DAG and IP3 signaling (Homo sapiens)

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1152, 38, 11, 137, 165, 17613915144endoplasmic reticulum lumennucleoplasmcytosolPRKACA GRK2 phospho-CaMKIV:CalmodulinITPR2 PRKACA ATPPDE1C ADCY4 ATPI(1,4,5)P3 PRKACG ITPR3 H2OPRKACG PRKAR2A Calmodulin:CaMK IVPRKACG ITPR2 ADCY1 CALM1 ATPPRKAR2A CAMK4Ca2+PRKACA Mg2+ PKA catalyticsubunitI(1,4,5)P3PRKAR1B p-S29-ADRBK1p-S133-CREB1homodimerCAMK4 ITPR2 ADPATPPPip-S133-CREB1 ITPR:I(1,4,5)P3tetramerPRKCD PRKAR1A ADCY7 ADPPRKAR2A H2Op-S12,S13-CAMK4 ADPATPADCY6 cAMPAHCYL1 PRKACA,(PRKACB,PRKACG,PRKX)p-4Y-PLCG1Adenylate cyclase(Mg2+ cofactor)ITPR3 ADCY5 activated PDE1B ITPR3 PRKAR2B PRKACB ADCY3 CALM1 PRKAR1A PRKCG Ca2+ PRKACB PRKACB I(1,4,5)P3 PRKX ADCY2 CALM1 PRKACB Ca2+ ADPCa2+ Calmodulin:CaMK IVCALM1PRKAR1A activated PDE1dimersPDE1 dimersCREB1ATPactivated PDE1A PKC-delta/epsilonCAMK4 ITPR1 cAMP:PKA regulatorysubunitPRKAR1B PRKACG ADPPRKAR2B PRKCD PRKAR1B PDE1A AMPCa2+cAMP p-S133-CREB1PKA tetramerPDE1B Ca2+ G-betagammacAMPp-T566,T710,S729-PRKCE AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerp-T507,S645,S664-PRKCD(1-676) PI(4,5)P2PRKACG CALM1:4xCa2+PRKACA Ca2+ ITPR1 Phospho-PKC-delta/epsiloncAMP activated PDE1C ITPR1 CALM1 Protein Kinase A,catalytic subunitsCREB1IP3 receptorhomotetramerPRKACB GRK2PRKCE CALM1 active PKC (alpha,gamma, delta)PKA tetramer:4xcAMPDAGsGRK2:calmodulinPRKACA NAD+ ADCY9 PRKCA PRKAR2B ADCY8 1012


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: 66
Reactome Author 
Reactome Author: Nasi, S, Annibali, D

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Ontology Terms



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  1. Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMed Europe PMC
  2. Wang QJ.; ''PKD at the crossroads of DAG and PKC signaling.''; PubMed Europe PMC
  3. Newton AC.; ''Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions.''; PubMed Europe PMC
  4. 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
  5. Gu C, Cooper DM.; ''Calmodulin-binding sites on adenylyl cyclase type VIII.''; PubMed Europe PMC
  6. 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
  7. Goraya TA, Masada N, Ciruela A, Cooper DM.; ''Sustained entry of Ca2+ is required to activate Ca2+-calmodulin-dependent phosphodiesterase 1A.''; PubMed Europe PMC
  8. Chuang TT, Paolucci L, De Blasi A.; ''Inhibition of G protein-coupled receptor kinase subtypes by Ca2+/calmodulin.''; PubMed Europe PMC
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. Gullingsrud J, Kim C, Taylor SS, McCammon JA.; ''Dynamic binding of PKA regulatory subunit RI alpha.''; PubMed Europe PMC
  16. 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
  17. Simpson RE, Ciruela A, Cooper DM.; ''The role of calmodulin recruitment in Ca2+ stimulation of adenylyl cyclase type 8.''; PubMed Europe PMC


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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:16761 (ChEBI)
AHCYL1 ProteinO43865 (Uniprot-TrEMBL)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerComplexR-HSA-5226920 (Reactome)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Adenylate cyclase (Mg2+ cofactor)ComplexR-HSA-170665 (Reactome)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:4xCa2+ComplexR-HSA-74294 (Reactome)
CALM1ProteinP0DP23 (Uniprot-TrEMBL)
CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
CAMK4ProteinQ16566 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Calmodulin:CaMK IVComplexR-HSA-111900 (Reactome)
Calmodulin:CaMK IVComplexR-HSA-112281 (Reactome)
DAGsMetaboliteCHEBI:18035 (ChEBI)
G-betagammaR-HSA-111865 (Reactome)
GRK2 ProteinP25098 (Uniprot-TrEMBL)
GRK2:calmodulinComplexR-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)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NAD+ MetaboliteCHEBI:15846 (ChEBI)
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)
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-S12,S13-CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
p-S133-CREB1 homodimerComplexR-HSA-111911 (Reactome)
p-S133-CREB1 ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S29-ADRBK1ProteinP25098 (Uniprot-TrEMBL)
p-T507,S645,S664-PRKCD(1-676) ProteinQ05655 (Uniprot-TrEMBL)
p-T566,T710,S729-PRKCE ProteinQ02156 (Uniprot-TrEMBL)
phospho-CaMK IV:CalmodulinComplexR-HSA-111904 (Reactome)

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)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerTBarR-HSA-169683 (Reactome)
AMPArrowR-HSA-111955 (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)
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+R-HSA-111913 (Reactome)
CALM1R-HSA-111966 (Reactome)
CALM1R-HSA-74448 (Reactome)
CAMK4R-HSA-111913 (Reactome)
CREB1R-HSA-111912 (Reactome)
CREB1R-HSA-111919 (Reactome)
Ca2+ArrowR-HSA-169683 (Reactome)
Ca2+R-HSA-169683 (Reactome)
Ca2+R-HSA-74448 (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)
DAGsArrowR-HSA-167686 (Reactome)
DAGsArrowR-HSA-198314 (Reactome)
G-betagammaTBarR-HSA-111930 (Reactome)
GRK2:calmodulinArrowR-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)
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)
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 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-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 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.
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) The calmodulin:CaMK IV complex enters the nucleus.
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-74448 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions.
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 signalling 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.
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-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)
phospho-CaMK IV:CalmodulinArrowR-HSA-111915 (Reactome)
phospho-CaMK IV:Calmodulinmim-catalysisR-HSA-111912 (Reactome)
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