KEGG PATHWAY: ko04723

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

Other DBs

GO:

0071926

Orthology

K12302

MFS transporter, ACS family, solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6/7/8

K05197

glutamate receptor 1

K05198

glutamate receptor 2

K05199

glutamate receptor 3

K05200

glutamate receptor 4

K04850

voltage-dependent calcium channel L type alpha-1C

K04851

voltage-dependent calcium channel L type alpha-1D

K04853

voltage-dependent calcium channel L type alpha-1F

K04857

voltage-dependent calcium channel L type alpha-1S

K04603

metabotropic glutamate receptor 1

K04604

metabotropic glutamate receptor 5

K04634

guanine nucleotide-binding protein G(q) subunit alpha

K05858

phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]

K04958

inositol 1,4,5-triphosphate receptor type 1

K04959

inositol 1,4,5-triphosphate receptor type 2

K04960

inositol 1,4,5-triphosphate receptor type 3

K13985

N-acyl-phosphatidylethanolamine-hydrolysing phospholipase D [EC:3.1.4.54]

K02677

classical protein kinase C alpha type [EC:2.7.11.13]

K19662

classical protein kinase C beta type [EC:2.7.11.13]

K19663

classical protein kinase C gamma type [EC:2.7.11.13]

K13806

sn1-specific diacylglycerol lipase [EC:3.1.1.116]

K11987

prostaglandin-endoperoxide synthase 2 [EC:1.14.99.1]

K13700

abhydrolase domain-containing protein 6 [EC:3.1.1.23]

K15528

fatty acid amide hydrolase [EC:3.5.1.99]

K04277

cannabinoid receptor 1

K04630

guanine nucleotide-binding protein G(i) subunit alpha

K04534

guanine nucleotide-binding protein G(o) subunit alpha

K04536

guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

K04537

guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2

K07825

guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3

K04538

guanine nucleotide-binding protein subunit beta-4

K04539

guanine nucleotide-binding protein subunit beta-5

K07826

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

K04540

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3

K04541

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4

K04542

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5

K04543

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7

K04544

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8

K04545

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10

K04546

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11

K04347

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12

K04547

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13

K04548

guanine nucleotide-binding protein G(T) subunit gamma-T1

K04549

guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2

K04997

potassium inwardly-rectifying channel subfamily J member 3

K05000

potassium inwardly-rectifying channel subfamily J member 6

K05002

potassium inwardly-rectifying channel subfamily J member 9

K04999

potassium inwardly-rectifying channel subfamily J member 5

K04344

voltage-dependent calcium channel P/Q type alpha-1A

K04849

voltage-dependent calcium channel N type alpha-1B

K04371

mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04440

mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]

K04441

p38 MAP kinase [EC:2.7.11.24]

K08041

adenylate cyclase 1 [EC:4.6.1.1]

K08042

adenylate cyclase 2 [EC:4.6.1.1]

K08043

adenylate cyclase 3 [EC:4.6.1.1]

K08044

adenylate cyclase 4 [EC:4.6.1.1]

K08045

adenylate cyclase 5 [EC:4.6.1.1]

K08046

adenylate cyclase 6 [EC:4.6.1.1]

K08047

adenylate cyclase 7 [EC:4.6.1.1]

K08048

adenylate cyclase 8 [EC:4.6.1.1]

K08049

adenylate cyclase 9 [EC:4.6.1.1]

K04345

protein kinase A [EC:2.7.11.11]

K01054

acylglycerol lipase [EC:3.1.1.23]

K03878

NADH-ubiquinone oxidoreductase chain 1 [EC:7.1.1.2]

K03879

NADH-ubiquinone oxidoreductase chain 2 [EC:7.1.1.2]

K03880

NADH-ubiquinone oxidoreductase chain 3 [EC:7.1.1.2]

K03881

NADH-ubiquinone oxidoreductase chain 4 [EC:7.1.1.2]

K03882

NADH-ubiquinone oxidoreductase chain 4L [EC:7.1.1.2]

K03883

NADH-ubiquinone oxidoreductase chain 5 [EC:7.1.1.2]

K03884

NADH-ubiquinone oxidoreductase chain 6 [EC:7.1.1.2]

K03942

NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:7.1.1.2]

K03943

NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:7.1.1.2]

K03944

NADH dehydrogenase (ubiquinone) flavoprotein 3

K03945

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 1

K03946

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2

K03947

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 3

K03948

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4

K03949

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5

K03950

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 6

K03951

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 7

K03952

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 8

K03953

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 9

K03954

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 10

K03955

NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1, acyl-carrier protein

K03956

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11

K11352

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 12

K11353

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 13

K03957

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 1

K03958

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2

K03959

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 3

K03960

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 4

K03961

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 5

K03962

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6

K03963

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7

K03964

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8

K03965

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9

K03966

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10

K11351

NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11

K03934

NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:7.1.1.2]

K03935

NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:7.1.1.2]

K03936

NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:7.1.1.2]

K03937

NADH dehydrogenase (ubiquinone) Fe-S protein 4

K03938

NADH dehydrogenase (ubiquinone) Fe-S protein 5

K03939

NADH dehydrogenase (ubiquinone) Fe-S protein 6

K03940

NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:7.1.1.2]

K03941

NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:7.1.1.2]

K03967

NADH dehydrogenase (ubiquinone) 1 subunit C1

K03968

NADH dehydrogenase (ubiquinone) 1 subunit C2

K15015

solute carrier family 32 (vesicular inhibitory amino acid transporter)

K15291

regulating synaptic membrane exocytosis protein 1

K05175

gamma-aminobutyric acid receptor subunit alpha

K05181

gamma-aminobutyric acid receptor subunit beta

K05186

gamma-aminobutyric acid receptor subunit gamma

K05184

gamma-aminobutyric acid receptor subunit delta

K05185

gamma-aminobutyric acid receptor subunit epsilon

K05192

gamma-aminobutyric acid receptor subunit theta

K05189

gamma-aminobutyric acid receptor subunit pi

K05190

gamma-aminobutyric acid receptor subunit rho

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