 Ca2+ PRKACG Ca2+ CALM1 p-S12.S13,T200-CAMK4:CALM1:4xCa2+Ca2+ PRKACG ATPp-T287-CAMK2B CAMK2G KPNA2 p-S29-ADRBK1ATPp-T287-CAMK2B Ca2+CREB1H2OCALM1 CAMK2D CAMK2B CAMKK2 CAMK4 Ca2+ activated PDE1B PRKAR1A ADCY8 cAMP PRKACG Protein Kinase A,catalytic subunitscAMP p-T286-CAMK2A AHCYL1 H2Op-T287-CAMK2GdodecamerPDE1B PDE1A CALM1:4xCa2+CAMK2D Ca2+ ADPITPR3 ATPp-T287-CAMK2Bdodecamer:CALM1:4xCa2+PRKACA Ca2+ CAMK2A ADPADPactive PKC (alpha,gamma, delta)activated PDE1C CALM1 ATPPKA tetramer:4xcAMPCAMK4:CALM1:4xCa2+PRKAR2APRKACB PRKACB CAMK4 p-T287-CAMK2G ADCY2 Phospho-PKC-delta/epsilonPRKACB AMPGRK2 ATPp-S133-CREB1homodimerCaMKII dodecamerITPR3 PRKACG I(1,4,5)P3 PRKAR2B DAGsADPKPNA2CAMKK1 p-T200-CAMK4:CALM1:4xCa2+PRKAR2A p-T287-CAMK2G ADCY1 PRKAR2A CALM1 PRKACA PRKAR2B CaMKKPRKACA PRKCE CAMK4CALM1cAMPADCY4 CALM1 ATPPRKCD p-S133-CREB1 p-CaMKK:CALM1:4xCa2+Mg2+ CAMKK2 CAMK2B Ca2+ NAD+ ITPR3 ITPR2 Ca2+ PRKCD ITPR2 I(1,4,5)P3PRKAR2A CALM1 p-4Y-PLCG1p-T287-CAMK2G CaMKIIdodecamer:CALM1:4xCa2+CALM1 CAMK4:KPNA2ITPR:I(1,4,5)P3tetramerGRK2p-T287-CAMK2D Ca2+ p-T200-CAMK4 ITPR1 19197


This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events. View original pathway at Reactome.


Pathway is converted from Reactome ID: 1489509
Reactome version: 75
Reactome Author 
Reactome Author: Nasi, Sergio, Annibali, D

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Ontology Terms



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  1. Gullingsrud J, Kim C, Taylor SS, McCammon JA.; ''Dynamic binding of PKA regulatory subunit RI alpha.''; PubMed Europe PMC Scholia
  2. Chuang TT, Paolucci L, De Blasi A.; ''Inhibition of G protein-coupled receptor kinase subtypes by Ca2+/calmodulin.''; PubMed Europe PMC Scholia
  3. Li X, Li HP, Amsler K, Hyink D, Wilson PD, Burrow CR.; ''PRKX, a phylogenetically and functionally distinct cAMP-dependent protein kinase, activates renal epithelial cell migration and morphogenesis.''; PubMed Europe PMC Scholia
  4. Gu C, Cooper DM.; ''Calmodulin-binding sites on adenylyl cyclase type VIII.''; PubMed Europe PMC Scholia
  5. Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMed Europe PMC Scholia
  6. Li W, Yu ZX, Kotin RM.; ''Profiles of PrKX expression in developmental mouse embryo and human tissues.''; PubMed Europe PMC Scholia
  7. Ross D, Joyner WL.; ''Resting distribution and stimulated translocation of protein kinase C isoforms alpha, epsilon and zeta in response to bradykinin and TNF in human endothelial cells.''; PubMed Europe PMC Scholia
  8. Newton AC.; ''Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions.''; PubMed Europe PMC Scholia
  9. 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 Scholia
  10. Vandeput F, Wolda SL, Krall J, Hambleton R, Uher L, McCaw KN, Radwanski PB, Florio V, Movsesian MA.; ''Cyclic nucleotide phosphodiesterase PDE1C1 in human cardiac myocytes.''; PubMed Europe PMC Scholia
  11. 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 Scholia
  12. Liang Z, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX.; ''Down-regulation of cAMP-dependent protein kinase by over-activated calpain in Alzheimer disease brain.''; PubMed Europe PMC Scholia
  13. 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 Scholia
  14. Goraya TA, Masada N, Ciruela A, Willoughby D, Clynes MA, Cooper DM.; ''Kinetic properties of Ca2+/calmodulin-dependent phosphodiesterase isoforms dictate intracellular cAMP dynamics in response to elevation of cytosolic Ca2+.''; PubMed Europe PMC Scholia
  15. Levay K, Satpaev DK, Pronin AN, Benovic JL, Slepak VZ.; ''Localization of the sites for Ca2+-binding proteins on G protein-coupled receptor kinases.''; PubMed Europe PMC Scholia
  16. Nagakura A, Takagi N, Takeo S.; ''Impairment of cerebral cAMP-mediated signal transduction system and of spatial memory function after microsphere embolism in rats.''; PubMed Europe PMC Scholia
  17. Wang QJ.; ''PKD at the crossroads of DAG and PKC signaling.''; PubMed Europe PMC Scholia
  18. Gonzalez GA, Montminy MR.; ''Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133.''; PubMed Europe PMC Scholia
  19. 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 Scholia
  20. Krasel C, Dammeier S, Winstel R, Brockmann J, Mischak H, Lohse MJ.; ''Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin.''; PubMed Europe PMC Scholia
  21. Goraya TA, Masada N, Ciruela A, Cooper DM.; ''Sustained entry of Ca2+ is required to activate Ca2+-calmodulin-dependent phosphodiesterase 1A.''; PubMed Europe PMC Scholia
  22. James MA, Lu Y, Liu Y, Vikis HG, You M.; ''RGS17, an overexpressed gene in human lung and prostate cancer, induces tumor cell proliferation through the cyclic AMP-PKA-CREB pathway.''; PubMed Europe PMC Scholia
  23. Di Pasquale G, Stacey SN.; ''Adeno-associated virus Rep78 protein interacts with protein kinase A and its homolog PRKX and inhibits CREB-dependent transcriptional activation.''; PubMed Europe PMC Scholia
  24. Simpson RE, Ciruela A, Cooper DM.; ''The role of calmodulin recruitment in Ca2+ stimulation of adenylyl cyclase type 8.''; PubMed Europe PMC Scholia


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114839view16:34, 25 January 2021ReactomeTeamReactome version 75
113285view11:35, 2 November 2020ReactomeTeamReactome version 74
112496view15:45, 9 October 2020ReactomeTeamReactome version 73
101408view11:29, 1 November 2018ReactomeTeamreactome version 66
100946view21:05, 31 October 2018ReactomeTeamreactome version 65
100483view19:39, 31 October 2018ReactomeTeamreactome version 64
100028view16:23, 31 October 2018ReactomeTeamreactome version 63
99581view14:55, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99203view12:43, 31 October 2018ReactomeTeamreactome version 62
93895view13:43, 16 August 2017ReactomeTeamreactome version 61
93468view11:24, 9 August 2017ReactomeTeamreactome version 61
87167view19:21, 18 July 2016MkutmonOntology Term : 'signaling pathway' added !
87166view19:21, 18 July 2016MkutmonOntology Term : 'immune response pathway' added !
86562view09:21, 11 July 2016ReactomeTeamreactome version 56
83288view10:39, 18 November 2015ReactomeTeamVersion54
81419view12:57, 21 August 2015ReactomeTeamVersion53
76890view08:16, 17 July 2014ReactomeTeamFixed remaining interactions
76595view11:57, 16 July 2014ReactomeTeamFixed remaining interactions
75926view09:58, 11 June 2014ReactomeTeamRe-fixing comment source
75628view10:50, 10 June 2014ReactomeTeamReactome 48 Update
74983view13:50, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74627view08:40, 30 April 2014ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADCY1 ProteinQ08828 (Uniprot-TrEMBL)
ADCY2 ProteinQ08462 (Uniprot-TrEMBL)
ADCY3 ProteinO60266 (Uniprot-TrEMBL)
ADCY4 ProteinQ8NFM4 (Uniprot-TrEMBL)
ADCY5 ProteinO95622 (Uniprot-TrEMBL)
ADCY6 ProteinO43306 (Uniprot-TrEMBL)
ADCY7 ProteinP51828 (Uniprot-TrEMBL)
ADCY8 ProteinP40145 (Uniprot-TrEMBL)
ADCY9 ProteinO60503 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
AHCYL1 ProteinO43865 (Uniprot-TrEMBL)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerComplexR-HSA-5226920 (Reactome)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
Adenylate cyclase (Mg2+ cofactor)ComplexR-HSA-170665 (Reactome)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:4xCa2+ComplexR-HSA-629658 (Reactome)
CALM1:4xCa2+ComplexR-HSA-74294 (Reactome)
CALM1ProteinP0DP23 (Uniprot-TrEMBL)
CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
CAMK2B ProteinQ13554 (Uniprot-TrEMBL)
CAMK2D ProteinQ13557 (Uniprot-TrEMBL)
CAMK2G ProteinQ13555 (Uniprot-TrEMBL)
CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
CAMK4:CALM1:4xCa2+ComplexR-HSA-112281 (Reactome)
CAMK4:KPNA2ComplexR-HSA-9619140 (Reactome)
CAMK4ProteinQ16566 (Uniprot-TrEMBL)
CAMKK1 ProteinQ8N5S9 (Uniprot-TrEMBL)
CAMKK2 ProteinQ96RR4 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CaMKII dodecamer:CALM1:4xCa2+ComplexR-HSA-9617587 (Reactome)
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.
CaMKK:CALM1:4xCa2+ComplexR-HSA-9618860 (Reactome)
CaMKKComplexR-HSA-9618862 (Reactome)
DAGsMetaboliteCHEBI:18035 (ChEBI)
G-betagammaR-HSA-111865 (Reactome)
GRK2 ProteinP25098 (Uniprot-TrEMBL)
GRK2:CALM1:4xCa2+ComplexR-HSA-111965 (Reactome)
GRK2ProteinP25098 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IP3 receptor homotetramerComplexR-HSA-169686 (Reactome)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
ITPR:I(1,4,5)P3 tetramerComplexR-HSA-169696 (Reactome)
KPNA2 ProteinP52292 (Uniprot-TrEMBL)
KPNA2ProteinP52292 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NAD+ MetaboliteCHEBI:57540 (ChEBI)
NBEA ProteinQ8NFP9 (Uniprot-TrEMBL)
NBEA:PRKAR2AComplexR-HSA-9668559 (Reactome)
NBEAProteinQ8NFP9 (Uniprot-TrEMBL)
PDE1 dimersComplexR-HSA-111952 (Reactome)
PDE1A ProteinP54750 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
PDE1B ProteinQ01064 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
PDE1C ProteinQ14123 (Uniprot-TrEMBL)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PKA catalytic subunitComplexR-HSA-111920 (Reactome)
PKA tetramer:4xcAMPComplexR-HSA-8951729 (Reactome)
PKA tetramerComplexR-HSA-111922 (Reactome)
PKC-delta/epsilonComplexR-HSA-198276 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACA,(PRKACB,PRKACG,PRKX)ComplexR-HSA-9615387 (Reactome)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PRKAR1A ProteinP10644 (Uniprot-TrEMBL)
PRKAR1B ProteinP31321 (Uniprot-TrEMBL)
PRKAR2A ProteinP13861 (Uniprot-TrEMBL)
PRKAR2AProteinP13861 (Uniprot-TrEMBL)
PRKAR2B ProteinP31323 (Uniprot-TrEMBL)
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCD ProteinQ05655 (Uniprot-TrEMBL)
PRKCE ProteinQ02156 (Uniprot-TrEMBL)
PRKCG ProteinP05129 (Uniprot-TrEMBL)
PRKX ProteinP51817 (Uniprot-TrEMBL)
Phospho-PKC-delta/epsilonComplexR-HSA-198265 (Reactome)
Protein Kinase A, catalytic subunitsComplexR-HSA-111917 (Reactome)
activated PDE1 dimersComplexR-HSA-9014905 (Reactome)
activated PDE1A ProteinP54750 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
activated PDE1B ProteinQ01064 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
activated PDE1C ProteinQ14123 (Uniprot-TrEMBL)
active PKC (alpha, gamma, delta)ComplexR-HSA-112002 (Reactome)
cAMP MetaboliteCHEBI:17489 (ChEBI)
cAMP:PKA regulatory subunitComplexR-HSA-111923 (Reactome)
cAMPMetaboliteCHEBI:17489 (ChEBI)
p-4Y-PLCG1ProteinP19174 (Uniprot-TrEMBL)
p-CAMKK1 ProteinQ8N5S9 (Uniprot-TrEMBL)
p-CAMKK2 ProteinQ96RR4 (Uniprot-TrEMBL)
p-CaMKK:CALM1:4xCa2+ComplexR-HSA-9618956 (Reactome)
p-S12,S13,T200-CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
p-S12.S13,T200-CAMK4:CALM1:4xCa2+ComplexR-HSA-111904 (Reactome)
p-S133-CREB1 homodimerComplexR-HSA-111911 (Reactome)
p-S133-CREB1 ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S29-ADRBK1ProteinP25098 (Uniprot-TrEMBL)
p-T200-CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
p-T200-CAMK4:CALM1:4xCa2+ComplexR-HSA-9619152 (Reactome)
p-T286-CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
p-T286-CaMKII dodecamer:CALM1:4xCa2+ComplexR-HSA-9617582 (Reactome)
p-T287-CAMK2B dodecamer:CALM1:4xCa2+ComplexR-HSA-9624331 (Reactome)
p-T287-CAMK2B ProteinQ13554 (Uniprot-TrEMBL)
p-T287-CAMK2D ProteinQ13557 (Uniprot-TrEMBL)
p-T287-CAMK2G dodecamer:CALM1:4xCa2+ComplexR-HSA-9618760 (Reactome)
p-T287-CAMK2G dodecamer:CALM1:4xCa2+ComplexR-HSA-9618775 (Reactome)
p-T287-CAMK2G dodecamerComplexR-HSA-9618773 (Reactome)
p-T287-CAMK2G ProteinQ13555 (Uniprot-TrEMBL)
p-T507,S645,S664-PRKCD(1-676) ProteinQ05655 (Uniprot-TrEMBL)
p-T566,T710,S729-PRKCE ProteinQ02156 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-111912 (Reactome)
ADPArrowR-HSA-111915 (Reactome)
ADPArrowR-HSA-111919 (Reactome)
ADPArrowR-HSA-111970 (Reactome)
ADPArrowR-HSA-198314 (Reactome)
ADPArrowR-HSA-442749 (Reactome)
ADPArrowR-HSA-9617583 (Reactome)
ADPArrowR-HSA-9619125 (Reactome)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerTBarR-HSA-169683 (Reactome)
AMPArrowR-HSA-111955 (Reactome)
ATPArrowR-HSA-112282 (Reactome)
ATPR-HSA-111912 (Reactome)
ATPR-HSA-111915 (Reactome)
ATPR-HSA-111919 (Reactome)
ATPR-HSA-111930 (Reactome)
ATPR-HSA-111970 (Reactome)
ATPR-HSA-198314 (Reactome)
ATPR-HSA-442749 (Reactome)
ATPR-HSA-9617583 (Reactome)
ATPR-HSA-9619125 (Reactome)
Adenylate cyclase (Mg2+ cofactor)mim-catalysisR-HSA-111930 (Reactome)
CALM1:4xCa2+ArrowR-HSA-111930 (Reactome)
CALM1:4xCa2+ArrowR-HSA-111956 (Reactome)
CALM1:4xCa2+ArrowR-HSA-74448 (Reactome)
CALM1:4xCa2+ArrowR-HSA-9618834 (Reactome)
CALM1:4xCa2+R-HSA-111913 (Reactome)
CALM1:4xCa2+R-HSA-111966 (Reactome)
CALM1:4xCa2+R-HSA-442725 (Reactome)
CALM1:4xCa2+R-HSA-9618863 (Reactome)
CALM1R-HSA-74448 (Reactome)
CAMK4:CALM1:4xCa2+ArrowR-HSA-111913 (Reactome)
CAMK4:CALM1:4xCa2+R-HSA-9619125 (Reactome)
CAMK4:KPNA2ArrowR-HSA-9619127 (Reactome)
CAMK4:KPNA2R-HSA-112282 (Reactome)
CAMK4ArrowR-HSA-112282 (Reactome)
CAMK4R-HSA-111913 (Reactome)
CAMK4R-HSA-9619127 (Reactome)
CREB1R-HSA-111912 (Reactome)
CREB1R-HSA-111919 (Reactome)
Ca2+ArrowR-HSA-169683 (Reactome)
Ca2+R-HSA-169683 (Reactome)
Ca2+R-HSA-74448 (Reactome)
CaMKII dodecamer:CALM1:4xCa2+ArrowR-HSA-442725 (Reactome)
CaMKII dodecamer:CALM1:4xCa2+R-HSA-9617583 (Reactome)
CaMKII dodecamer:CALM1:4xCa2+mim-catalysisR-HSA-9617583 (Reactome)
CaMKII dodecamerR-HSA-442725 (Reactome)
CaMKK:CALM1:4xCa2+ArrowR-HSA-9618863 (Reactome)
CaMKK:CALM1:4xCa2+R-HSA-442749 (Reactome)
CaMKK:CALM1:4xCa2+mim-catalysisR-HSA-442749 (Reactome)
CaMKKR-HSA-9618863 (Reactome)
DAGsArrowR-HSA-167686 (Reactome)
DAGsArrowR-HSA-198314 (Reactome)
G-betagammaTBarR-HSA-111930 (Reactome)
GRK2:CALM1:4xCa2+ArrowR-HSA-111966 (Reactome)
GRK2R-HSA-111966 (Reactome)
GRK2R-HSA-111970 (Reactome)
H2OR-HSA-111955 (Reactome)
H2OR-HSA-167686 (Reactome)
I(1,4,5)P3ArrowR-HSA-167686 (Reactome)
I(1,4,5)P3ArrowR-HSA-169683 (Reactome)
I(1,4,5)P3R-HSA-169680 (Reactome)
IP3 receptor homotetramerR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramerArrowR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramermim-catalysisR-HSA-169683 (Reactome)
KPNA2ArrowR-HSA-112282 (Reactome)
KPNA2R-HSA-9619127 (Reactome)
NBEA:PRKAR2AArrowR-HSA-9668558 (Reactome)
NBEAR-HSA-9668558 (Reactome)
PDE1 dimersR-HSA-111956 (Reactome)
PI(4,5)P2R-HSA-167686 (Reactome)
PKA catalytic subunitArrowR-HSA-111925 (Reactome)
PKA catalytic subunitR-HSA-111924 (Reactome)
PKA tetramer:4xcAMPArrowR-HSA-8951727 (Reactome)
PKA tetramer:4xcAMPR-HSA-111925 (Reactome)
PKA tetramerR-HSA-8951727 (Reactome)
PKC-delta/epsilonR-HSA-198314 (Reactome)
PKC-delta/epsilonmim-catalysisR-HSA-198314 (Reactome)
PPiArrowR-HSA-111930 (Reactome)
PRKACA,(PRKACB,PRKACG,PRKX)mim-catalysisR-HSA-111919 (Reactome)
PRKAR2AR-HSA-9668558 (Reactome)
Phospho-PKC-delta/epsilonArrowR-HSA-198314 (Reactome)
Protein Kinase A, catalytic subunitsArrowR-HSA-111924 (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 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 (CAMK4) phosphorylates CREB1 at S133, thereby initiating the transcription of CREB1-regulated set of genes, leading to protein synthesis and long lasting changes that underlie synaptic plasticity.
R-HSA-111913 (Reactome) CaMKIV (CAMK4) becomes fully activated after a three-step mechanism. In the first step, upon a transient increase in intracellular calcium, calcium-bound calmodulin (Ca2+/CaM) binds to its autoregulatory domain, which relieves intersteric inhibition (Chatila et al. 1996, Tokumitsu et al. 2004). In the second step, 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 (Chatila et al. 1996, Anderson et al. 1998, Tokumitsu et al. 2004). In the third step, CaMKK-phosphorylated CAMK4 autophosphorylates on two serine residues at the N-terminus (Chatila et al. 1996). 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-terminal serine residues, S12 and S13, of CAMK4 is required for full activation after Ca2+/calmodulin binding and phosphorylation of the Ca2+/calmodulin-bound enzyme on threonine residue T200 by a Ca2+/calmodulin-dependent protein kinase kinase (CAMKK1 or CAMKK2) (Chatila et al. 1996).
R-HSA-111916 (Reactome) Based on studies in rat cells, activation of CREB1 by phosphorylation at serine residue S133 induces formation of CREB1 homodimers which are able to bind DNA (Yamamoto et al. 1988). The DNA binding and dimerization domains reside in the C-terminal region of CREB1 (Yun et al. 1990).
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-111924 (Reactome) When cAMP level rises, the PKA catalytic subunit (C subunit) released from the holoenzyme enters the nucleus by passive diffusion whereas termination of signaling to the nucleus involves an active mechanism. In the nucleus, the C subunit binds to the heat-stable protein kinase inhibitor (PKI), and this binding not only inactivates the C subunit but also by conformational change unveils a nuclear export signal in PKI which leads to export of the C-PKI complex from the nucleus.
R-HSA-111925 (Reactome) The protein kinase A (PKA) regulatory subunit isoforms differ in their tissue specificity and functional characteristics. The specific isoform activated in response to glucagon signaling is not known. The PKA kinase is a tetramer of two regulatory and two catalytic subunits. The regulatory subunits block the catalytic subunits. Binding of cAMP to the regulatory subunit triggers dissociation of the tetramer into two active dimers made up of a regulatory and a catalytic subunit.
R-HSA-111930 (Reactome) Adenylate cyclase is responsive to calcium and calmodulin and produces cAMP. One important physiological role for Calmodulin is the regulation of adenylylcyclases. Four of the ten known adenylylcyclases are calcium sensitive, in particular type 8 (AC8).
R-HSA-111955 (Reactome) Phosphodiesterases (PDEs) hydrolyze cAMP and cGMP, inactivating these second messengers.
R-HSA-111956 (Reactome) Increased Ca2+ levels, acting via calmodulin, can activate PDE which can then act upon cAMP.
R-HSA-111966 (Reactome) ADRBK1 (also known as GRK2) is a Serine/Threonine kinase. G-protein-coupled receptor kinases (GRKs) are important regulators of G-protein-coupled receptor function. Binding of calmodulin to ADRBK1 results in inhibition of the kinase activity. This inhibition is almost completely abolished when ADRBK1 is phosphorylated by PKC.
R-HSA-111970 (Reactome) ADRBK1 (also known as GRK2) is phosphorylated at serine 29 in vitro and in vivo by the alpha, gamma and delta isoforms of PKC. PKC-mediated phosphorylation at Ser29 increases ADRBK1 kinase activity towards GPCR substrates, contributing to GPCR desensitization. Phosphorylation at Ser29, which falls within the calmodulin-binding region of ADRBK1, abolishes the inhibitory effect of calmodulin on ADRBK1 kinase activity.
R-HSA-112282 (Reactome) CAMK4 (CaMKIV) entry into the nucleus is facilitated by importin alpha (KPNA2). Importin beta and RAN GTPase are not needed for CAMK4 nuclear import (Kotera et al. 2004). CAMK4 nuclear import requires functional kinase domain of CAMK4 (Lemrow et al. 2004) and ATP, but ATP hydrolysis is not needed (Kotera et al. 2005).
R-HSA-167686 (Reactome) Inositol 1,4,5-triphosphate (IP3) is a second messenger produced by phospholipase C (PLC) metabolism of phosphoinositol 4,5-bisphosphate (PIP2) (Canossa et al. 2001).
R-HSA-169680 (Reactome) The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening.
R-HSA-169683 (Reactome) IP3 promotes the release of intracellular calcium.
R-HSA-198314 (Reactome) Diacylglycerol (DAG) positively regulates the autophosphorylation of protein kinase C-delta (PKC-delta), which stimulates ERK1/2 and triggers neurite outgrowth. DAG also stimulates the translocation of PKC from the cytosol to the plasma membrane. PKC-delta contributes to growth factor specificity and response to neuronal cells by promoting cell-type-specific differences in growth factor signalling. DAG can also activate PKC-epsilon in the same manner (Newton 2001).
R-HSA-442725 (Reactome) CaMKII is fully activated upon binding to the complex of calcium and calmodulin (CALM1:4xCa2+), which forms upon influx of calcium ions through activated NMDA receptors. Autophosphorylation increases the affinity of CaMKII for the active calmodulin (CALM1:4xCa2+) (Meyer et al. 1992).
R-HSA-442749 (Reactome) Both isoforms of CaMKK, CAMKK1 (CaMKK-alpha) and CAMKK2 (CaMKK-beta) are fully activated upon autophosphorylation, which, under physiological conditions, takes places after binding to the Ca2+/calmodulin complex (CALM1:4xCa2+) (Okuno et al. 1997, Yamamori et al. 2004). While several autophosphorylation sites in both CAMKK1 and CAMKK2 have been reported, it is not clear whether these sites are calmodulin-dependent and physiologically relevant (Tokumitsu et al. 2011, Scott et al. 2015). CAMKK1 is negatively regulated by phosphorylation of S74 and T108 by PKA. Constitutive phosphorylation of CAMKK2 by GSK3B and CDK5 may be required to prevent calmodulin-independent phosphorylation (Green et al. 2011). Once activated, CaMKK phosphorylates CaMKIV in a Ca2+/Calmodulin dependent manner (Yamamori et al. 2004). Because of uncertain localization of CaMKKs (Nakamura et al. 1996, Sakagami et al. 2000, Nakamura et al. 2001, Kitani et al. 2003), CaMKK autophosphorylation may occur in the nucleus, or in the cytosol, or in both cellular compartments.
R-HSA-444792 (Reactome) Autophosphorylated, calmodulin-bound CaMKII-gamma (CAMK2G) translocates to the nucleus (Ma et al. 2014, Cohen et al. 2018). Translocation of CaMKII-gamma to the nucleus is positively regulated by activated CaMKII-beta through an unknown mechanism (Ma et al. 2014).
R-HSA-74448 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions (Crouch and Klee 1980).
R-HSA-8951727 (Reactome) Protein kinase A (PKA) regulatory subunit isoforms differ in their tissue specificity and functional characteristics. The isoform activated in response to glucagon signaling is not known.

PKA kinase is a tetramer of two regulatory and two catalytic subunits. The regulatory subunits block the activity of the catalytic subunits.

cAMP binds the regulatory subunits, which leads to dissociation of the tetramer into two active dimers made up of a regulatory and a catalytic subunit.
R-HSA-9617583 (Reactome) Binding of the complex of calcium and calmodulin (CALM1:4xCa2+) to CaMKII dodecamer, upon calcium influx through activated NMDA receptors, activates the kinase activity of CaMKII, leading to CaMKII autophosphorylation on threonine residue T286 (T286 in the alpha isoform of CaMKII corresponds to T287 in the beta isoforms of CaMKII). Autophosphorylation increases the affinity of CaMKII for calmodulin, but once autophosphorylated, CaMKII remains partially catalytically active even after dissociation of calmodulin (Schworer et al. 1986, Meyer et al. 1992).
R-HSA-9618834 (Reactome) In the nucleus, activated calmodulin (CALM1:4xCa2+) dissociates from CaMKII-gamma (p-T287-CAMK2G dodecamer) (Ma et al. 2014, Cohen et al. 2018).
R-HSA-9618863 (Reactome) Two isoforms of CaMKK, CAMKK1 (CaMKK alpha) and CAMKK2 (CaMKK beta) are expressed in the brain and involved in signaling downstream of the NMDA receptor (Schmitt et al. 2005, Mairet-Coello et al. 2013). CAMKK1 (Lee et al. 2010) and CAMKK2 (Kylarova et al. 2018) become catalytically active upon binding to the calcium-bound calmodulin (CALM1:4xCa2+). Calcium-bound calmodulin needs to translocate to the nucleus for CaMKK activation that precedes CAMK4 phosphorylation in glutamatergic neurons (Ma et al. 2014).
R-HSA-9619125 (Reactome) Activated CaMKKs, CAMKK1 (CaMKK-alpha) and CAMKK2 (CaMKK-beta), phosphorylate calmodulin-bound CAMK4 (CaMKIV) on evolutionarily conserved threonine residue T200 (Chatila et al. 1996, Anderson et al. 1998, Tokumitsu et al. 2004).
R-HSA-9619127 (Reactome) CAMK4 (CaMKIV) forms a complex with KPNA2 (Importin alpha-1). Importin beta is not required for the formation of this complex, but interferes with CAMK4 binding to KPNA2 (Kotera et al. 2005).
R-HSA-9668558 (Reactome) NBEA (neurobeachin) binds to the regulatory subunit of PKA, PRKAR2A (PKA RIIalpha). This binding may be involved in localizing PKA to specific subcellular regions, e.g. postsynaptic density in neurons (Wang et al. 2000), but the experimental evidence is not conclusive. Mice that are heterozygous for NBEA gene knockout have NBEA haploinsufficiency and show aberrant PKA activity and changes in platelet morphology (Nuytens et al. 2013). PRKAR2A-binding domain of NBEA is not essential for NBEA-mediated targeting of glutamate and GABA receptors to the synapse (Farzana et al. 2016).
activated PDE1 dimersArrowR-HSA-111956 (Reactome)
activated PDE1 dimersmim-catalysisR-HSA-111955 (Reactome)
active PKC (alpha, gamma, delta)TBarR-HSA-111966 (Reactome)
active PKC (alpha, gamma, delta)mim-catalysisR-HSA-111970 (Reactome)
cAMP:PKA regulatory subunitArrowR-HSA-111925 (Reactome)
cAMPArrowR-HSA-111930 (Reactome)
cAMPR-HSA-111955 (Reactome)
cAMPR-HSA-8951727 (Reactome)
p-4Y-PLCG1mim-catalysisR-HSA-167686 (Reactome)
p-CaMKK:CALM1:4xCa2+ArrowR-HSA-442749 (Reactome)
p-CaMKK:CALM1:4xCa2+mim-catalysisR-HSA-9619125 (Reactome)
p-S12.S13,T200-CAMK4:CALM1:4xCa2+ArrowR-HSA-111915 (Reactome)
p-S12.S13,T200-CAMK4:CALM1:4xCa2+mim-catalysisR-HSA-111912 (Reactome)
p-S133-CREB1 homodimerArrowR-HSA-111916 (Reactome)
p-S133-CREB1ArrowR-HSA-111912 (Reactome)
p-S133-CREB1ArrowR-HSA-111919 (Reactome)
p-S133-CREB1R-HSA-111916 (Reactome)
p-S29-ADRBK1ArrowR-HSA-111970 (Reactome)
p-T200-CAMK4:CALM1:4xCa2+ArrowR-HSA-9619125 (Reactome)
p-T200-CAMK4:CALM1:4xCa2+R-HSA-111915 (Reactome)
p-T200-CAMK4:CALM1:4xCa2+mim-catalysisR-HSA-111915 (Reactome)
p-T286-CaMKII dodecamer:CALM1:4xCa2+ArrowR-HSA-9617583 (Reactome)
p-T287-CAMK2B dodecamer:CALM1:4xCa2+ArrowR-HSA-444792 (Reactome)
p-T287-CAMK2G dodecamer:CALM1:4xCa2+ArrowR-HSA-444792 (Reactome)
p-T287-CAMK2G dodecamer:CALM1:4xCa2+R-HSA-444792 (Reactome)
p-T287-CAMK2G dodecamer:CALM1:4xCa2+R-HSA-9618834 (Reactome)
p-T287-CAMK2G dodecamerArrowR-HSA-9618834 (Reactome)
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