Opioid signaling (Homo sapiens)

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43, 48, 5524, 5847, 5921, 26, 5153513347, 332311724528, 14, 504620, 2517, 44, 4536, 38, 60, 6319, 402741244237, 3910, 611112, 30, 6228, 492183432434, 6, 22, 29, 31...1315, 16119242432nucleoplasmendoplasmic reticulum lumencytosolPPP3CC GNAT3 p-T34,T75,S137-PPP1R1B PKA catalyticsubunitADCY3 GNAT1 GNAT3 GNB4 PRKCA cAMP p-T34,S102-PPP1R1B ADCY1 ADCY5 p-T75-DARPP32sOpioid:MOR:G-proteincomplexGNAI1 ADCY7 AMPGNAI1 GNGT1 H2OPOMC(237-267) POMC(237-267) Opioid peptidePRKACG p-S133-CREB1homodimerKPNA2 GNG4 GNGT1 ADCY8 PRKACA p-S12,S13,T200-CAMK4 POMC(237-241) Fe3+ ADCY9 GNB5 CAMKK2 GNG10 GNAI3 p-T34-PPP1R1B PRKACG p-S102-PPP1R1B GTP ADCY1 p-T287-CAMK2GdodecamerDARPP-32phosphorylated onT34ARAGNG13 H2OADPADCY9 GNAL GNAO1 GNG5 GNG13 OPRM1 ADCY9 p-S505,S727-PLA2G4APLCB1 PPP1CA ADCY1 ADCY8 ADPGNAO1 PPP3CA,B,C:Fe3+:Zn2+:4xCa2+:CaMGNG3 p-T34,T75,S137-PPP1R1B GNAZ CAMKK1 Adenylate cyclase(Mg2+ cofactor)ADPGRK2G alpha-olf:GTPATPCa2+ GNGT1 GNAI1 GNGT2 PRKAR2B CAMK4:KPNA2ITPR1 GNAO1 POMC(237-267) CALM1 PDE4A,C,DATPGNAT3 GNG8 ADCY2 NBEA G protein-GDPcomplexADCY6 PRKCD PLCB2 ADCY3 ADCY1 p-T34,S102,S137-PPP1R1B CALM1 PCp-S133-CREB1 PiPRKACB GNAT3 p-CAMKK2 GNB4 GNG7 CaMKKGNB1 GTP ADCY4 cAMP:PKA regulatorysubunitp-CAMKK1 GNB1 (Gialpha1:GTP:Adenylate cyclase):(G alpha-olf:GTP)Ca2+ Pip-S12.S13,T200-CAMK4:CALM1:4xCa2+PPP2CA GDP ITPR2 p-T287-CAMK2B PLCB1 ADCY4 ADCY1 OPRM1 ADCY9 GNB1 Protein Kinase A,catalytic subunitsGNG13 GNAI2 ADCY2 GNG3 CAMK2A p-S54-PDE4BPRKAR2A GNAT3 GNAT2 p-S29-ADRBK1GDP p-T34,T75,S137-PPP1R1B GNAT2 GNGT1 GNAI2 POMC(237-241) p-T34,T75-PPP1R1B GNG11 GNAI3 ADCY7 GNB1 ADCY7 GNAI1 G-protein alpha(i):GDPGNG2 Mg2+ GNAI2 PKA tetramerADCY3 GNAT2 CALM1 ADCY7 p-S102,S137-PPP1R1B GNB4 GNB3 GNG2 CALM1ATPGNG5 ATPADCY1 G-protein beta-gammacomplexPOMC(237-267) G protein alpha:GTPcomplexADCY3 ADCY5 G-betagammaGNG11 PiG-protein alpha:GDPPDYN(226-230) Adenylate cyclase(Mg2+ cofactor)ADCY4 GNAI3 PRKACB GNAI2 Ca2+ p-T34,S102-PPP1R1B ADCY8 PRKAR1A I(1,4,5)P3 PRKAR2A ADCY6 GNAL Opioid:MORPDE1A PLCB4 ADCY9 GNAI1 ATPGNB5 CAMK2G PDYN(226-230) Mg2+ PP2A-ABdeltaCcomplexPOMC(237-241) PPP3CA PPP1R1B GTP Mg2+ CALM1 ADCY5 p-T287-CAMK2D p-T75,S102,S137-PPP1R1B PLC-betaGNB1 GNAT2 PPP3R1 GNB5 GNB3 G protein alpha:GTPcomplexOPRM1 PRKACG GNG3 Ca2+p-S137-PPP1R1B CaMKK:CALM1:4xCa2+CAMK4:CALM1:4xCa2+GNG11 PKA tetramer:4xcAMPGRK2:CALM1:4xCa2+GNAT3 PDE1 dimersGTP ADCY2 GNAT3 CAMK2B GRK2 Fe2+ GNG10 GNAI3 CAMK4 p-T34,S102,S137-PPP1R1B ADCY8 p-T34,T75,S102-PPP1R1B p-T287-CAMK2G PRKACB GNG4 GNAI1 Mn2+ p-T286-CaMKIIdodecamer:CALM1:4xCa2+ADCY7 cAMPGNB2 PPP3CC ADCY5 ADCY8 GNB5 GDPGNG2 GTP PRKACB ATPGNAT1 ADCY6 CALM1 GNAI3 PLA2G4APPP3CA ADCY3 GNAI1 GNAT1 PPP3CA GNAT1 CALM1 ATPPRKACG ITPR3 PRKAR2AG-protein alpha(i):GTP:AdenylatecyclaseCALM1:4xCa2+GNAL ADCY8 NBEA:PRKAR2AGNAI1 PRKACA Ca2+ GNAZ GNAT3 ADCY5 Fe3+ ADPGNAT2 p-T34,T75,S102-PPP1R1B ATPGNG12 Mg2+ ADCY4 GNAT3 GNAT1 POMC(237-241) POMC(237-241) PRKACA,(PRKACB,PRKACG,PRKX)GNAT3 GNG7 ADCY8 ADCY2 GNG12 GNAT2 GNAI2 p-T34,T75,S137-PPP1R1B p-T287-CAMK2G p-T287-CAMK2B ADCY2 OPRM1Ca2+ GNGT2 GNAT1 GNAI3 Zn2+ p-T75,S137-PPP1R1B GNAI1 GDP PLCB2 PRKAR1B Opioid:MOR:Gprotein-GDP complexADCY9 GNAO1 ADCY1 PDE4C GNAI3 Ca2+AHCYL1 GNG11 p-S102-PPP1R1B ADCY2 PPP3CC p-T287-CAMK2Bdodecamer:CALM1:4xCa2+ITPR2 G alpha (i): GTPAHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetrameractive PKC (alpha,gamma, delta)ADCY1 p-T34,T75-PPP1R1B ITPR3 CALM1 ADCY6 GTPGNGT1 p-T185,Y187-MAPK1Mg2+ p-T75-PPP1R1B ADCY4 PRKACB ActivePLA2:phosphatidylcholinep-T34,S137-PPP1R1B CAMK4 KPNA2KPNA2GNAI3 ADCY4 p-S102,S137-PPP1R1B GNG4 PDE1C DARPP-32 (and/orphosphorylated)PRKACA CAMK2B ADCY4 ADPGNG4 GNG12 PDE1B p-T286-CAMK2A PPP2R1A activated PDE1B GNB3 NAD+ NBEAGNAZ PPiADPGTP GNG12 p-T75,S102,S137-PPP1R1B Ca2+ PRKACG PDYN(226-230) GNAO1 GNAT1 PDE4A Ca2+ GNAI2 G alpha-olf:GDPcomplexPPP2R1B ADCY7 ADCY7 GNAT2 G alpha-olf:GDPcomplexH2OPRKACG Opioid:MOR:Gprotein-GTP complexGNB2 GDP LPCGNG5 ADCY8 ADCY6 OPRM1 ADCY8 CAMK2A GNG5 I(1,4,5)P3p-T34,T75,S102-PPP1R1B PLCB3 p-T34-PPP1R1B p-T287-CAMK2Gdodecamer:CALM1:4xCa2+Ca2+ p-T200-CAMK4:CALM1:4xCa2+ATPp-T34,T75,S102,S137-PPP1R1B GNAT3 Mg2+ I(1,4,5)P3 GNAL GNAI3 GNB2 GNAZ ADPPPP3CB GNGT2 CAMK4GNAZ DARPP-32 (for CDK5phosphorylation)AMPGNAL GNG8 p-T75-DARPP32s:PRKACAPRKACAGNAZ ADCY6 GTP PPP3 complexPRKCG PCPRKX H2OPI(4,5)P2cAMPGNAO1 ITPR2 PC GNB4 Adenylate cyclase(Mg2+ cofactor)H2OGNB4 H2OADCY4 ADCY4 GTPActivated PLC beta1/4CALM1 ADCY9 GNG5 (Gialpha1:GTP:Adenylate cyclase):(G alpha-olf:GDP)GNB5 GNAT1 PRKACG CALM1:4xCa2+Ca2+ ADCY2 Mg2+ Ca2+ GNAI2 GNAI3 GNG7 GNAT1 GNG2 GNB3 ADCY9 GNAT2 PRKACA ADCY5 ATPGNG10 Adenylate cyclase(Mg2+ cofactor)p-T75,S102,S137-PPP1R1B PRKACA GNAI1 Ca2+ GTP p-T287-CAMK2G activated PDE1C GNG7 GDP GNG8 p-T75,S102-PPP1R1B CALM1 GNAT3 GNAI2 CALM1 PP2B catalytic(Fe3+, Zn2+)ADCY5 p-T75,S102-PPP1R1B H2OADCY8 GNAI2 GDP ADCY5 p-T34,S137-PPP1R1B GNAZ PiGNAI1 PRKAR2B PRKAR1A p-T75,S137-PPP1R1B GNAT3 GNAZ Galpha-olf:GTP:Adenylate cyclase (active) complexFe3+ PPP1CAGNG10 GNAI2 POMC(237-267) PLCB4 ADCY9 GNAI1 p-T34,T75-PPP1R1B Mg2+ CAMKK1 GTP PRKACA GTP IP3 receptorhomotetramerCaMKIIdodecamer:CALM1:4xCa2+ADCY6 p-T34,S137-PPP1R1B p-T34,T75,S102,S137-PPP1R1B GDP p-T75-PPP1R1B p-S54-PDE4BADCY6 ADCY6 ADCY7 ITPR:I(1,4,5)P3tetramerADCY5 ADCY3 GNAI3 p-S505,S727-PLA2G4A GNG11 PDE4D cAMP p-T34,S102-PPP1R1B p-T34,S102,S137-PPP1R1B GNAI3 CAMK2G ADCY3 PDYN(226-230) PPP2R5D Mg2+ Ca2+ CALM1 CDK5Phosphorylated (T34)DARPP-32:PP1AADCY1 CALM1 GNAL GNB2 p-S137-PPP1R1B Ca2+ PPP1R1B p-T34,T75-PPP1R1B p-T200-CAMK4 PRKACB p-T75-PPP1R1B p-T34,T75,S102-PPP1R1B GNG2 PDYN(226-230) GNAT2 GNAI3 GNAO1 p-CaMKK:CALM1:4xCa2+p-T34,T75,S102,S137-PPP1R1B GNG4 PRKAR1B ADCY7 GNB3 PDE4BCALM1:4xCa2+CALM1 PKA catalyticsubunitGNG13 cAMPp-T75,S137-PPP1R1B GNAZ CAMKK2 CAMK2D GDP GDP GNAO1 GNB2 PPP3CB PPP2CB ITPR3 GNAI2 GDP PRKAR1B GNAI1 CALM1 CaMKII dodecamerGNAL ITPR1 PRKACB ITPR1 Ca2+ DAGsp-T287-CAMK2Gdodecamer:CALM1:4xCa2+GNG7 CALM1 p-S133-CREB1CAMK4PRKAR2B ADCY3 Galpha-olf:GDP:Adenylate cyclase (active) complexactivated PDE1A CREB1GNGT2 Ca2+ GNAI2 PPiGNAT3 GNG13 PRKACA GNAI1 GNG12 G-protein alpha(i/o/z/t) subunitGNAI2 Mg2+ GNAI3 GNAT3 CAMK2D Zn2+ GNAI2 ADCY7 PLCB3 PRKAR2A PRKACA GNG8 ADCY6 ADCY2 GNG10 Zn2+ ADCY3 PPP3CB GNGT2 Ca2+ ADCY9 GDPGNG8 ADCY2 PRKAR1A Ca2+ (Gialpha1:GDP:Adenylate cyclase):(G alpha-olf:GDP)PKA catalyticsubunitGNAI1 ADCY3 CALM1 p-T34,T75,S102,S137-PPP1R1B ADCY5 p-T75,S102-PPP1R1B ADPCa2+ ADCY2 ATPactivated PDE1dimersADCY1 Pip-T34-PPP1R1B GNAI2 ADCY4 PRKAR2A GNAO1 GNAL GNG3 ATPGNG3 GNAI3 ADPp-T287-CAMK2G 56565756


Description

Opioids are chemical substances similar to opiates, the active substances found in opium (morphine, codeine etc.). Opioid action is mediated by the receptors for endogenous opioids; peptides such as the enkephalins, the endorphins or the dynorphins. Opioids possess powerful analgesic and sedative effects, and are widely used as pain-killers. Their main side-effect is the rapid establishment of a strong addiction. Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP). View original pathway at Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 111885
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Le Novere, Nicholas, Jassal, Bijay

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Bibliography

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History

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CompareRevisionActionTimeUserComment
116415view09:08, 7 May 2021EweitzModified title
115086view17:03, 25 January 2021ReactomeTeamReactome version 75
113528view12:00, 2 November 2020ReactomeTeamReactome version 74
112726view16:12, 9 October 2020ReactomeTeamReactome version 73
101642view11:50, 1 November 2018ReactomeTeamreactome version 66
101178view21:37, 31 October 2018ReactomeTeamreactome version 65
100704view20:10, 31 October 2018ReactomeTeamreactome version 64
100254view16:55, 31 October 2018ReactomeTeamreactome version 63
99807view15:20, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99353view12:48, 31 October 2018ReactomeTeamreactome version 62
93848view13:40, 16 August 2017ReactomeTeamreactome version 61
93406view11:22, 9 August 2017ReactomeTeamreactome version 61
88062view14:04, 25 July 2016RyanmillerOntology Term : 'chemical compound signaling pathway' added !
88061view14:04, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86494view09:19, 11 July 2016ReactomeTeamreactome version 56
83304view10:42, 18 November 2015ReactomeTeamVersion54
81440view12:58, 21 August 2015ReactomeTeamVersion53
76919view08:19, 17 July 2014ReactomeTeamFixed remaining interactions
76624view11:59, 16 July 2014ReactomeTeamFixed remaining interactions
75955view10:01, 11 June 2014ReactomeTeamRe-fixing comment source
75657view10:55, 10 June 2014ReactomeTeamReactome 48 Update
75012view13:52, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74656view08:43, 30 April 2014ReactomeTeamReactome46
56299view16:38, 5 January 2013EgonwData typed a ChEBI metabolite as such.
42186view23:51, 4 March 2011MaintBotModified categories
42185view23:51, 4 March 2011MaintBot
42184view23:50, 4 March 2011MaintBotNew pathway

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NameTypeDatabase referenceComment
(Gi alpha1:GDP:Adenylate cyclase):(G alpha-olf:GDP)ComplexR-HSA-170656 (Reactome)
(Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GDP)ComplexR-HSA-170659 (Reactome)
(Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GTP)ComplexR-HSA-170683 (Reactome)
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)
ARAMetaboliteCHEBI:15843 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
Activated PLC beta 1/4ComplexR-HSA-111856 (Reactome)
Active PLA2:phosphatidylcholineComplexR-HSA-111860 (Reactome)
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)
CDK5ProteinQ00535 (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)
DARPP-32

phosphorylated on

T34
ComplexR-HSA-180075 (Reactome)
DARPP-32 (and/or phosphorylated)ComplexR-HSA-180056 (Reactome)
DARPP-32 (for CDK5 phosphorylation)ComplexR-HSA-180044 (Reactome)
Fe2+ MetaboliteCHEBI:29033 (ChEBI)
Fe3+ MetaboliteCHEBI:29034 (ChEBI)
G alpha-olf:GDP:Adenylate cyclase (active) complexComplexR-HSA-170679 (Reactome)
G alpha-olf:GTP:Adenylate cyclase (active) complexComplexR-HSA-170655 (Reactome)
G alpha (i): GTPComplexR-HSA-392161 (Reactome)
G alpha-olf:GDP complexComplexR-HSA-170669 (Reactome)
G alpha-olf:GTPComplexR-HSA-170661 (Reactome)
G protein alpha:GTP complexComplexR-HSA-167438 (Reactome)
G protein-GDP complexComplexR-HSA-167418 (Reactome)
G-betagammaR-HSA-111865 (Reactome)
G-protein alpha (i):GDPComplexR-HSA-392164 (Reactome)
G-protein alpha

(i):GTP:Adenylate

cyclase
ComplexR-HSA-396910 (Reactome)
G-protein alpha (i/o/z/t) subunitComplexR-HSA-167413 (Reactome)
G-protein alpha:GDPComplexR-HSA-111864 (Reactome)
G-protein beta-gamma complexComplexR-HSA-167434 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GNAI1 ProteinP63096 (Uniprot-TrEMBL)
GNAI2 ProteinP04899 (Uniprot-TrEMBL)
GNAI3 ProteinP08754 (Uniprot-TrEMBL)
GNAL ProteinP38405 (Uniprot-TrEMBL)
GNAO1 ProteinP09471 (Uniprot-TrEMBL)
GNAT1 ProteinP11488 (Uniprot-TrEMBL)
GNAT2 ProteinP19087 (Uniprot-TrEMBL)
GNAT3 ProteinA8MTJ3 (Uniprot-TrEMBL)
GNAZ ProteinP19086 (Uniprot-TrEMBL)
GNB1 ProteinP62873 (Uniprot-TrEMBL)
GNB2 ProteinP62879 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNB4 ProteinQ9HAV0 (Uniprot-TrEMBL)
GNB5 ProteinO14775 (Uniprot-TrEMBL)
GNG10 ProteinP50151 (Uniprot-TrEMBL)
GNG11 ProteinP61952 (Uniprot-TrEMBL)
GNG12 ProteinQ9UBI6 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GNG2 ProteinP59768 (Uniprot-TrEMBL)
GNG3 ProteinP63215 (Uniprot-TrEMBL)
GNG4 ProteinP50150 (Uniprot-TrEMBL)
GNG5 ProteinP63218 (Uniprot-TrEMBL)
GNG7 ProteinO60262 (Uniprot-TrEMBL)
GNG8 ProteinQ9UK08 (Uniprot-TrEMBL)
GNGT1 ProteinP63211 (Uniprot-TrEMBL)
GNGT2 ProteinO14610 (Uniprot-TrEMBL)
GRK2 ProteinP25098 (Uniprot-TrEMBL)
GRK2:CALM1:4xCa2+ComplexR-HSA-111965 (Reactome)
GRK2ProteinP25098 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
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)
LPCMetaboliteCHEBI:17504 (ChEBI)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mn2+ MetaboliteCHEBI:29035 (ChEBI)
NAD+ MetaboliteCHEBI:57540 (ChEBI)
NBEA ProteinQ8NFP9 (Uniprot-TrEMBL)
NBEA:PRKAR2AComplexR-HSA-9668559 (Reactome)
NBEAProteinQ8NFP9 (Uniprot-TrEMBL)
OPRM1 ProteinP35372 (Uniprot-TrEMBL)
OPRM1ProteinP35372 (Uniprot-TrEMBL)
Opioid peptideComplexR-HSA-167443 (Reactome)
Opioid:MOR:G protein-GDP complexComplexR-HSA-167403 (Reactome)
Opioid:MOR:G protein-GTP complexComplexR-HSA-167426 (Reactome)
Opioid:MOR:G-protein complexComplexR-HSA-167436 (Reactome)
Opioid:MORComplexR-HSA-112039 (Reactome)
PC MetaboliteCHEBI:16110 (ChEBI)
PCMetaboliteCHEBI:16110 (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)
PDE4A ProteinP27815 (Uniprot-TrEMBL)
PDE4A,C,DComplexR-HSA-111960 (Reactome) cAMP selective hydrolase
PDE4BProteinQ07343 (Uniprot-TrEMBL)
PDE4C ProteinQ08493 (Uniprot-TrEMBL)
PDE4D ProteinQ08499 (Uniprot-TrEMBL)
PDYN(226-230) ProteinP01213 (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)
PLA2G4AProteinP47712 (Uniprot-TrEMBL)
PLC-betaComplexR-HSA-111854 (Reactome)
PLCB1 ProteinQ9NQ66 (Uniprot-TrEMBL)
PLCB2 ProteinQ00722 (Uniprot-TrEMBL)
PLCB3 ProteinQ01970 (Uniprot-TrEMBL)
PLCB4 ProteinQ15147 (Uniprot-TrEMBL)
POMC(237-241) ProteinP01189 (Uniprot-TrEMBL)
POMC(237-267) ProteinP01189 (Uniprot-TrEMBL)
PP2A-ABdeltaC complexComplexR-HSA-165961 (Reactome)
PP2B catalytic (Fe3+, Zn2+)ComplexR-HSA-201779 (Reactome)
PPP1CA ProteinP62136 (Uniprot-TrEMBL)
PPP1CAProteinP62136 (Uniprot-TrEMBL)
PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPP3 complexComplexR-HSA-201788 (Reactome)
PPP3CA ProteinQ08209 (Uniprot-TrEMBL)
PPP3CA,B,C:Fe3+:Zn2+:4xCa2+:CaMComplexR-HSA-201762 (Reactome)
PPP3CB ProteinP16298 (Uniprot-TrEMBL)
PPP3CC ProteinP48454 (Uniprot-TrEMBL)
PPP3R1 ProteinP63098 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACA,(PRKACB,PRKACG,PRKX)ComplexR-HSA-9615387 (Reactome)
PRKACAProteinP17612 (Uniprot-TrEMBL)
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)
PRKCG ProteinP05129 (Uniprot-TrEMBL)
PRKX ProteinP51817 (Uniprot-TrEMBL)
Phosphorylated (T34) DARPP-32:PP1AComplexR-HSA-180025 (Reactome)
PiMetaboliteCHEBI:43474 (ChEBI)
Protein Kinase A, catalytic subunitsComplexR-HSA-111917 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
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-CAMKK1 ProteinQ8N5S9 (Uniprot-TrEMBL)
p-CAMKK2 ProteinQ96RR4 (Uniprot-TrEMBL)
p-CaMKK:CALM1:4xCa2+ComplexR-HSA-9618956 (Reactome)
p-S102,S137-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-S102-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
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-S137-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-S29-ADRBK1ProteinP25098 (Uniprot-TrEMBL)
p-S505,S727-PLA2G4A ProteinP47712 (Uniprot-TrEMBL)
p-S505,S727-PLA2G4AProteinP47712 (Uniprot-TrEMBL)
p-S54-PDE4BProteinQ07343 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1ProteinP28482 (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-T34,S102,S137-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T34,S102-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T34,S137-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T34,T75,S102,S137-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T34,T75,S102-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T34,T75,S137-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T34,T75-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T34-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T75,S102,S137-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T75,S102-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T75,S137-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
p-T75-DARPP32s:PRKACAComplexR-HSA-180050 (Reactome)
p-T75-DARPP32sComplexR-HSA-180026 (Reactome)
p-T75-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
(Gi alpha1:GDP:Adenylate cyclase):(G alpha-olf:GDP)ArrowR-HSA-170686 (Reactome)
(Gi alpha1:GDP:Adenylate cyclase):(G alpha-olf:GDP)R-HSA-170674 (Reactome)
(Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GDP)ArrowR-HSA-170666 (Reactome)
(Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GTP)ArrowR-HSA-170671 (Reactome)
(Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GTP)R-HSA-170666 (Reactome)
(Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GTP)R-HSA-170686 (Reactome)
(Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GTP)mim-catalysisR-HSA-170666 (Reactome)
(Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GTP)mim-catalysisR-HSA-170686 (Reactome)
ADPArrowR-HSA-111898 (Reactome)
ADPArrowR-HSA-111912 (Reactome)
ADPArrowR-HSA-111915 (Reactome)
ADPArrowR-HSA-111919 (Reactome)
ADPArrowR-HSA-111970 (Reactome)
ADPArrowR-HSA-177275 (Reactome)
ADPArrowR-HSA-177284 (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)
AMPArrowR-HSA-111962 (Reactome)
AMPArrowR-HSA-9644869 (Reactome)
ARAArrowR-HSA-111883 (Reactome)
ATPArrowR-HSA-112282 (Reactome)
ATPR-HSA-111898 (Reactome)
ATPR-HSA-111912 (Reactome)
ATPR-HSA-111915 (Reactome)
ATPR-HSA-111919 (Reactome)
ATPR-HSA-111930 (Reactome)
ATPR-HSA-111970 (Reactome)
ATPR-HSA-170676 (Reactome)
ATPR-HSA-177275 (Reactome)
ATPR-HSA-177284 (Reactome)
ATPR-HSA-442749 (Reactome)
ATPR-HSA-9617583 (Reactome)
ATPR-HSA-9619125 (Reactome)
Activated PLC beta 1/4ArrowR-HSA-111870 (Reactome)
Activated PLC beta 1/4R-HSA-112037 (Reactome)
Activated PLC beta 1/4mim-catalysisR-HSA-111879 (Reactome)
Active PLA2:phosphatidylcholineArrowR-HSA-111881 (Reactome)
Active PLA2:phosphatidylcholinemim-catalysisR-HSA-111883 (Reactome)
Adenylate cyclase (Mg2+ cofactor)ArrowR-HSA-170674 (Reactome)
Adenylate cyclase (Mg2+ cofactor)ArrowR-HSA-170677 (Reactome)
Adenylate cyclase (Mg2+ cofactor)R-HSA-170672 (Reactome)
Adenylate cyclase (Mg2+ cofactor)R-HSA-392206 (Reactome)
Adenylate cyclase (Mg2+ cofactor)mim-catalysisR-HSA-111930 (Reactome)
Adenylate cyclase (Mg2+ cofactor)mim-catalysisR-HSA-170672 (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-201783 (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)
CDK5mim-catalysisR-HSA-180047 (Reactome)
CREB1R-HSA-111912 (Reactome)
CREB1R-HSA-111919 (Reactome)
Ca2+ArrowR-HSA-169683 (Reactome)
Ca2+R-HSA-111881 (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-111879 (Reactome)
DARPP-32

phosphorylated on

T34
ArrowR-HSA-177275 (Reactome)
DARPP-32

phosphorylated on

T34
R-HSA-180038 (Reactome)
DARPP-32

phosphorylated on

T34
R-HSA-201787 (Reactome)
DARPP-32 (and/or phosphorylated)ArrowR-HSA-201787 (Reactome)
DARPP-32 (and/or phosphorylated)R-HSA-177275 (Reactome)
DARPP-32 (for CDK5 phosphorylation)ArrowR-HSA-201790 (Reactome)
DARPP-32 (for CDK5 phosphorylation)R-HSA-180047 (Reactome)
G alpha-olf:GDP:Adenylate cyclase (active) complexArrowR-HSA-170685 (Reactome)
G alpha-olf:GDP:Adenylate cyclase (active) complexR-HSA-170677 (Reactome)
G alpha-olf:GTP:Adenylate cyclase (active) complexArrowR-HSA-170672 (Reactome)
G alpha-olf:GTP:Adenylate cyclase (active) complexR-HSA-170685 (Reactome)
G alpha-olf:GTP:Adenylate cyclase (active) complexmim-catalysisR-HSA-170676 (Reactome)
G alpha-olf:GTP:Adenylate cyclase (active) complexmim-catalysisR-HSA-170685 (Reactome)
G alpha (i): GTPR-HSA-392206 (Reactome)
G alpha-olf:GDP complexArrowR-HSA-170674 (Reactome)
G alpha-olf:GDP complexArrowR-HSA-170677 (Reactome)
G alpha-olf:GTPR-HSA-170671 (Reactome)
G alpha-olf:GTPR-HSA-170672 (Reactome)
G protein alpha:GTP complexArrowR-HSA-112271 (Reactome)
G protein alpha:GTP complexR-HSA-111870 (Reactome)
G protein alpha:GTP complexR-HSA-167415 (Reactome)
G protein-GDP complexArrowR-HSA-167433 (Reactome)
G protein-GDP complexR-HSA-167408 (Reactome)
G-betagammaTBarR-HSA-111930 (Reactome)
G-protein alpha (i):GDPArrowR-HSA-170674 (Reactome)
G-protein alpha

(i):GTP:Adenylate

cyclase
ArrowR-HSA-392206 (Reactome)
G-protein alpha

(i):GTP:Adenylate

cyclase
R-HSA-170671 (Reactome)
G-protein alpha (i/o/z/t) subunitmim-catalysisR-HSA-167415 (Reactome)
G-protein alpha (i/o/z/t) subunitmim-catalysisR-HSA-167429 (Reactome)
G-protein alpha:GDPArrowR-HSA-112037 (Reactome)
G-protein alpha:GDPArrowR-HSA-167415 (Reactome)
G-protein alpha:GDPR-HSA-167433 (Reactome)
G-protein beta-gamma complexArrowR-HSA-112271 (Reactome)
G-protein beta-gamma complexR-HSA-167433 (Reactome)
GDPArrowR-HSA-167419 (Reactome)
GDPR-HSA-167415 (Reactome)
GRK2:CALM1:4xCa2+ArrowR-HSA-111966 (Reactome)
GRK2R-HSA-111966 (Reactome)
GRK2R-HSA-111970 (Reactome)
GTPArrowR-HSA-167415 (Reactome)
GTPR-HSA-167429 (Reactome)
H2OR-HSA-111879 (Reactome)
H2OR-HSA-111883 (Reactome)
H2OR-HSA-111955 (Reactome)
H2OR-HSA-111962 (Reactome)
H2OR-HSA-112037 (Reactome)
H2OR-HSA-201787 (Reactome)
H2OR-HSA-201790 (Reactome)
H2OR-HSA-9644869 (Reactome)
I(1,4,5)P3ArrowR-HSA-111879 (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)
LPCArrowR-HSA-111883 (Reactome)
NBEA:PRKAR2AArrowR-HSA-9668558 (Reactome)
NBEAR-HSA-9668558 (Reactome)
OPRM1ArrowR-HSA-167427 (Reactome)
OPRM1R-HSA-112042 (Reactome)
Opioid peptideArrowR-HSA-167427 (Reactome)
Opioid peptideR-HSA-112042 (Reactome)
Opioid:MOR:G protein-GDP complexArrowR-HSA-167408 (Reactome)
Opioid:MOR:G protein-GDP complexR-HSA-167419 (Reactome)
Opioid:MOR:G protein-GTP complexArrowR-HSA-167429 (Reactome)
Opioid:MOR:G protein-GTP complexR-HSA-112271 (Reactome)
Opioid:MOR:G-protein complexArrowR-HSA-167419 (Reactome)
Opioid:MOR:G-protein complexR-HSA-167429 (Reactome)
Opioid:MORArrowR-HSA-112042 (Reactome)
Opioid:MORArrowR-HSA-112271 (Reactome)
Opioid:MORR-HSA-167408 (Reactome)
Opioid:MORR-HSA-167427 (Reactome)
Opioid:MORmim-catalysisR-HSA-167408 (Reactome)
PCR-HSA-111881 (Reactome)
PCR-HSA-111883 (Reactome)
PDE1 dimersR-HSA-111956 (Reactome)
PDE4A,C,Dmim-catalysisR-HSA-111962 (Reactome)
PDE4BR-HSA-177284 (Reactome)
PI(4,5)P2R-HSA-111879 (Reactome)
PKA catalytic subunitArrowR-HSA-111925 (Reactome)
PKA catalytic subunitR-HSA-111924 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-177275 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-177284 (Reactome)
PKA tetramer:4xcAMPArrowR-HSA-8951727 (Reactome)
PKA tetramer:4xcAMPR-HSA-111925 (Reactome)
PKA tetramerR-HSA-8951727 (Reactome)
PLA2G4AR-HSA-111898 (Reactome)
PLC-betaArrowR-HSA-112037 (Reactome)
PLC-betaR-HSA-111870 (Reactome)
PP2A-ABdeltaC complexmim-catalysisR-HSA-201790 (Reactome)
PP2B catalytic (Fe3+, Zn2+)R-HSA-201783 (Reactome)
PPP1CAR-HSA-180038 (Reactome)
PPP3 complexmim-catalysisR-HSA-201787 (Reactome)
PPP3CA,B,C:Fe3+:Zn2+:4xCa2+:CaMArrowR-HSA-201783 (Reactome)
PPiArrowR-HSA-111930 (Reactome)
PPiArrowR-HSA-170676 (Reactome)
PRKACA,(PRKACB,PRKACG,PRKX)mim-catalysisR-HSA-111919 (Reactome)
PRKACAR-HSA-180073 (Reactome)
PRKAR2AR-HSA-9668558 (Reactome)
Phosphorylated (T34) DARPP-32:PP1AArrowR-HSA-180038 (Reactome)
Phosphorylated (T34) DARPP-32:PP1Amim-catalysisR-HSA-180038 (Reactome)
PiArrowR-HSA-112037 (Reactome)
PiArrowR-HSA-170666 (Reactome)
PiArrowR-HSA-170685 (Reactome)
PiArrowR-HSA-170686 (Reactome)
PiArrowR-HSA-201787 (Reactome)
PiArrowR-HSA-201790 (Reactome)
Protein Kinase A, catalytic subunitsArrowR-HSA-111924 (Reactome)
R-HSA-111870 (Reactome) The active form of G protein alpha subunit q (Gq-alpha) was found to activate phospholipase C beta-1 (PLC-beta1), in investigations using bovine membranes. Subsequently, all 4 human isoforms have been shown to be activated by Gq, though activation of PLCbeta-4 is limited. In recombinant assays, several activated rat G alpha q family members were found to stimulate human PLC-beta isoforms with the same rank order of decreasing potency. PLC-beta1 stimulation was slightly more than for PLC-beta3; PLC-beta3 stimulation was 10-fold greater than for beta-2. PLC-beta2 is expressed specifically in hematopoietic cells. PLC-beta acts directly on Gq to accelerate hydrolysis of bound GTP, thus PLC-betas are GTPase activating proteins (GAPs). The crystal structure of the C-terminal region from Turkey PLC-beta, revealed a novel fold composed almost entirely of three long helices forming a coiled-coil that dimerizes along its long axis in an antiparallel orientation. The extent of the dimer interface and gel exclusion chromatography data suggest that PLC-betas are functionally dimeric.
R-HSA-111879 (Reactome) The phospholipase C (PLC) family of enzymes is both diverse and complex. The isoforms beta, gamma and delta (each have subtypes) make up the members of this family. One type, PLC-beta1, hydrolyzes phosphatidylinositol bisphosphate (PIP2) into two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular calcium stores while DAG activates protein kinase C isoforms which are involved in regulatory functions.
R-HSA-111881 (Reactome) The 85kDa cytosolic phospholipase A2 (cPLA2 - PLA2G4A) is involved in cell signalling processes and inflammatory response and is regulated by phosphorylation and calcium concentrations. cPLA2 is phosphorylated at Ser727 and by a MAPK at Ser505. When phosphorylation is coupled with an influx of calcium ions, PLA2 becomes stimulated and translocates to the membrane where it releases arachidonic acid (AA) from membrane phospholipids. Calcium does not itself activate cPLA2. cPLA2 contains an N-terminal calcium-dependent phospholipid binding domain (CaLB) which shares homology with C2 domains (plays roles in signal transduction and membrane trafficking) and binds it to the membrane. Arachidonic acid is both a signalling molecule and the precursor for other signalling molecules termed eicosanoids (e.g., prostaglandins, leukotrienes and platelet-activating factor). A strict regulation of the activity of phospholipase enzyme is essential.
R-HSA-111883 (Reactome) Once bound to the membrane, cPLA2 hydrolyzes phosphatidylcholine to produce arachidonic acid (AA), a precursor to inflammatory mediators. While several phospholipases can catalyze this reaction in cells overexpressing the enzymes, PLA2G4A is the major enzyme that catalyzes this reaction in vivo (Reed et al. 2011). At the same time, possible physiological roles have been described for soluble phospholipases (sPLA) in the mobilization of arachidonic acid in some cell types or under some physiological conditions (Murakami et al. 2011). Here, the major role of PLA2G4A has been annotated.
R-HSA-111898 (Reactome) ERK2 phosphorylates cPLA2, increasing enzymatic activity. The site of cPLA2 phosphorylation by ERK2 is Ser-505, the major site of cPLA2 phosphorylation observed in phorbol ester-treated cells.
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-111962 (Reactome) cAMP-specific 3',5'-cyclic phosphodiesterases (PDE4A-D) hydrolyze cAMP to AMP (Huston et al. 1997).
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-112037 (Reactome) PLC-beta1 is a GTPase-activating protein (GAP) for Gq-alpha, exchanging GTP for GDP and releasing the alpha subunit to cycle back to the membrane and reassociate with the beta-gamma subunits. Between itself and the receptor, they regulate the amplitude of the PLC signal and the rates of signal initiation and termination.
R-HSA-112042 (Reactome) The binding of an opiate peptide to the mu opiate receptor stabilises the receptor conformation in a state of high affinity, both for the ligand itself, and for the G-protein.
R-HSA-112271 (Reactome) The ternary complex neurotransmitter:receptor:G-protein dissociates. Both the alpha-i subunit and beta:gamma complex become active, by conformational transition and surface exposure, and both are free to activate downstream effectors.
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-167408 (Reactome) The high affinity complex beta-endorphin:mu opioid receptor binds to the heterotrimeric G-protein. This binding stabilises a conformation of the G-protein alpha i subunit presenting a low affinity for GDP, but a high affinity for GTP
R-HSA-167415 (Reactome) Slow intrisinc GTPase activity results in an inactivation of the alpha-i subunit by hydrolyzing GTP to GDP.
R-HSA-167419 (Reactome) G proteins are inactive in the GDP-bound state. The ternary complex neurotransmitter:receptor:G-protein releases GDP.
R-HSA-167427 (Reactome) Different ligands of the MOR receptor can promote MOR phosphorylation, uncoupling, endocytosis or inactivation. For example, the endogenous peptide ligands at the MOR induce rapid desensitization, endocytosis and rapid receptor recycling. By contrast, morphine induces little to no endocytosis, tolerance and dependence. The agonist-dependent phosphorylation of opioid receptors changes the receptor conformation and increases the affinity of the receptors for cytosolic beta-arrestin proteins. This results in an uncoupling of G protein signalling and recruitment of the endocytotic machinery leading to receptor internalization and rapid resensitization. By contrast, PKC phosphorylation by non internalizing opioid ligands (e.g., morphine) cause receptors to remain inactivated in the plasma membrane, leading to signaling desensitization and opioid tolerance. In this case receptors appear to require activity of a phosphatase to be resensitized.
R-HSA-167429 (Reactome) The ternary complex neurotransmitter:receptor:G-protein binds GTP, resulting in activation of G protein.
R-HSA-167433 (Reactome) Gbetagamma rebinds Galpha-olfactory:GDP, stopping its activity
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-170666 (Reactome) G proteins can deactivate themselves via their intrinsic GTPase activity, which hydrolyzes GTP to GDP. Effectors such as adenylate cyclase can increase the G protein GTPase rate, acting like GTPase-activating proteins (GAPs).
R-HSA-170671 (Reactome) The chronic activation of mu-opioid receptors, which, when coupled to pertussis toxin-sensitive Galpha-i/o proteins, inhibit adenylyl cyclase (AC).
R-HSA-170672 (Reactome) G alpha-olf:GTP binds to inactive adenylate cyclase, causing a conformational transition in adenylate cyclase exposing the catalytic site and activating it.
R-HSA-170674 (Reactome) Once the intrinsic GTPase hydrolyzes GTP to GDP, Galpha-i dissociates from adenylate cyclase, allowing it to re-associate with G-beta-gamma and starting a new cycle.
R-HSA-170676 (Reactome) Once activated, adenylate cyclase utilizes one molecule of ATP to synthesize one molecule of cyclic AMP and pyrophosphate.
R-HSA-170677 (Reactome) Once the intrinsic GTPase hydrolyzes GTP to GDP, Galpha-olf dissociates from adenylate cyclase, allowing it to re-associate with G-beta-gamma and starting a new cycle.
R-HSA-170685 (Reactome) G proteins can deactivate themselves via their intrinsic GTPase activity, which hydrolyzes GTP to GDP. Effectors such as adenylate cyclase can increase the G protein GTPase rate, acting like GTPase-activating proteins (GAPs).
R-HSA-170686 (Reactome) G proteins can deactivate themselves via their intrinsic GTPase activity, which hydrolyzes GTP to GDP. Effectors such as adenylate cyclase can increase the G protein GTPase rate, acting like GTPase-activating proteins (GAPs).
R-HSA-177275 (Reactome) DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) on a single threonine residue, Thr34, resulting in its conversion into a potent inhibitor of protein phosphatase-1.
R-HSA-177284 (Reactome) The phosphorylation of the phosphodiesterase increases its activity, forming a negative feedback loop of the cAMP signal.
R-HSA-180038 (Reactome) DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) on a single threonine residue, Thr34, resulting in its conversion into a potent inhibitor of protein phosphatase-1.
R-HSA-180047 (Reactome) The amino-acid sequence of DARPP-32 contains consensus phosphorylation sites for proline-directed kinases, including Cdk5, a cyclin-dependent kinase family member which is present in post-mitotic neurons expressing high levels of DARPP-32.
R-HSA-180073 (Reactome) DARPP-32 is converted into an inhibitor of protein kinase A (PKA) when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5) in brain cells.
R-HSA-201783 (Reactome) PP2B (calcineurin) is a calcium-dependent, calmodulin-stimulated protein phosphatase. It comprises of two components; a catalytic subunit and a regulatory subunit which confers calcium sensitivity to the complex. PP2B is in equilibrium between active and inactive forms. Because the affinity of calmodulin for the active form is higher than for the inactive form, it stabilises PP2B.
R-HSA-201787 (Reactome) Calcineurin has been identified as a Ca2+- and calmodulin-dependent phosphoprotein phosphatase. The concentration of the enzyme is relatively high in mammalian brain.
R-HSA-201790 (Reactome) PP2A is ubiquitously expressed in eukaryotic cells, existing as a heterotrimeric enzyme composed of a 36-kDa catalytic C subunit, a 64-kDa scaffolding A subunit, and multiple regulatory B subunits. The B subunits are thought to influence enzyme activity, substrate specificity, and subcellular localization. PKA phosphorylates PP2A thereby activating the enzyme and is responsible for dopamine/cAMP-dependent dephosphorylation of Thr-75 of DARPP-32.
R-HSA-392206 (Reactome) G-proteins in the Gi class inhibit adenylate cyclase activity, decreasing the production of cAMP from ATP, which has many consequences but classically results in decreased activity of Protein Kinase A (PKA). cAMP also activates the cyclic nucleotide-gated ion channels, a process that is particularly important in olfactory cells.
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-9644869 (Reactome) cAMP-specific 3',5'-cyclic phosphodiesterase 4B (PDE4B) hydrolyzes cAMP to AMP (Huston et al. 1997). Phosphorylation of serine 54 on PDE4B increases its activity.
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)
cAMPArrowR-HSA-170676 (Reactome)
cAMPR-HSA-111955 (Reactome)
cAMPR-HSA-111962 (Reactome)
cAMPR-HSA-8951727 (Reactome)
cAMPR-HSA-9644869 (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-S505,S727-PLA2G4AArrowR-HSA-111898 (Reactome)
p-S505,S727-PLA2G4AR-HSA-111881 (Reactome)
p-S54-PDE4BArrowR-HSA-177284 (Reactome)
p-S54-PDE4Bmim-catalysisR-HSA-9644869 (Reactome)
p-T185,Y187-MAPK1mim-catalysisR-HSA-111898 (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)
p-T75-DARPP32s:PRKACAArrowR-HSA-180073 (Reactome)
p-T75-DARPP32sArrowR-HSA-180047 (Reactome)
p-T75-DARPP32sR-HSA-180073 (Reactome)
p-T75-DARPP32sR-HSA-201790 (Reactome)
p-T75-DARPP32sTBarR-HSA-177284 (Reactome)
p-T75-DARPP32smim-catalysisR-HSA-180073 (Reactome)
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