KEGG   PATHWAY: ko04723
Entry
ko04723                     Pathway                                
Name
Retrograde endocannabinoid signaling
Description
Endogenous cannabinoids (endocannabinoids) serve as retrograde messengers at synapses in various regions of the brain. The family of endocannabinoids includes at least five derivatives of arachidonic acid; the two best characterized are arachydonoyl ethanolamide (anandamide, AEA) and 2-arachydonoil glycerol (2AG). They are released from postsynaptic neurons upon postsynaptic depolarization and/or receptor activation. The released endocannabinoids then activate the CB1 receptors (CB1R) at presynaptic terminals and suppress the release of inhibitory transmitter GABA (depolarization-induced suppression of inhibition, DSI) or excitatory transmitter glutamate (depolarization-induced suppression of excitation, DSE) by inhibiting Ca2+ channels. Besides the well-known expression of the CB1R in the plasma membrane, this receptor is also present in mitochondrial membranes, where it reduces the mitochondrial respiration and contributes to DSI. Whereas DSI and DSE result in short-term synaptic plasticity, endocannabinoids also mediate long-term synaptic changes (eCB-LTD). Persistent activation of CB1 receptors over a period of minutes triggers eCB-LTD by a RIM1alpha-dependent mechanism.
Class
Organismal Systems; Nervous system
Pathway map
ko04723  Retrograde endocannabinoid signaling
ko04723

Other DBs
GO: 0071926
Orthology
K01054  MGLL; acylglycerol lipase [EC:3.1.1.23]
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K03878  ND1; NADH-ubiquinone oxidoreductase chain 1 [EC:7.1.1.2]
K03879  ND2; NADH-ubiquinone oxidoreductase chain 2 [EC:7.1.1.2]
K03880  ND3; NADH-ubiquinone oxidoreductase chain 3 [EC:7.1.1.2]
K03881  ND4; NADH-ubiquinone oxidoreductase chain 4 [EC:7.1.1.2]
K03882  ND4L; NADH-ubiquinone oxidoreductase chain 4L [EC:7.1.1.2]
K03883  ND5; NADH-ubiquinone oxidoreductase chain 5 [EC:7.1.1.2]
K03884  ND6; NADH-ubiquinone oxidoreductase chain 6 [EC:7.1.1.2]
K03934  NDUFS1; NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:7.1.1.2]
K03935  NDUFS2; NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:7.1.1.2]
K03936  NDUFS3; NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:7.1.1.2]
K03937  NDUFS4; NADH dehydrogenase (ubiquinone) Fe-S protein 4
K03938  NDUFS5; NADH dehydrogenase (ubiquinone) Fe-S protein 5
K03939  NDUFS6; NADH dehydrogenase (ubiquinone) Fe-S protein 6
K03940  NDUFS7; NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:7.1.1.2]
K03941  NDUFS8; NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:7.1.1.2]
K03942  NDUFV1; NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:7.1.1.2]
K03943  NDUFV2; NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:7.1.1.2]
K03944  NDUFV3; NADH dehydrogenase (ubiquinone) flavoprotein 3
K03945  NDUFA1; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 1
K03946  NDUFA2; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2
K03947  NDUFA3; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 3
K03948  NDUFA4; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4
K03949  NDUFA5; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5
K03950  NDUFA6; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 6
K03951  NDUFA7; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 7
K03952  NDUFA8; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 8
K03953  NDUFA9; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 9
K03954  NDUFA10; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 10
K03955  NDUFAB1; NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1, acyl-carrier protein
K03956  NDUFA11; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11
K03957  NDUFB1; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 1
K03958  NDUFB2; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2
K03959  NDUFB3; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 3
K03960  NDUFB4; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 4
K03961  NDUFB5; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 5
K03962  NDUFB6; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6
K03963  NDUFB7; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7
K03964  NDUFB8; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8
K03965  NDUFB9; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9
K03966  NDUFB10; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10
K03967  NDUFC1; NADH dehydrogenase (ubiquinone) 1 subunit C1
K03968  NDUFC2; NADH dehydrogenase (ubiquinone) 1 subunit C2
K04277  CNR1; cannabinoid receptor 1
K04344  CACNA1A, CAV2.1; voltage-dependent calcium channel P/Q type alpha-1A
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04347  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04440  JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K04441  P38; p38 MAP kinase [EC:2.7.11.24]
K04534  GNAO, G-ALPHA-O; guanine nucleotide-binding protein G(o) subunit alpha
K04536  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
K04537  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2
K04538  GNB4; guanine nucleotide-binding protein subunit beta-4
K04539  GNB5; guanine nucleotide-binding protein subunit beta-5
K04540  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3
K04541  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4
K04542  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5
K04543  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
K04544  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8
K04545  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10
K04546  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11
K04547  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13
K04548  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1
K04549  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2
K04603  GRM1; metabotropic glutamate receptor 1
K04604  GRM5; metabotropic glutamate receptor 5
K04630  GNAI; guanine nucleotide-binding protein G(i) subunit alpha
K04634  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04849  CACNA1B, CAV2.2; voltage-dependent calcium channel N type alpha-1B
K04850  CACNA1C, CAV1.2; voltage-dependent calcium channel L type alpha-1C
K04851  CACNA1D, CAV1.3; voltage-dependent calcium channel L type alpha-1D
K04853  CACNA1F, CAV1.4; voltage-dependent calcium channel L type alpha-1F
K04857  CACNA1S, CAV1.1; voltage-dependent calcium channel L type alpha-1S
K04958  ITPR1; inositol 1,4,5-triphosphate receptor type 1
K04959  ITPR2; inositol 1,4,5-triphosphate receptor type 2
K04960  ITPR3; inositol 1,4,5-triphosphate receptor type 3
K04997  KCNJ3, KIR3.1; potassium inwardly-rectifying channel subfamily J member 3
K04999  KCNJ5, KIR3.4; potassium inwardly-rectifying channel subfamily J member 5
K05000  KCNJ6, KIR3.2; potassium inwardly-rectifying channel subfamily J member 6
K05002  KCNJ9, KIR3.3; potassium inwardly-rectifying channel subfamily J member 9
K05175  GABRA; gamma-aminobutyric acid receptor subunit alpha
K05181  GABRB; gamma-aminobutyric acid receptor subunit beta
K05184  GABRD; gamma-aminobutyric acid receptor subunit delta
K05185  GABRE; gamma-aminobutyric acid receptor subunit epsilon
K05186  GABRG; gamma-aminobutyric acid receptor subunit gamma
K05189  GABRP; gamma-aminobutyric acid receptor subunit pi
K05190  GABRR; gamma-aminobutyric acid receptor subunit rho
K05192  GABRQ; gamma-aminobutyric acid receptor subunit theta
K05197  GRIA1; glutamate receptor 1
K05198  GRIA2; glutamate receptor 2
K05199  GRIA3; glutamate receptor 3
K05200  GRIA4; glutamate receptor 4
K05858  PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K07825  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3
K07826  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
K08041  ADCY1; adenylate cyclase 1 [EC:4.6.1.1]
K08042  ADCY2; adenylate cyclase 2 [EC:4.6.1.1]
K08043  ADCY3; adenylate cyclase 3 [EC:4.6.1.1]
K08044  ADCY4; adenylate cyclase 4 [EC:4.6.1.1]
K08045  ADCY5; adenylate cyclase 5 [EC:4.6.1.1]
K08046  ADCY6; adenylate cyclase 6 [EC:4.6.1.1]
K08047  ADCY7; adenylate cyclase 7 [EC:4.6.1.1]
K08048  ADCY8; adenylate cyclase 8 [EC:4.6.1.1]
K08049  ADCY9; adenylate cyclase 9 [EC:4.6.1.1]
K11351  NDUFB11; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11
K11352  NDUFA12; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 12
K11353  NDUFA13; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 13
K11987  PTGS2, COX2; prostaglandin-endoperoxide synthase 2 [EC:1.14.99.1]
K12302  SLC17A6_7_8; MFS transporter, ACS family, solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6/7/8
K13700  ABHD6; abhydrolase domain-containing protein 6 [EC:3.1.1.23]
K13806  DAGL; sn1-specific diacylglycerol lipase [EC:3.1.1.116]
K13985  NAPEPLD; N-acyl-phosphatidylethanolamine-hydrolysing phospholipase D [EC:3.1.4.54]
K15015  SLC32A, VGAT; solute carrier family 32 (vesicular inhibitory amino acid transporter)
K15291  RIMS1, RIM1; regulating synaptic membrane exocytosis protein 1
K15528  FAAH; fatty acid amide hydrolase [EC:3.5.1.99]
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
K19663  PRKCG; classical protein kinase C gamma type [EC:2.7.11.13]
Compound
C00025  L-Glutamate
C00076  Calcium cation
C00116  Glycerol
C00157  Phosphatidylcholine
C00165  Diacylglycerol
C00189  Ethanolamine
C00219  Arachidonate
C00238  Potassium cation
C00334  4-Aminobutanoate
C00350  Phosphatidylethanolamine
C00427  Prostaglandin H2
C00575  3',5'-Cyclic AMP
C00689  alpha,alpha'-Trehalose 6-phosphate
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C11695  Anandamide
C13856  2-Arachidonoylglycerol
C19912  N-Arachidonoyl-phosphatidylethanolamine
C19913  Phospho-anandamide
Reference
PMID:17419048
  Authors
Hashimotodani Y, Ohno-Shosaku T, Kano M
  Title
Ca(2+)-assisted receptor-driven endocannabinoid release: mechanisms that associate presynaptic and postsynaptic activities.
  Journal
Curr Opin Neurobiol 17:360-5 (2007)
DOI:10.1016/j.conb.2007.03.012
Reference
PMID:21531987
  Authors
Ohno-Shosaku T, Tanimura A, Hashimotodani Y, Kano M
  Title
Endocannabinoids and retrograde modulation of synaptic transmission.
  Journal
Neuroscientist 18:119-32 (2012)
DOI:10.1177/1073858410397377
Reference
PMID:18084639
  Authors
Basavarajappa BS
  Title
Neuropharmacology of the endocannabinoid signaling system-molecular mechanisms, biological actions and synaptic plasticity.
  Journal
Curr Neuropharmacol 5:81-97 (2007)
DOI:10.2174/157015907780866910
Reference
PMID:16968947
  Authors
Pacher P, Batkai S, Kunos G
  Title
The endocannabinoid system as an emerging target of pharmacotherapy.
  Journal
Pharmacol Rev 58:389-462 (2006)
DOI:10.1124/pr.58.3.2
Reference
PMID:15340387
  Authors
Di Marzo V, Bifulco M, De Petrocellis L
  Title
The endocannabinoid system and its therapeutic exploitation.
  Journal
Nat Rev Drug Discov 3:771-84 (2004)
DOI:10.1038/nrd1495
Reference
PMID:17404373
  Authors
Hashimotodani Y, Ohno-Shosaku T, Kano M
  Title
Endocannabinoids and synaptic function in the CNS.
  Journal
Neuroscientist 13:127-37 (2007)
DOI:10.1177/1073858406296716
Reference
PMID:19126760
  Authors
Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M
  Title
Endocannabinoid-mediated control of synaptic transmission.
  Journal
Physiol Rev 89:309-80 (2009)
DOI:10.1152/physrev.00019.2008
Reference
PMID:19640475
  Authors
Regehr WG, Carey MR, Best AR
  Title
Activity-dependent regulation of synapses by retrograde messengers.
  Journal
Neuron 63:154-70 (2009)
DOI:10.1016/j.neuron.2009.06.021
Reference
PMID:17636069
  Authors
Benarroch E
  Title
Endocannabinoids in basal ganglia circuits: implications for Parkinson disease.
  Journal
Neurology 69:306-9 (2007)
DOI:10.1212/01.wnl.0000267407.79757.75
Reference
PMID:16085309
  Authors
Ohno-Shosaku T, Hashimotodani Y, Maejima T, Kano M
  Title
Calcium signaling and synaptic modulation: regulation of endocannabinoid-mediated synaptic modulation by calcium.
  Journal
Cell Calcium 38:369-74 (2005)
DOI:10.1016/j.ceca.2005.06.014
Reference
PMID:18801434
  Authors
Harkany T, Mackie K, Doherty P
  Title
Wiring and firing neuronal networks: endocannabinoids take center stage.
  Journal
Curr Opin Neurobiol 18:338-45 (2008)
DOI:10.1016/j.conb.2008.08.007
Reference
PMID:18515270
  Authors
Hosking RD, Zajicek JP
  Title
Therapeutic potential of cannabis in pain medicine.
  Journal
Br J Anaesth 101:59-68 (2008)
DOI:10.1093/bja/aen119
Reference
PMID:21187849
  Authors
Di Marzo V
  Title
Endocannabinoid signaling in the brain: biosynthetic mechanisms in the limelight.
  Journal
Nat Neurosci 14:9-15 (2011)
DOI:10.1038/nn.2720
Reference
PMID:18948642
  Authors
McPartland JM
  Title
The endocannabinoid system: an osteopathic perspective.
  Journal
J Am Osteopath Assoc 108:586-600 (2008)
DOI:10.7556/jaoa.2008.108.10.586
Reference
PMID:17553427
  Authors
Chevaleyre V, Heifets BD, Kaeser PS, Sudhof TC, Castillo PE
  Title
Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1alpha.
  Journal
Neuron 54:801-12 (2007)
DOI:10.1016/j.neuron.2007.05.020
Reference
PMID:19553483
  Authors
Lafourcade CA
  Title
Presynaptic mechanisms of endocannabinoid-mediated long-term depression in the hippocampus.
  Journal
J Neurophysiol 102:2009-12 (2009)
DOI:10.1152/jn.00441.2009
Reference
PMID:21328621
  Authors
Ueda N, Tsuboi K, Uyama T, Ohnishi T
  Title
Biosynthesis and degradation of the endocannabinoid 2-arachidonoylglycerol.
  Journal
Biofactors 37:1-7 (2011)
DOI:10.1002/biof.131
Reference
PMID:14978245
  Authors
Guo J, Ikeda SR
  Title
Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons.
  Journal
Mol Pharmacol 65:665-74 (2004)
DOI:10.1124/mol.65.3.665
Reference
PMID:22388959
  Authors
Benard G, Massa F, Puente N, Lourenco J, Bellocchio L, Soria-Gomez E, Matias I, Delamarre A, Metna-Laurent M, Cannich A, Hebert-Chatelain E, Mulle C, Ortega-Gutierrez S, Martin-Fontecha M, Klugmann M, Guggenhuber S, Lutz B, Gertsch J, Chaouloff F, Lopez-Rodriguez ML, Grandes P, Rossignol R, Marsicano G
  Title
Mitochondrial CB(1) receptors regulate neuronal energy metabolism.
  Journal
Nat Neurosci 15:558-64 (2012)
DOI:10.1038/nn.3053
Reference
PMID:26260530
  Authors
Busquets-Garcia A, Desprez T, Metna-Laurent M, Bellocchio L, Marsicano G, Soria-Gomez E
  Title
Dissecting the cannabinergic control of behavior: The where matters.
  Journal
Bioessays 37:1215-25 (2015)
DOI:10.1002/bies.201500046
Reference
PMID:28076767
  Authors
Harkany T, Horvath TL
  Title
(S)Pot on Mitochondria: Cannabinoids Disrupt Cellular Respiration to Limit Neuronal Activity.
  Journal
Cell Metab 25:8-10 (2017)
DOI:10.1016/j.cmet.2016.12.020
Reference
PMID:22449955
  Authors
Alger BE, Tang AH
  Title
Do cannabinoids reduce brain power?
  Journal
Nat Neurosci 15:499-501 (2012)
DOI:10.1038/nn.3072
Related
pathway
ko00190  Oxidative phosphorylation
ko04020  Calcium signaling pathway
ko04721  Synaptic vesicle cycle
ko04724  Glutamatergic synapse
ko04727  GABAergic synapse

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