Opioid signaling (Homo sapiens)

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24, 31, 524428, 446, 3747444930, 51182312, 468, 1733, 4016251, 134422413821, 34, 437449, 14, 50, 5310, 2939204432, 32, 365, 15, 4526, 274111, 194248473521Active Calmodulin G-protein beta-gamma complex Opioid peptide PLC-beta Adenylate cyclase Adenylate cyclase G-protein alpha phospho-CREB dimer Active PLA2phosphatidylcholine G-protein alpha Adenylate cyclase G-protein alpha Cam-PDE 1C homodimer Cam-PDE 1A homodimer PKA regulatory subunit OpioidMORG protein-GTP complex Adenylate cyclase PP2B catalytic G-protein alpha G alpha-olfGTP G protein-GTP Adenylate cyclase active Calmodulin Adenylate cyclase IP3 receptorIP3 complex Adenylate cyclase OpioidMOR OpioidMORG protein-GDP complex G-protein alpha G-protein alpha DARPP-32 phosporylated on T34 IP3 receptor homotetramer PP2B catalytic G-protein alpha G protein alphaGDP complex Cam-PDE 1B homodimer Active Calmodulin Active Calmodulin Cam-PDE 1C homodimer OpioidMORG-protein complex Adenylate cyclase Heterotrimeric G-protein Active Calmodulin Cam-PDE 1A homodimer PP2B catalytic subunit active Cam-PDE 1 G-protein alpha Phosphorylated Adenylate cyclase G alpha-olfGDP complex G protein alphaGDP complex PP2B catalytic subunit Opioid peptide G protein alphaGTP complex PP1AG-protein alpha G protein alphaGTP complex G-protein alpha G-protein alpha OpioidMOR Opioid peptide Adenylate cyclase IP3 receptors G alpha-olfGDP complex Adenylate cyclase G-protein beta-gamma complex G alpha-olfGDP complex Activated PLC beta 1/4 G-protein beta-gamma complex G alpha-olfGDPAdenylate cyclase G protein-GDP complex endoplasmic reticulum lumenphospho-CaMK IVCalmodulin PP2B complex G-protein alpha PP2B catalytic Cam-PDE 1 homodimer G-protein beta-gamma complex Adenylate cyclase CalmodulinCaMK IV Adenylate cyclase G-protein alpha p-T75-DARPP32sPRKACA G alpha-olfGTP cytosolAdenylate cyclase G protein alphaGTP complex OpioidMOR G protein-GDP complex G alpha-olfGDP complex PKA catalytic subunit Adenylate cyclase Opioid peptide G-protein alpha G alpha-olfGDP complex CalmodulinCaMK IV G-protein alpha IP3 receptor homotetramer G-protein alpha Adenylate cyclase Adenylate cyclase PKA tetramer G-protein alphaGDP p-T75-DARPP32s OpioidMOR PKA regulatory subunit G-protein alpha active PKC G alpha-olfGTPAdenylate cyclase G-protein alpha GRK2calmodulin G alpha-olfGTP IP3 receptors G-protein alpha Active Calmodulin G-protein alpha Adenylate cyclase cAMPPKA regulatory subunit G-protein alpha G-protein alpha Adenylate cyclase PP2B catalytic subunit Cam-PDE 1B homodimer nucleoplasmAdenylate cyclase Cam-PDE 1 homodimer Protein kinase C PP2A-ABdeltaC complex AMPp-T34,T75,S102-PPP1R1B ADCY4 p-T34,T75,S102,S137-PPP1R1B ADCY9 PRKAR2B ADCY7 p-T75-DARPP32sp-T34,T75,S102-PPP1R1B Ca2+ ITPR3 GNAZ Mg2+ GDP CALM1 PDE4BActive PLA2phosphatidylcholineGNAT3GNAI2PDYNOPRM1 ADCY8 PPP3CC GNAI1ADCY9 GNAI2GNAT3ITPR2 OpioidMORG protein-GTP complexITPR2 DARPP-32 ITPR1 ADCY5 IGTP ITPR3 GNAI3p-T75-DARPP32sPRKACAGNAO1 H2OH2OActive CalmodulinFe3+ GNAT1 GDP GNAI1GNAT1 p-S54-PDE4B2-LysophosphatidylcholineADCY5 G alpha-olfGTPAdenylate cyclase GNAI2Mg2+ ADCY4 ATPGNAI1PRKAR1B ADRBK1ADCY3 ITPR1 PDYNPOMCADCY8 GNAT2PRKCG Mn2+ p-S133-CREB1PPiADCY6 cAMPPKA regulatory subunitADCY5 GNAI2ADPCALM1 ADCY3 ADP3',5'-Cyclic AMPPRKACA PCGNAT1 GDP PLCB2 PPP3CBOpioid peptideGDP GNAI3G-protein alpha Ca2+ ADCY2 ADCY5 GNALPPP2R5D ADCY7 OpioidMORADCY6 GNAI1ATPCALM1 Ca2+ ADCY9 ADCY8 PRKACB Fe3+ GNAI3ADCY5 GNAI2PRKAR2B G-protein alpha ATPCALM1 GNAI3GNAI2GNAO1 ADCY6 Fe3+ p-S505,S727-PLA2G4APRKACG GNAI3GNAI2Mg2+ PDE 4GDP p-T75,S137-PPP1R1B GNALGNAT3POMCGNAZ GNAT3GNAI2ADCY8 OpioidMORG protein-GDP complexGNAT2GNAI3PDE1C 3',5'-Cyclic AMP PPP3CA GNAT3ADCY2 IP3 receptor homotetramerH2OADCY8 H2OG protein-GDP complexG-protein alphaGDPAMPPPP3CA ADCY3 Protein Kinase A, catalytic subunitsp-T34,T75,S102,S137-PPP1R1B G alpha-olfGDP complexPRKAR1AGTP DAGsp-S505,S727-PLA2G4A CAMK4 G protein alphaGTP complexGNAZ G-protein alpha Phosphorylated ADPGNAT3GNAI3PPP3R1 GTP GNAO1 GDP GNAI1GTPCa2+ CAMK4p-T34,T75-PPP1R1B CDK5GNAI1Arachidonic acidATPPRKAR2A GDPPDE1A ADCY6 PPP3CC GDPADCY2 ADCY9 ADPOpioidMORG-protein complexATPADCY1 PiPPP3CA ADCY7 ADCY1 active Cam-PDE 1p-T34,T75,S137-PPP1R1B GNAI1ADCY6 ADCY1 CREB1GNAZ GNAT3Cam-PDE 1 homodimerPDE1A GNAI1ATPPLCB3p-T75,S102,S137-PPP1R1B OPRM1 p-T75-PPP1R1B GNAT2GTP ADCY5 POMCCa2+ ADCY6 ADCY9 ADCY2 G alpha-olfGDP complexPRKAR1AGNAI2p-S12,S13-CAMK4 GNAT3ADCY4 Ca2+ ADCY6 PRKCA phospho-CaMK IVCalmodulinGNAT1 ADCY8 PiGDP GNAI1ADCY9 PLC-betaGNAT1 ADCY7 ADCY1 ADCY3 p-S133-CREB1active PKC ADCY5 3',5'-Cyclic AMPMg2+ Mg2+ ADCY5 Mg2+ ADCY2 GNAT3GTPp-S133-CREB1 ADCY4 PRKCDp-T75,S102-PPP1R1B GNAI1p-T34,S102-PPP1R1B H2OPRKAR2A G alpha-olfGDPAdenylate cyclase ADCY2 POMCADCY6 GTP PPiCa2+ GDP CALM1ADCY7 POMCADCY1 PhosphatidylcholineOPRM1 Mg2+ ADCY8 GNAT2ADCY7 GNAZ PLA2G4AADPGNAT2CALM1 p-T34,S137-PPP1R1B ADRBK1GNAT2p-T34-PPP1R1B Zn2+ PiADCY1 G alpha-olfGTPGNAI3PDE1B OPRM1 GTP ADCY3 Mg2+ GNALPiH2OGNALADCY1 Adenylate cyclase Zn2+ ADCY4 GDP PLCB1 ADCY7 PKA catalytic subunitATPADPADCY8 ADCY9 ADCY1 ADCY2 PDYNGNAI1Adenylate cyclase PP2B complexMg2+ PDE1C p-S29-ADRBK1GNAI2ATPADCY2 ADCY9 PP2B catalytic OPRM1IP3 receptorIP3 complexGNAI2ADCY3 ADCY4 GNAT2GTP GNAI3phospho-CREB dimerCalmodulinCaMK IVDARPP-32 ADCY7 GNAI1PDYNPPP3CBGNAI3GNAO1 DARPP-32 phosporylated on T34ADCY8 GNAT3G-protein alpha PKA catalytic subunitPOMCPDE1B ADCY1 ADCY6 Zn2+ ADCY9 GNAT3CAMK4 ADCY4 PPP1CA GNALADCY3 PPP1CAGNAI2GNAZ GTP PRKACA Ca2+ GNAI3GNALActivated PLC beta 1/4Adenylate cyclase ADCY4 GNAT3p-T34,T75,S137-PPP1R1B ADCY5 PRKAR1B GNAO1 ADCY3 3',5'-Cyclic AMPGTP PC Ca2+ADCY9 CALM1 G-protein beta-gamma complexPLCB4 GNAI3IGNAT1 GDP ADCY3 ADCY8 ADCY6 POMCFe2+ GRK2calmodulinADCY3 ADCY7 ADCY2 Adenylate cyclase ADCY5 GNAI1ADCY2 ADCY1 CALM1 PIADCY4 ATPPKA tetramerMg2+ H2OPiGTP ADCY4 p-T34,T75-PPP1R1B Ca2+GNAI2GNAO1 PP2A-ABdeltaC complexADPGNAI3GNALGNAO1 p-T34,S102,S137-PPP1R1B GNAZ PP2B catalytic 3',5'-Cyclic AMPPOMCGNALPPP3CC GNAT1 p-T185,Y187-MAPK1PRKACAGNAT3CalmodulinCaMK IVCREB1PPP3CBADCY7 4


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). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=111885

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Bibliography

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History

View all...
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

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2-LysophosphatidylcholineCHEBI:17504 (ChEBI)
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)
Activated PLC beta 1/4ComplexREACT_15568 (Reactome)
Active CalmodulinComplexREACT_3178 (Reactome)
Active PLA2 phosphatidylcholineComplexREACT_15631 (Reactome)
Adenylate cyclase ComplexREACT_17689 (Reactome)
Arachidonic acidMetaboliteCHEBI:15843 (ChEBI)
CALM1 ProteinP62158 (Uniprot-TrEMBL)
CALM1ProteinP62158 (Uniprot-TrEMBL)
CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
CAMK4ProteinQ16566 (Uniprot-TrEMBL)
CDK5ProteinQ00535 (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)
DARPP-32 ProteinREACT_17763 (Reactome)
DARPP-32 ProteinREACT_17935 (Reactome)
DARPP-32 phosporylated on T34ProteinREACT_15578 (Reactome)
Fe2+ MetaboliteCHEBI:18248 (ChEBI)
Fe3+ MetaboliteCHEBI:29034 (ChEBI)
G alpha-olf

GDP

Adenylate cyclase 		ComplexREACT_15796 (Reactome)
G alpha-olf GDP complexComplexREACT_17352 (Reactome)
G alpha-olf

GTP

Adenylate cyclase 		ComplexREACT_17212 (Reactome)
G alpha-olf GTPComplexREACT_16015 (Reactome)
G protein alpha GTP complexComplexREACT_17389 (Reactome)
G protein-GDP complexComplexREACT_15793 (Reactome)
G-protein alpha GDPComplexREACT_17952 (Reactome)
G-protein alpha ProteinREACT_16054 (Reactome)
G-protein alpha ComplexREACT_19580 (Reactome)
G-protein alpha ComplexREACT_19806 (Reactome)
G-protein alpha ComplexREACT_19914 (Reactome)
G-protein beta-gamma complexComplexREACT_15674 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GNAI1ProteinP63096 (Uniprot-TrEMBL)
GNAI2ProteinP04899 (Uniprot-TrEMBL)
GNAI3ProteinP08754 (Uniprot-TrEMBL)
GNALProteinP38405 (Uniprot-TrEMBL)
GNAO1 ProteinP09471 (Uniprot-TrEMBL)
GNAT1 ProteinP11488 (Uniprot-TrEMBL)
GNAT2ProteinP19087 (Uniprot-TrEMBL)
GNAT3ProteinA8MTJ3 (Uniprot-TrEMBL)
GNAZ ProteinP19086 (Uniprot-TrEMBL)
GRK2 calmodulinComplexREACT_17570 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
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)
Mn2+ MetaboliteCHEBI:18291 (ChEBI)
OPRM1 ProteinP35372 (Uniprot-TrEMBL)
OPRM1ProteinP35372 (Uniprot-TrEMBL)
Opioid

MOR

G protein-GDP complex		ComplexREACT_15815 (Reactome)
Opioid

MOR

G protein-GTP complex		ComplexREACT_15831 (Reactome)
Opioid

MOR

G-protein complex		ComplexREACT_15585 (Reactome)
Opioid MORComplexREACT_15680 (Reactome)
Opioid peptideProteinREACT_15976 (Reactome)
PC MetaboliteCHEBI:16110 (ChEBI)
PCMetaboliteCHEBI:16110 (ChEBI)
PDE 4REACT_5541 (Reactome) cAMP selective hydrolase
PDE1A ProteinP54750 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
PDE1B ProteinQ01064 (Uniprot-TrEMBL) Can hydrolyze both cAMP and cGMP
PDE1C ProteinQ14123 (Uniprot-TrEMBL)
PDE4BProteinQ07343 (Uniprot-TrEMBL)
PDYNProteinP01213 (Uniprot-TrEMBL)
PIMetaboliteCHEBI:18348 (ChEBI)
PKA catalytic subunitProteinREACT_3031 (Reactome)
PKA tetramerComplexREACT_5749 (Reactome)
PLA2G4AProteinP47712 (Uniprot-TrEMBL)
PLC-betaProteinREACT_15673 (Reactome)
PLCB1 ProteinQ9NQ66 (Uniprot-TrEMBL)
PLCB2 ProteinQ00722 (Uniprot-TrEMBL)
PLCB3ProteinQ01970 (Uniprot-TrEMBL)
PLCB4 ProteinQ15147 (Uniprot-TrEMBL)
POMCProteinP01189 (Uniprot-TrEMBL)
PP2A-ABdeltaC complexComplexREACT_5648 (Reactome)
PP2B catalytic ComplexREACT_17373 (Reactome)
PP2B catalytic ComplexREACT_18243 (Reactome)
PP2B complexComplexREACT_17149 (Reactome)
PPP1CA ProteinP62136 (Uniprot-TrEMBL)
PPP1CAProteinP62136 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPP3CA ProteinQ08209 (Uniprot-TrEMBL)
PPP3CBProteinP16298 (Uniprot-TrEMBL)
PPP3CC ProteinP48454 (Uniprot-TrEMBL)
PPP3R1 ProteinP63098 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACAProteinP17612 (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)
PhosphatidylcholineCHEBI:16110 (ChEBI)
Phosphorylated ComplexREACT_17348 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
Protein Kinase A, catalytic subunitsProteinREACT_2480 (Reactome)
ComplexREACT_15853 (Reactome)
ComplexREACT_15896 (Reactome)
ComplexREACT_15996 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
active Cam-PDE 1ComplexREACT_3728 (Reactome)
active PKC ComplexREACT_16103 (Reactome)
cAMP PKA regulatory subunitComplexREACT_4571 (Reactome)
p-S12,S13-CAMK4 ProteinQ16566 (Uniprot-TrEMBL)
p-S133-CREB1 ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (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-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 PRKACAComplexREACT_17157 (Reactome)
p-T75-DARPP32sProteinREACT_16096 (Reactome)
p-T75-PPP1R1B ProteinQ9UD71 (Uniprot-TrEMBL)
phospho-CREB dimerComplexREACT_17630 (Reactome)
phospho-CaMK IV CalmodulinComplexREACT_15743 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2-LysophosphatidylcholineArrowREACT_15331 (Reactome)
3',5'-Cyclic AMPArrowREACT_15399 (Reactome)
3',5'-Cyclic AMPArrowREACT_1963 (Reactome)
3',5'-Cyclic AMPREACT_1257 (Reactome)
3',5'-Cyclic AMPREACT_1532 (Reactome)
3',5'-Cyclic AMPREACT_827 (Reactome)
ADPArrowREACT_15320 (Reactome)
ADPArrowREACT_15377 (Reactome)
ADPArrowREACT_15427 (Reactome)
ADPArrowREACT_15519 (Reactome)
ADPArrowREACT_15529 (Reactome)
ADPArrowREACT_15534 (Reactome)
ADPArrowREACT_23990 (Reactome)
ADRBK1REACT_15422 (Reactome)
ADRBK1REACT_15534 (Reactome)
ATPREACT_15320 (Reactome)
ATPREACT_15377 (Reactome)
ATPREACT_15427 (Reactome)
ATPREACT_15519 (Reactome)
ATPREACT_15529 (Reactome)
ATPREACT_15534 (Reactome)
ATPREACT_23990 (Reactome)
Activated PLC beta 1/4REACT_15301 (Reactome)
Activated PLC beta 1/4REACT_15353 (Reactome)
Active CalmodulinArrowREACT_15450 (Reactome)
Active CalmodulinREACT_15299 (Reactome)
Active CalmodulinREACT_15339 (Reactome)
Active PLA2 phosphatidylcholineREACT_15331 (Reactome)
Adenylate cyclase ArrowREACT_15384 (Reactome)
Adenylate cyclase ArrowREACT_15547 (Reactome)
Adenylate cyclase REACT_15385 (Reactome)
Adenylate cyclase REACT_19222 (Reactome)
Adenylate cyclase REACT_1963 (Reactome)
Arachidonic acidArrowREACT_15331 (Reactome)
ArrowREACT_15335 (Reactome)
ArrowREACT_15495 (Reactome)
CALM1REACT_12602 (Reactome)
CALM1REACT_15422 (Reactome)
CAMK4REACT_15339 (Reactome)
CDK5REACT_15365 (Reactome)
CREB1REACT_15377 (Reactome)
CREB1REACT_15427 (Reactome)
Ca2+REACT_12602 (Reactome)
Ca2+REACT_15311 (Reactome)
Calmodulin CaMK IVREACT_15320 (Reactome)
DAGsArrowREACT_15353 (Reactome)
DARPP-32 ArrowREACT_15438 (Reactome)
DARPP-32 ArrowREACT_15494 (Reactome)
DARPP-32 REACT_15529 (Reactome)
DARPP-32 phosporylated on T34ArrowREACT_15529 (Reactome)
DARPP-32 phosporylated on T34REACT_15494 (Reactome)
DARPP-32 phosporylated on T34REACT_15496 (Reactome)
G alpha-olf

GDP

Adenylate cyclase 		ArrowREACT_15449 (Reactome)
G alpha-olf GDP complexArrowREACT_15384 (Reactome)
G alpha-olf GDP complexArrowREACT_15547 (Reactome)
G alpha-olf

GTP

Adenylate cyclase 		REACT_15399 (Reactome)
G alpha-olf

GTP

Adenylate cyclase 		REACT_15449 (Reactome)
G alpha-olf GTPREACT_15385 (Reactome)
G alpha-olf GTPREACT_15435 (Reactome)
G protein alpha GTP complexArrowREACT_15336 (Reactome)
G protein alpha GTP complexREACT_15316 (Reactome)
G protein alpha GTP complexREACT_15402 (Reactome)
G protein-GDP complexREACT_15298 (Reactome)
G-protein alpha GDPArrowREACT_15301 (Reactome)
G-protein alpha GDPArrowREACT_15316 (Reactome)
G-protein alpha GDPREACT_15387 (Reactome)
G-protein alpha ArrowREACT_15384 (Reactome)
G-protein alpha REACT_15316 (Reactome)
G-protein alpha REACT_15435 (Reactome)
G-protein alpha REACT_15491 (Reactome)
G-protein alpha REACT_19222 (Reactome)
G-protein beta-gamma complexArrowREACT_15336 (Reactome)
G-protein beta-gamma complexREACT_15387 (Reactome)
GDPArrowREACT_15549 (Reactome)
GDPREACT_15316 (Reactome)
GTPArrowREACT_15316 (Reactome)
GTPREACT_15491 (Reactome)
H2OREACT_1257 (Reactome)
H2OREACT_15301 (Reactome)
H2OREACT_15331 (Reactome)
H2OREACT_15353 (Reactome)
H2OREACT_15438 (Reactome)
H2OREACT_15494 (Reactome)
H2OREACT_827 (Reactome)
IArrowREACT_12074 (Reactome)
IArrowREACT_15353 (Reactome)
IP3 receptor IP3 complexREACT_12074 (Reactome)
IP3 receptor homotetramerREACT_12008 (Reactome)
IREACT_12008 (Reactome)
OPRM1ArrowREACT_15388 (Reactome)
OPRM1REACT_15473 (Reactome)
Opioid

MOR

G-protein complex		ArrowREACT_15549 (Reactome)
Opioid

MOR

G-protein complex		REACT_15491 (Reactome)
Opioid MORArrowREACT_15336 (Reactome)
Opioid MORREACT_15298 (Reactome)
Opioid peptideArrowREACT_15388 (Reactome)
Opioid peptideREACT_15473 (Reactome)
PCREACT_15311 (Reactome)
PDE 4REACT_1257 (Reactome)
PDE4BREACT_15519 (Reactome)
PIREACT_15353 (Reactome)
PKA catalytic subunitArrowREACT_1532 (Reactome)
PKA tetramerREACT_1532 (Reactome)
PLA2G4AREACT_23990 (Reactome)
PLC-betaArrowREACT_15301 (Reactome)
PLC-betaREACT_15402 (Reactome)
PP2A-ABdeltaC complexREACT_15438 (Reactome)
PP2B catalytic REACT_15299 (Reactome)
PP2B complexREACT_15494 (Reactome)
PPP1CAREACT_15496 (Reactome)
PPiArrowREACT_15399 (Reactome)
PPiArrowREACT_1963 (Reactome)
PRKACAREACT_15519 (Reactome)
PRKACAREACT_15529 (Reactome)
PRKACAREACT_15540 (Reactome)
PhosphatidylcholineREACT_15331 (Reactome)
Phosphorylated REACT_15496 (Reactome)
PiArrowREACT_15301 (Reactome)
PiArrowREACT_15335 (Reactome)
PiArrowREACT_15438 (Reactome)
PiArrowREACT_15449 (Reactome)
PiArrowREACT_15494 (Reactome)
PiArrowREACT_15495 (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_12074 (Reactome) IP3 promotes the release of intracellular calcium.
REACT_1257 (Reactome) PDE4 hydrolyzes cAMP to AMP.
REACT_12602 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions.
REACT_15298 (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
REACT_15299 (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.
REACT_15301 (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.
REACT_15311 (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.
REACT_15316 (Reactome) Slow intrisinc GTPase activity results in an inactivation of the alpha-i subunit by hydrolyzing GTP to GDP.
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_15331 (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.
REACT_15332 (Reactome) The calmodulin:CaMK IV complex enters the nucleus.
REACT_15335 (Reactome)
REACT_15336 (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.
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_15353 (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.
REACT_15365 (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.
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_15384 (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.
REACT_15385 (Reactome) G alpha-olf:GTP binds to inactive adenylate cyclase, causing a conformational transition in adenylate cyclase exposing the catalytic site and activating it.
REACT_15387 (Reactome) Gbetagamma rebinds Galpha-olfactory:GDP, stopping its activity
REACT_15388 (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.
REACT_15399 (Reactome) Once activated, adenylate cyclase utilizes one molecule of ATP to synthesize one molecule of cyclic AMP and pyrophosphate.
REACT_15402 (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.
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_15435 (Reactome) The chronic activation of mu-opioid receptors, which, when coupled to pertussis toxin-sensitive Galpha-i/o proteins, inhibit adenylyl cyclase (AC).
REACT_15438 (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.
REACT_15449 (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).
REACT_15450 (Reactome) Increased Ca2+ levels, acting via calmodulin, can activate PDE which can then act upon cAMP.
REACT_15473 (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.
REACT_15491 (Reactome) The ternary complex neurotransmitter:receptor:G-protein binds GTP, resulting in activation of G protein.
REACT_15494 (Reactome) Calcineurin has been identified as a Ca2+- and calmodulin-dependent phosphoprotein phosphatase. The concentration of the enzyme is relatively high in mammalian brain.
REACT_15495 (Reactome)
REACT_15496 (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.
REACT_15519 (Reactome) The phosphorylation of the phosphodiesterase increases its activity, forming a negative feedback loop of the cAMP signal.
REACT_15529 (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.
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_15540 (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.
REACT_15547 (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.
REACT_15549 (Reactome) G proteins are inactive in the GDP-bound state. The ternary complex neurotransmitter:receptor:G-protein releases GDP.
REACT_19222 (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.
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_23990 (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.
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-S133-CREB1ArrowREACT_15377 (Reactome)
p-S133-CREB1ArrowREACT_15427 (Reactome)
p-S29-ADRBK1ArrowREACT_15534 (Reactome)
p-S505,S727-PLA2G4AArrowREACT_23990 (Reactome)
p-S505,S727-PLA2G4AREACT_15311 (Reactome)
p-S54-PDE4BArrowREACT_15519 (Reactome)
p-T185,Y187-MAPK1REACT_23990 (Reactome)
p-T75-DARPP32sREACT_15438 (Reactome)
p-T75-DARPP32sREACT_15540 (Reactome)
p-T75-DARPP32sTBarREACT_15519 (Reactome)
phospho-CaMK IV CalmodulinArrowREACT_15320 (Reactome)
phospho-CaMK IV CalmodulinREACT_15427 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1978"
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