Endocannabinoid System

Vincenzo Di Marzo, Endocannabinoid Research Group, Pozzuoli (NA), Italy

Published online: June 2011

DOI: 10.1002/9780470015902.a0023403

The endocannabinoid system (ECS) is defined as the signalling system composed of: (1) the two G-protein-coupled receptors known as cannabinoid receptors of type-1 and -2 (CB1 and CB2); (2) the two most studied endogenous agonists of such receptors, the endocannabinoids anandamide (N-arachidonoyl-ethanolamine) and 2-AG (2-arachidonoyl-glycerol); (3) enzymes and other proteins regulating the tissue levels of endocannabinoids; and (4) enzymes and other proteins that, together with endocannabinoids, regulate the activity of cannabinoid receptors. A key role of the ECS is emerging in the control not only of central and peripheral nervous system functions, but also of most aspects of mammalian physiology, including energy intake, processing and storage, the immune response, reproduction and cell fate. The ECS is also subject to dysregulation, and this seems to contribute to the symptoms and progress of several diseases. Hence, the possibility of developing new therapies starting from our increasing knowledge of the ECS is discussed.

Key Concepts:

  • Endocannabinoids are local mediators with autocrine or paracrine function.
  • Endocannabinoids are usually produced de novo and ‘on demand’ following elevation of intracellular Ca2+ concentrations.
  • Endocannabinoids often act in the central nervous system as ‘retrograde neuromodulators’, that is, they are released from post-synaptic neurons and act at cannabinoid CB1 receptors on pre-synaptic axon terminals.
  • Endocannabinoids possess immune-modulatory functions and usually inhibit cytokine release from immune cells and regulate the migration of the latter.
  • Endocannabinoids are key regulators of food intake, gastrointestinal function, energy storage in the adipose tissue and energy processing by the liver and the skeletal muscle.
  • Endocannabinoids are deeply involved in pain processing at peripheral, spinal and supra-spinal sites.
  • Endocannabinoids regulate both male and female reproduction.
  • Endocannabinoid can differentially affect cell fate in healthy and cancer cells by regulating differentiation, proliferation and apoptosis.
  • Endocannabinoids, and anandamide in particular, also directly interact with non-CB1, non-CB2 receptors, the most studied of which is the transient receptor potential vanilloid type-1 (TRPV1) channel.
  • Dysregulation of the ECS underlies several neurological, immune and metabolic disorders, and therapeutic strategies manipulating the ECS are being developed.

Keywords: cannabinoid; receptor; arachidonic acid; obesity; neuromodulator; pain; Pharmacology

Figure 1. From THC to endocannabinoids. Chemical structures of Cannabis sativa main psychoactive constituent, (-)-9-tetrahydrocannabinol, and of the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol.
Figure 2. Retrograde signalling by endocannabinoids. Schematic representation of different types of endocannabinoid- and CB1-mediated retrograde signalling in the brain. When their receptor is preferentially distributed presynaptically (as in the case of cannabinoid CB1 receptors), signals produced postsynaptically might act retrogradely to reduce excitatory and inhibitory neurotransmitter release in a way that is either ‘homosynaptic metabotropic-driven’ (1) or ‘depolarisation-driven’ (i.e. depolarisation-induced suppression of excitatory or inhibitory signalling, [DSE or DSI]) (2). One such signal for at least the former type of synaptic signalling is 2-arachidonoylglycerol (2-AG), since its Ca2+-sensitive biosynthetic machinery, comprising phospholipase C (PLC) and diacylglycerol lipase- (DAGL), is located on the somatodendritic membrane in proximity of metabotropic glutamate or acetylcholine receptors (e.g. mGluR1 or mGluR5 or M1 receptors), their G-protein, Gq/11, and the scaffolding protein, Homer 1, as well as of inositol-tris-phosphate (IP3) receptors on the endoplasmic reticulum. In this way, activation of the metabotropic receptor can stimulate PLC via Gq/11, and produce diacylgycerol substrates for DAGL, and, through activation of IP3 receptors, release from the ER the Ca2+ necessary for DAGL- activity. In retrograde signalling, the enzyme responsible for inactivation of the signal should be presynaptic, as is the case of the major 2-AG degrading enzyme, monoacylglycerol lipase (MAGL). Lipophilic retrograde neuromodulators such as the endocannabinoids can also act at synapses near to, but different from, those from the activity of which the signal is ultimately generated, as in ‘heterosynaptic metabotropic-driven’ retrograde signalling (3). Solid arrows denote activation, transformation or movement; broken arrows denote inhibition; small circles denote neurotransmitters; large circles denote secretory vesicles.
Figure 3. Endocannabinoid system-based therapeutic drugs. Chemical structures of the FAAH inhibitor, PF04457845, currently undergoing clinical trials, of the CB1 antagonist/inverse agonist, rimonabant, previously marketed as Acomplia, and of cannabidiol, which, together with THC, is the major active principle of Sativex.
close
 References
    Bab I and Zimmer A (2009) Cannabinoid receptors and the regulation of bone mass. British Journal of Pharmacology 153(2): 182–188.
    Bisogno T and Di Marzo V (2007) Short- and long-term plasticity of the endocannabinoid system in neuropsychiatric and neurological disorders. Pharmacological Research 56(5): 428–442.
    Bisogno T and Di Marzo V (2010) Cannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders. CNS & Neurological Disorders – Drug Targets 9(5): 564–573.
    Bisogno T, Howell F, Williams G et al. (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. Journal of Cell Biology 163(3): 463–468.
    Bisogno T, Sepe N, Melck D et al. (1997) Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells. Biochemical Journal 322(2): 671–677.
    Blankman JL, Simon GM and Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chemistry & Biology 14(12): 1347–1356.
    Blázquez C, Chiarlone A, Sagredo O et al. (2011) Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease. Brain 134(Pt 1): 119–136.
    Catani MV, Fezza F, Baldassarri S et al. (2009) Expression of the endocannabinoid system in the bi-potential HEL cell line: commitment to the megakaryoblastic lineage by 2-arachidonoylglycerol. Journal of Molecular Medicine 87(1): 65–74.
    Cobellis G, Ricci G, Cacciola G et al. (2010) A gradient of 2-arachidonoylglycerol regulates mouse epididymal sperm cell start-up. Biology of Reproduction 82(2): 451–458.
    Cravatt BF, Giang DK, Mayfield SP et al. (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384(6604): 83–87.
    Cristino L, Starowicz K, De Petrocellis L et al. (2008) Immunohistochemical localization of anabolic and catabolic enzymes for anandamide and other putative endovanilloids in the hippocampus and cerebellar cortex of the mouse brain. Neuroscience 151(4): 955–968.
    Devane WA, Dysarz FA 3rd, Johnson MR et al. (1988) Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology 34(5): 605–613.
    Devane WA, Hanus L, Breuer A et al. (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258(5090): 1946–1949.
    Di Marzo V (2008) Targeting the endocannabinoid system: to enhance or reduce? Nature Reviews Drug Discovery 7(5): 438–455.
    Di Marzo V (2010) Anandamide serves two masters in the brain. Nature Neuroscience 13(12): 1446–1448.
    Di Marzo V (2011) Endocannabinoid signaling in the brain: biosynthetic mechanisms in the limelight. Nature Neuroscience 14(1): 9–15.
    Di Marzo V and Després JP (2009) CB1 antagonists for obesity – what lessons have we learned from rimonabant. Nature Reviews Endocrinology 5(11): 633–638.
    Di Marzo V and Fontana A (1995) Anandamide, an endogenous cannabinomimetic eicosanoid: ‘killing two birds with one stone’. Prostaglandins Leukot Essent Fatty Acids 53(1): 1–11.
    Di Marzo V, Fontana A, Cadas H et al. (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372(6507): 686–669.
    Di Marzo V, Ligresti A and Cristino L (2009) The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation. International Journal of Obesity 33(suppl. 2): S18–24.
    Dinh TP, Freund TF and Piomelli D (2002) A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. Chemistry and Physics of Lipids 121(1–2): 149–158.
    Gao Y, Vasilyev DV, Goncalves MB et al. (2010) Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. Journal of Neuroscience 30(6): 2017–2024.
    Grimaldi P, Orlando P, Di Siena S et al. (2009) The endocannabinoid system and pivotal role of the CB2 receptor in mouse spermatogenesis. Proceedings of the National Academy of Sciences of the United States of America 106(27): 11131–11136.
    Guindon J and Hohmann AG (2009) The endocannabinoid system and pain. CNS & Neurological Disorders Drug Targets 8(6): 403–421.
    Hill MN, Patel S, Campolongo P et al. (2010) Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output. Journal of Neuroscience 30(45): 14980–14986.
    Idris AI and Ralston SH (2009) Cannabinoids and bone: friend or foe? Calcified Tissue International 87(4): 285–297.
    Izzo AA and Camilleri M (2009) Cannabinoids in intestinal inflammation and cancer. Pharmacological Research 60(2): 117–125.
    Jiang S, Alberich-Jorda M, Zagozdzon R et al. (2011) Cannabinoid receptor 2 and its agonists mediate hematopoiesis and hematopoietic stem and progenitor cell mobilization. Blood 117(3): 827–838.
    Karasu T, Marczylo TH, Maccarrone M, Konje JC, (2011) The role of sex steroid hormones, cytokines and the endocannabinoid system in female fertility. Human Reproduction Update 17(3): 347–361.
    Karsak M, Cohen-Solal M, Freudenberg J et al. (2005) Cannabinoid receptor type 2 gene is associated with human osteoporosis. Human Molecular Genetics 14(22): 3389–3396.
    Ligresti A, De Petrocellis L, Hernán Pérez de la Ossa D et al. (2010) Exploiting nanotechnologies and TRPV1 channels to investigate the putative anandamide membrane transporter. PLoS One 5(4): e10239.
    Maccarrone M, Barboni B, Paradisi A et al. (2005) Characterization of the endocannabinoid system in boar spermatozoa and implications for sperm capacitation and acrosome reaction. Journal of Cell Science 118(part 19): 4393–4404.
    Mackie K (2008) Cannabinoid receptors: where they are and what they do. Journal of Neuroendocrinology 20(suppl. 1): 10–14.
    Maione S, Bisogno T, de Novellis V et al. (2006) Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. Journal of Pharmacology and Experimental Therapeutics 316(3): 969–982.
    Malfitano AM, Ciaglia E and Gangemi G (2011) Update on the endocannabinoid system as an anticancer target. Expert Opinion on Therapeutic Targets [Epub ahead of print].
    Marrs WR, Blankman JL, Horne EA et al. (2010) The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nature Neuroscience 13(8): 951–957.
    Matias I, Chen J, De Petrocellis L and Bisogno T (2004) Prostaglandin ethanolamides (prostamides): in vitro pharmacology and metabolism. Journal of Pharmacology and Experimental Therapeutics 309(2): 745–757.
    Matsuda LA, Lolait SJ, Brownstein MJ et al. (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346(6284): 561–564.
    Mechoulam R, Ben-Shabat S, Hanus L et al. (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical Pharmacology 50(1): 83–90.
    Mechoulam R, Devane WA, Breuer A et al. (1991) A random walk through a cannabis field. Pharmacology Biochemistry and Behavior 40(3): 461–464.
    Min R, Di Marzo V and Mansvelder HD (2010) DAG lipase involvement in depolarization-induced suppression of inhibition: does endocannabinoid biosynthesis always meet the demand? Neuroscientist 16(6): 608–613.
    Moreira FA and Crippa JA (2009) The psychiatric side-effects of rimonabant. Revista Brasileira de Psiquiatria 31(2): 145–153.
    Muccioli GG, Naslain D, Bäckhed F et al. (2010) The endocannabinoid system links gut microbiota to adipogenesis. Molecular Systems Biology 6: 392.
    Munro S, Thomas KL and Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365(6441): 61–65.
    Okamoto Y, Tsuboi K and Ueda N (2009) Enzymatic formation of anandamide. Vitamins and Hormones 81: 1–24.
    Pacher P and Steffens S (2010) The emerging role of the endocannabinoid system in cardiovascular disease. Seminars in Immunopathology 31(1): 63–77.
    Pandey R, Mousawy K, Nagarkatti M et al. (2009) Endocannabinoids and immune regulation. Pharmacological Research 60(2): 85–92.
    Parolaro D, Realini N, Vigano D et al. (2010) The endocannabinoid system and psychiatric disorders. Experimental Neurology 224(1): 3–14.
    Pertwee RG (2009) Emerging strategies for exploiting cannabinoid receptor agonists as medicines. British Journal of Pharmacology 156(3): 397–411.
    Petrosino S and Di Marzo V (2010) FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels. Current Opinion in Investigational Drugs 11(1): 51–62.
    Rossi F, Bellini G, Luongo L et al. (2011) The endovanilloid/endocannabinoid system: a new potential target for osteoporosis therapy. Bone 48(5): 997–1007.
    Sagar DR, Gaw AG, Okine BN et al. (2009) Dynamic regulation of the endocannabinoid system: implications for analgesia. Molecular Pain 5: 59.
    Schlosburg JE, Blankman JL, Long JZ et al. (2010) Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nature Neuroscience 13(9): 1113–1119.
    Simon GM and Cravatt BF (2010) Characterization of mice lacking candidate N-acyl ethanolamine biosynthetic enzymes provides evidence for multiple pathways that contribute to endocannabinoid production in vivo. Molecular BioSystems 6(8): 1411–1418.
    Sugiura T and Waku K (1995) 2-Arachidonoylglycerol and the cannabinoid receptors. Chemistry and Physics of Lipids 108(1-2): 89–106.
    Sun X and Dey SK (2009) Cannabinoid/endocannabinoid signaling impact on early pregnancy events. Current Topics in Behavioral Neurosciences 1: 255–273.
    Tam J, Vemuri VK, Liu J et al. (2010) Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. Journal of Clinical Investigation 120(8): 2953–2966.
    Tanimura A, Yamazaki M, Hashimotodani Y et al. (2010) The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission. Neuron 65(3): 320–327.
    Vellani V, Petrosino S, De Petrocellis L et al. (2008) Functional lipidomics. Calcium-independent activation of endocannabinoid/endovanilloid lipid signalling in sensory neurons by protein kinases C and A and thrombin. Neuropharmacology 55(8): 1274–1279.
    Vila A, Rosengarth A, Piomelli D et al. (2007) Hydrolysis of prostaglandin glycerol esters by the endocannabinoid-hydrolyzing enzymes, monoacylglycerol lipase and fatty acid amide hydrolase. Biochemistry 46(33): 9578–9585.
    Wettschureck N, van der Stelt M, Tsubokawa H et al. (2006) Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation. Molecular and Cellular Biology 26(15): 5888–5894.
    Yates ML and Barker EL (2009) Organized trafficking of anandamide and related lipids. Vitamins and Hormones 81: 25–53.
    Zhang L, Wang M, Bisogno T et al. (2011) Endocannabinoids generated by Ca2+ or by metabotropic glutamate receptors appear to arise from different pools of diacylglycerol lipase. Plos One 6(1): e1635.

Related Sub-Topics:

Neurotransmitters | Drugs and the Brain | Receptors for Neurotransmitters | Cell Signalling | Other Biomolecules: Structure, Function, Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Endocannabinoid System
 
How to Cite close
Di Marzo, Vincenzo(Jun 2011) Endocannabinoid System. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023403]