Jalur Sinyal dan Metabolisme Endocannabinoid: Tinjauan Pustaka

Loo Hariyanto Raharjo, Harman Agusaputra


Efek biologis dari tumbuhan Cannabis Sativa dimediasi oleh dua buah reseptor dari kelompok G-protein coupled receptor; reseptor cannabinoid 1 (CB1R) dan 2 (CB2R). CB1R lebih banyak didapatkan pada Susunan Saraf Pusat dan berhubungan dengan pemberian terapi pada gangguan neuropsikologis dan penyakit neurodegeneratif. Selain itu endocannabinoid juga memodulasi jalur tranduksi sinyal dan menimbulkan efek pada jaringan perifer. Meskipun cannabionoid memiliki efek terapeutik, tetapi efek psikoaktifnya menyebabkan terbatasnya penggunaan endocannabionoid dalam praktek klinis. Namun kemajuan terkini dalam distribusi fisiologis dan pengaturan fungsional dari endocannabinoid memungkinkan adanya penelitian eksploitasi penggunaan endocannabionoid sebagai bahan terapeutik serta pengembangan obat baru dengan keunggulan farmakologis. Pada tinjauan pustaka ini, kami meninjau secara singkat tentang jalur metabolik dan jalur transduksi sinyal dari dua endocannabionoid utama; Anandamide (AEA) dan 2- arachidonoyglycerol (2-AG) yang mempunyai potensi terapeutik.



Endocannabinoid, Anandamide (AEA), arachidonoyglycerol (2-AG), Jalur metabolik, Jalur transduksi sinyal

Full Text:



Ahn KH, 2012. Allosteric modulator ORG27569 induces CB1 cannabinoid receptor high affinity agonist binding state, receptor internalization, and Gi protein-independent ERK1/2 kinase activation. The Journal of Biological Chemistry. (287): 12070–12082.

Baggelaar MP, 2015. Highly selective, reversible inhibitor identified by comparative chemoproteomics modulates diacylglycerol lipase activity in neurons. Journal of the American Chemical Society. (137): 322-338.

Battista N, Di Tommaso M, Bari M, & Maccarrone M, 2014. The endocannabinoid system: an overview. BEHAVIORAL NEUROSCIENCE.1-8.

Bisogno TC, 2006. Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochimica et Biophysica Acta. (1761): 205-212.

Bisogno TH, 2003. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. The Journal of Cell Biology. (163): 463-468.

Blankman JL, 2007. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chemistry & Biology.(14): 1347–1356.

Bouaboula MH, 2005. Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. European Journal of Pharmacology. (517): 174-181.

Buczynski MW, 2010. Quantification of brain endocannabinoid levels:Methods, interpretations and pitfalls. British Journal of Pharmacology. (160): 423-442.

Cadas HG, 1996. Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. Journal of Neuroscience. 12(16): 3934–3942.

Carlisle SJC, 2002. Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. International Immunopharmacology.(2): 69-82.

Castillo P, Younts T, Chavez A, & Hashimotodani Y, 2012. Endocannabinoid signaling and synaptic function. Neuron.(76): 70-81.

Devane WAHL, 1992. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science.(258): 1946-1949.

Di Marzo V, 2008. Targeting the endocannabinoid system: To enhance or reduce? Nat. Rev. Drug Discov.(7): 438-455.

Di Marzo V, & de Petrocellis L. 2012. Why do cannabinoid receptors have more than one endogenous ligand? Philosophical Transactions of the Royal Society B: Biological Sciences.(367): 3216-3228.

Du HK, 2013. Neuregulin-1 impairs the long-term depression of hippocampal inhibitory synapses by facilitating the degradation of endocannabinoid 2-AG. The Journal of Neuroscience.(33): 15022–15031.

ES O, 2011. Commentary: functional neuronal CB2 cannabinoid receptors in the CNS. Current Neuropharmacology.(9): 205-208.

Fu JB, 2011. A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat. Neurosci.(15): 64-69.

Galli GG, 2014. Prdm5 suppresses Apc(Min)-driven intestinal adenomas and regulates monoacylglycerol lipase expression. Oncogene.(33): 3342–3350.

Gaoni Y, & Mechoulam R, 1964. Isolation, structure, and partial synthesis of an active constituent of hashish. Journal of the American Chemical Society.(86): 1646–1647.

Gerdeman G, & Lovinger D, 2001. CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J. Neurophysiol: 468-471.

Glass MDM, 1997. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience.(77): 299-318.

Golczak MK, 2012. Structural basis for the acyltransferase activity of lecithin:Retinol acyltransferase-like proteins. The Journal of Biological Chemistry.(287): 23790–23807.

Gomez, O. S.-R.-C.-H.-H. (2011). Cannabinoid receptor agonists modulate oligodendrocyte differentiation by activating PI3K/Akt and the mammalian target of rapamycin (mTOR) pathways. British Journal of Pharmacology(163), 1520-1532.

Guerciolini R, 1997. Mode of action of orlistat. International Journal of Obesity and Related Metabolic Disorders.(21): S12-S23.

Hashimotodani YOS, 2008. Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization induced endocanabinoid release. Neuropharmacology.(54): 58-67.

Hashimotodani YOS, 2013. Acute inhibition of diacylglycerol lipase blocks endocannabinoid-mediated retrograde signalling: Evidence for on-demand biosynthesis of 2-arachidonoylglycerol. The Journal of Physiology.(591): 4765–4776.

Hillard CJ, W. K. (2012). Contributions of the endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence. Neuroscience(204), 207-229.

Howlett AC, 1985. Cannabinoid inhibition of adenylate cyclase. Biochemistry of the response in neuroblastoma cell membranes. Molecular Pharmacology.(27): 429-436.

Izzo A,& Sharkey K, 2010. Cannabinoids and the gut: New developments and emerging concepts. Pharmacol.Ther.(126): 21-38.

Jung KMMR, 2005. Stimulation of endocannabinoid formation in brain slice cultures through activation of group I metabotropic glutamate receptors. Mol Pharmacol.(68): 1196-1202.

Jung KM, 2007. A key role for diacylglycerol lipase-{alpha} in metabotropic glutamate receptor-dependent endocannabinoid mobilization. Molecular Pharmacology.(72): 612-621.

Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, & Watanabe M, 2009. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev.(89): 309-380.

Katayama KU, 1997. Distribution of anandamide amidohydrolase in rat tissues with special reference to small intestine. Biochimica et Biophysica Act.(1347): 212-218.

Katona IFT, 2012. Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci.(35): 529-558.

Kim SR, 2007. Roles of transient receptor potential vanilloid subtype 1 and cannabinoid type 1 receptors in the brain: Neuroprotection versus neurotoxicity. Molecular Neurobiology.(35): 245-254.

Kumar SZ, 2018. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. International Journal of Molecular Sciences: 2-23.

Kurahashi YU, 1997. Reversible hydrolysis and synthesis of anandamide demonstrated by recombinant rat fatty-acid amide hydrolase. Biochemical and Biophysical Research Communications. (273): 512-515.

Laurentiis AD, Araujo H, & Rettori V, (2014). Role of the Endocannabinoid System in the Neuroendocrine Responses to Inflammation. Current Pharmaceutical Design.(20): 1-10.

Liu JWW, 2008. Multiple pathways involved in the biosynthesis of anandamide. Neuropharmacology.(54): 1-7.

Lo Verme, J. F. (2005). The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Molecular Pharmacology(67), 15-19.

Lograno, M. D. (2004). Cannabinoid agonists induce contractile responses through Gi/o-dependent activation of phospholipase C in the bovine ciliary muscle. European Journal of Pharmacology,(494), 55-62.

Maccarrone MD, 2010. Intracellular trafficking of anandamide: new concepts for signaling. Trends Biochemical Sciences.(35): 601-608.

Maccarrone M, Bab R, Biro T, Cabral G, Dey S, di Marzo, V, 2015. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci.(36): 277-296.

Mackie K, 1992. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proceedings of the National Academy of Sciences of the United States of America.(89): 3825-3829.

Mackie K, 2005. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb. Exp.Pharmacol: 299-325.

Mai PY, 2015. Endocannabinoid system contributes to liver injury and inflammation by activation of bone marrow-derived monocytes/macrophages in a CB1-dependent manner. Journal of Immunology.(195): 3390–3401.

Marinelli S, Pacioni S, Bisogno T, di Marzo V, Prince D, Huguenard J, & Bacci A, 2008. The endocannabinoid 2-arachidonoylglycerol is responsible for the slow self-inhibition in neocortical interneurons. J. Neurosci. (28):13532–13541.

Marinelli S, Pacioni S, Cannich A, Marsicano G, & Bacci A, 2009. Self-modulation of neocortical pyramidalneurons by endocannabinoids. Nat. Neurosci.(12): 1488-1490.

Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, 2003. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. (302): 84-88.

Matyas FU, 2008. Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area. Neuropharmacology.(54): 95-107.

McPartland J, Guy G, & Marzo V, 2014. Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System. PLoS ONE. 3(9): 1-22.

Miller L, & Devi L, 2011. The highs and lows of cannabinoid receptor expression in disease: Mechanisms and their therapeutic implications. Pharmacol. Rev.(63): 461-470.

Muccioli G, 2010. Endocannabinoid biosynthesis and inactivation, from simple to complex. . Drug Discov. Today: 474-483.

Munro STS, 1193. Molecular characterization of a peripheral receptor for cannabinoids. Nature.(365): 61-65.

Murataeva N, Straiker A, & Mackie K, (2014). Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br. J. Pharmacol.(171): 1379-1391.

Okamoto YM, 2004. Molecular characterization of a phospholipase D generating anandamide and its congeners. The Journal of Biological Chemistry.(279): 5298–5305.

Okamoto YT, 2009. Enzymatic formation of anandamide. Vitam. Horm.:1-24.

Ortar GB, 2008. Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism. Journal of Medicinal Chemistry.(51): 6970-6979.

Parsons L, & Hill M, 2015. INTERNATIONAL REVIEW OF NEUROBIOLOGY: Endocannabinoids (125 ed.). London, United Kingdom: Elsevier Inc.

Pickel VM, 2012. Cannabinoid-1 receptors in the mouse ventral pallidum are targeted to axonal profiles expressing functionally opposed opioid peptides and contacting N-acylphosphatidylethanolamine-hydrolyzing phospholipase D terminals. Neuroscience: 10-21.

Puente N, Cui Y, Lassalle O, Lafourcade M, Georges F, Venance L, Manzoni O, 2011. Polymodal activation of the endocannabinoid system in the extended amygdala. Nat. Neurosci.(14): 1542-1567.

Reguero LEUL, 2014. Subcellular localization of NAPE-PLD and DAGL-alpha in the ventromedial nucleus of the hypothalamus by a preembedding immunogold method. Histochemistry and Cell Biology.(141): 543-550. doi:http://dx.doi.org/10.1007/s00418-013-1174-x

Roloff AM, 2010. Homer 1a gates the induction mechanism for endocannabinoid-mediated synaptic plasticity. Journal of Neuroscience.(30): 3072–3081.

Saghatelian AM, 2006. A FAAH-regulated class of N-acyl taurines that activates TRP ion channels. Biochemistry.(45): 9007-9015.

Sanchez-Blazquez P, Rodriguez-Munoz M, Vicente-Sanchez A, & Garzon J, 2013. Cannabinoid receptors couple to nmda receptors to reduce the production of no and the mobilization of zinc induced by glutamate. Antioxid. Redox Signal.(19): 1766-1782.

Schlosburg J, Blankman J, Long J, Nomura D, Pan B, Kinsey S, 2010. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat. Neurosci.(13): 1113-1119.

Schmid HH, 1990. N-acylated glycerophospholipids and their derivatives. Progress in Lipid Research.(29): 1-43.

Shonesy BC, 2013. CaMKII regulates diacylglycerol lipase-alpha and striatal endocannabinoid signaling. Nature Neuroscience.(16): 456-463.

Simon GM, 2006. Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for {alpha}/beta-hydrolase 4 in this pathway. The Journal of Biological Chemistry.(281): 26465–26472.

Simon GM, 2008. Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamine precursors in mouse brain. The Journal of Biological Chemistry.(283):9341–9349.

Stella N, 2009. Endocannabinoid signaling in microglial cells. Neuropharmacology.(56): 244-253.

Sugiura TKY, 2002. Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fatty Acids.(66):173-192.

Sumislawski JJ, 2011. Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: A potential role for monoacylglycerol lipaseinhibition in the prevention of stress-induced behavioral adaptation. Neuropsychopharmacology.(36): 2750–2761.

Tam, Trembovler V, di Marzo V, Petrosino S, Leo G, Alexandrovich A, 2008. The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling. FASEB J.(22): 285-294.

Turu G, & Hunyady L, 2010. Signal transduction of the CB1 cannabinoid receptor. Journal of Molecular Endocrinology.(44): 75-85.

Ueda NT, 2011. Biosynthesis and degradation of the endocannabinoid 2-arachidonoylglycerol. Biofactors.(37): 1-7.

Uyama TI, 2013. Involvement of phospholipase A/acyltransferase-1 in N-acylphosphatidylethanolamine generation. Biochimica et Biophysica Acta.(1831): 1690–1701.

Van der Stelt MTM, 2005. Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels. EMBO J.(24): 3026-3037.

Van Sickle MD, 2005. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science.(310): 329-332.

Vellani VP, 2008. Functional lipidomics. Calcium-independent activation of endocannabinoid/endovanilloid lipid signalling in sensory neurons by protein kinasesC and A and thrombin. Neuropharmacology: 1274–1279.

Yang WD, 2010. Proteome scale characterization of human S-acylated proteins in lipid raft-enriched and non-raft membranes. Molecular & Cellular Proteomics.(9): 54-70.

Zhao L, 2014. BDNF-endocannabinoid interactions at neocortical inhibitory synapses require phospholipase C signaling. Journal of Neurophysiology.(111): 1008-1015.

Zou S, & Kumar U, 2018. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. International Journal of Molecular Sciences: 1-23.

DOI: http://dx.doi.org/10.30742/jikw.v8i1.574


  • There are currently no refbacks.

Copyright (c) 2019 Loo Hariyanto Raharjo, Harman Agusaputra

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Jurnal Ilmiah Kedokteran Wijaya Kusuma is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License