DAG and IP3 signaling (Homo sapiens)

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12513682, 103, 4, 1319, 11Adenylate cyclase Cam-PDE 1 homodimer endoplasmic reticulum lumenActive Calmodulin nucleoplasmIP3 receptor homotetramer phospho-CREB dimer PKA tetramer PKA regulatory subunit cytosolIP3 receptorIP3 complex Cam-PDE 1C homodimer Adenylate cyclase PKA regulatory subunit CalmodulinCaMK IV Active Calmodulin IP3 receptor homotetramer phospho-CaMK IVCalmodulin PKA catalytic subunit active PKC IP3 receptors CalmodulinCaMK IV Protein kinase C GRK2calmodulin active Calmodulin Active Calmodulin IP3 receptors Cam-PDE 1B homodimer cAMPPKA regulatory subunit active Cam-PDE 1 Cam-PDE 1A homodimer Ca2+ CALM1 ADPAdenylate cyclase ADPPRKCDp-S12,S13-CAMK4 active Cam-PDE 13',5'-Cyclic AMPPhospho-PKC-delta/epsilonCREB1PDE1B PRKCG ADCY5 ITPR3 PRKAR2B ITPR3 p-S133-CREB1 Cam-PDE 1 homodimerp-4Y-PLCG1Mg2+ PRKAR2B PRKACA PDE1A p-S29-ADRBK1ADCY4 ITPR2 PICAMK4 ATPADRBK13',5'-Cyclic AMP IIP3 receptor homotetramerPKA catalytic subunitCalmodulinCaMK IVCa2+ CalmodulinCaMK IVATPATPCa2+ADCY3 ADPPRKACG CALM1Active CalmodulinAMPPKC-delta/epsilonCREB1ATPADCY7 phospho-CaMK IVCalmodulin3',5'-Cyclic AMPPRKCA Ca2+ CALM1 ADRBK1ADPADCY2 PRKAR1B ADCY8 PRKAR1Aactive PKC Ca2+H2OCa2+ CALM1 ATPATPphospho-CREB dimerDAGsPKA tetramerCAMK4Protein Kinase A, catalytic subunitsADCY6 PPiITPR1 ITPR2 ADPPRKAR2A Ca2+ IP3 receptorIP3 complexCALM1 PRKAR2A PDE1C cAMPPKA regulatory subunitH2Op-S133-CREB1GRK2calmodulinCAMK4 CALM1 PRKAR1AIADCY1 PRKACB ITPR1 CALM1PRKAR1B ADCY9 7


Description

This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1489509

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Bibliography

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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

History

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CompareRevisionActionTimeUserComment
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

DataNodes

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NameTypeDatabase referenceComment
3',5'-Cyclic AMP MetaboliteCHEBI:17489 (ChEBI)
3',5'-Cyclic AMPMetaboliteCHEBI:17489 (ChEBI)
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:16761 (ChEBI)
ADRBK1ProteinP25098 (Uniprot-TrEMBL)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active CalmodulinComplexREACT_3178 (Reactome)
Adenylate cyclase ComplexREACT_17689 (Reactome)
CALM1 ProteinP62158 (Uniprot-TrEMBL)
CALM1ProteinP62158 (Uniprot-TrEMBL)
CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
CAMK4ProteinQ16566 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Calmodulin CaMK IVComplexREACT_15739 (Reactome)
Calmodulin CaMK IVComplexREACT_15747 (Reactome)
Cam-PDE 1 homodimerComplexREACT_5507 (Reactome)
DAGsMetaboliteCHEBI:18035 (ChEBI)
GRK2 calmodulinComplexREACT_17570 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
IMetaboliteCHEBI:16595 (ChEBI)
IP3 receptor IP3 complexComplexREACT_12249 (Reactome)
IP3 receptor homotetramerComplexREACT_12247 (Reactome)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
PDE1A ProteinP54750 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
PDE1B ProteinQ01064 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
PDE1C ProteinQ14123 (Uniprot-TrEMBL)
PIMetaboliteCHEBI:18348 (ChEBI)
PKA catalytic subunitProteinREACT_3031 (Reactome)
PKA tetramerComplexREACT_5749 (Reactome)
PKC-delta/epsilonProteinREACT_12301 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PRKAR1AProteinP10644 (Uniprot-TrEMBL)
PRKAR1B ProteinP31321 (Uniprot-TrEMBL)
PRKAR2A ProteinP13861 (Uniprot-TrEMBL)
PRKAR2B ProteinP31323 (Uniprot-TrEMBL)
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCDProteinQ05655 (Uniprot-TrEMBL)
PRKCG ProteinP05129 (Uniprot-TrEMBL)
Phospho-PKC-delta/epsilonProteinREACT_12203 (Reactome)
Protein Kinase A, catalytic subunitsProteinREACT_2480 (Reactome)
active Cam-PDE 1ComplexREACT_3728 (Reactome)
active PKC ComplexREACT_16103 (Reactome)
cAMP PKA regulatory subunitComplexREACT_4571 (Reactome)
p-4Y-PLCG1ProteinP19174 (Uniprot-TrEMBL)
p-S12,S13-CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
p-S133-CREB1 ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S29-ADRBK1ProteinP25098 (Uniprot-TrEMBL)
phospho-CREB dimerComplexREACT_17630 (Reactome)
phospho-CaMK IV CalmodulinComplexREACT_15743 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
3',5'-Cyclic AMPArrowREACT_1963 (Reactome)
3',5'-Cyclic AMPREACT_1532 (Reactome)
3',5'-Cyclic AMPREACT_827 (Reactome)
ADPArrowREACT_12062 (Reactome)
ADPArrowREACT_15320 (Reactome)
ADPArrowREACT_15377 (Reactome)
ADPArrowREACT_15427 (Reactome)
ADPArrowREACT_15534 (Reactome)
ADRBK1REACT_15422 (Reactome)
ADRBK1REACT_15534 (Reactome)
ATPREACT_12062 (Reactome)
ATPREACT_15320 (Reactome)
ATPREACT_15377 (Reactome)
ATPREACT_15427 (Reactome)
ATPREACT_15534 (Reactome)
Active CalmodulinArrowREACT_15450 (Reactome)
Active CalmodulinREACT_15339 (Reactome)
Adenylate cyclase REACT_1963 (Reactome)
CALM1REACT_12602 (Reactome)
CALM1REACT_15422 (Reactome)
CAMK4REACT_15339 (Reactome)
CREB1REACT_15377 (Reactome)
CREB1REACT_15427 (Reactome)
Ca2+REACT_12602 (Reactome)
Calmodulin CaMK IVREACT_15320 (Reactome)
DAGsArrowREACT_12062 (Reactome)
DAGsArrowREACT_12078 (Reactome)
H2OREACT_12078 (Reactome)
H2OREACT_827 (Reactome)
IArrowREACT_12074 (Reactome)
IArrowREACT_12078 (Reactome)
IP3 receptor IP3 complexREACT_12074 (Reactome)
IP3 receptor homotetramerREACT_12008 (Reactome)
IREACT_12008 (Reactome)
PIREACT_12078 (Reactome)
PKA catalytic subunitArrowREACT_1532 (Reactome)
PKA tetramerREACT_1532 (Reactome)
PKC-delta/epsilonREACT_12062 (Reactome)
PPiArrowREACT_1963 (Reactome)
Phospho-PKC-delta/epsilonArrowREACT_12062 (Reactome)
Protein Kinase A, catalytic subunitsREACT_15377 (Reactome)
REACT_1031 (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.
REACT_12008 (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.
REACT_12062 (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.
REACT_12074 (Reactome) IP3 promotes the release of intracellular calcium.
REACT_12078 (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).
REACT_12602 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions.
REACT_15320 (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.
REACT_1532 (Reactome) The four protein kinase A (PKA) regulatory subunit isoforms differ in their tissue specificity and functional characteristics. The specific isoform activated in response to glucagon signalling is not known. The PKA kinase is a tetramer of two regulatory and two catalytic. The regulatory subunits block the catalytic subunits. Binding of cAMP to the regulatory subunit leads to the dissociation of the tetramer into two active dimers made up of a regulatory and a catalytic subunit.
REACT_15332 (Reactome) The calmodulin:CaMK IV complex enters the nucleus.
REACT_15339 (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.
REACT_15377 (Reactome) cAMP-dependent protein kinase A (PKA) phosphorylates in vitro CREB at a specific residue, serine 133; Phosphorylation of Ser133 is required for signal-induced transcription in vivo.
REACT_15415 (Reactome) CREB readily dimerizes.
REACT_15422 (Reactome) 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 GRK2 results in inhibition of the kinase activity. This inhibition is almost completely abolished when GRK2 is phosphorylated by PKC.
REACT_15427 (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.
REACT_15450 (Reactome) Increased Ca2+ levels, acting via calmodulin, can activate PDE which can then act upon cAMP.
REACT_15534 (Reactome) 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 GRK2 kinase activity towards GPCR substrates, contributing to GPCR desensitization. Phosphorylation at Ser29, which falls within the calmodulin-binding region of GRK2, abolishes the inhibitory effect of calmodulin on GRK2 kinase activity.
REACT_1963 (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).
REACT_827 (Reactome) Phosphodiesterases (PDEs) hydrolyze cAMP and cGMP, inactivating these second messengers.
active Cam-PDE 1REACT_827 (Reactome)
active PKC REACT_15534 (Reactome)
cAMP PKA regulatory subunitArrowREACT_1532 (Reactome)
p-4Y-PLCG1REACT_12078 (Reactome)
p-S133-CREB1ArrowREACT_15377 (Reactome)
p-S133-CREB1ArrowREACT_15427 (Reactome)
p-S29-ADRBK1ArrowREACT_15534 (Reactome)
phospho-CaMK IV CalmodulinArrowREACT_15320 (Reactome)
phospho-CaMK IV CalmodulinREACT_15427 (Reactome)
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