Abstract
Endocannabinoids (eCBs) are endogenous lipids able to bind to cannabinoid receptors, the primary molecular targets of the cannabis (Cannabis sativa) active principle Δ9-tetrahydrocannabinol. During the last 20 years, several N-acylethanolamines and acylesters have been shown to act as eCBs, and a complex array of receptors, metabolic enzymes, and transporters (that altogether form the so-called “eCB system”) has been shown to finely tune their manifold biological activities. It appears now urgent to develop methods and protocols that allow to assay in a specific and quantitative manner the distinct components of the eCB system and that can properly localize them within the cell. A brief overview of eCBs and of the proteins that bind, transport, and metabolize these lipids is presented here, in orderto put in a better perspective, the relevance of methodologies that help to disclose molecular details of eCB signaling in health and disease. Proper methodological approaches form also the basis for a more rationale and effective drug design and therapeutic strategy to combat human disorders.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Pertwee RG, Howlett AC, Abood ME et al (2010) International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631
ElSohly MA, Radwan MM, Gul W et al (2017) Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod 103:1–36
Friedman D, French JA, Maccarrone M (2019) Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders. Lancet Neurol 18:504–512
Radwan MM, Chandra S, Gul S, ElSohly MA (2021) Cannabinoids, phenolics, terpenes and alkaloids of Cannabis. Molecules 26:2774
Maccarrone M, Guzmán M, Mackie K et al (2014) Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci 15:786–801
Di Marzo V, Stella N, Zimmer A (2015) Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci 16:30–42
Di Patrizio NV, Piomelli D (2012) The thrifty lipids: endocannabinoids and the neural control of energy conservation. Trends Neurosci 35:403–411
Maccarrone M (2020) Missing pieces to the endocannabinoid puzzle. Trends Mol Med 26:263–272
Artmann A, Petersen G, Hellgren LI et al (2008) Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Biochim Biophys Acta 1781:200–212
Lucanic M, Held JM, Vantipalli MC et al (2011) N-acylethanolamine signalling mediates the effect of diet on lifespan in Caenorhabditis elegans. Nature 473:226–229
Brown I, Cascio MG, Wahle KW et al (2010) Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. Carcinogenesis 31:1584–1591
Tyrtyshnaia A, Konovalova S, Bondar A et al (2021) Anti-inflammatory activity of N-docosahexaenoylethanolamine and N-eicosapentaenoylethanolamine in a mouse model of lipopolysaccharide-induced neuroinflammation. Int J Mol Sci 22:10728
Ueda N, Tsuboi K, Uyama T (2013) Metabolism of endocannabinoids and related N-acylethanolamines: canonical and alternative pathways. FEBS J 280:1874–1894
Fezza F, Bari M, Florio R et al (2014) Endocannabinoids, related compounds and their metabolic routes. Molecules 19:17078–17106
Cristino L, Bisogno T, Di Marzo V (2020) Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 16:9–29
Jin XH, Uyama T, Wang J et al (2009) cDNA cloning and characterization of human and mouse Ca2+-independent phosphatidylethanolamine N-acyltransferases. Biochim Biophys Acta 1791:32–38
Hussain Z, Uyama T, Tsuboi K, Ueda N (2017) Mammalian enzymes responsible for the biosynthesis of N-acylethanolamines. Biochim Biophys Acta Mol Cell Biol Lipids 1862:1546–1561
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. J Cell Biol 163:463–468
Chicca A, Marazzi J, Nicolussi S et al (2012) Evidence for bidirectional endocannabinoid transport across cell membranes. J Biol Chem 287:34660–34682
McKinney K, Cravatt BF (2005) Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 74:411–432
Fezza F, De Simone C, Amadio D et al (2008) Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system. Subcell Biochem 49:101–132
Tsuboi K, Takezaki N, Ueda N (2007) The N-acylethanolamine-hydrolyzing acid amidase (NAAA). Chem Biodiv 4:1914–1925
Miller MR, Mannowetz N, Iavarone AT et al (2016) Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone. Science 352:555–559
Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356
Rouzer CA, Marnett LJ (2011) Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases, and cytochromes P450: cross-talk between the eicosanoid and endocannabinoid signaling pathways. Chem Rev 111:5899–5921
Van der Stelt M, van Kuik JA, Bari M et al (2002) Oxygenated metabolites of anandamide and 2-arachidonoylglycerol: conformational analysis and interaction with cannabinoid receptors, membrane transporter, and fatty acid amide hydrolase. J Med Chem 45:3709–3720
Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:1871–1875
Snider NT, Walker VJ, Hollenberg PF (2010) Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications. Pharmacol Rev 62:136–154
Maccarrone M, Dainese E, Oddi S (2010) Intracellular trafficking of anandamide: new concepts for signaling. Trends Biochem Sci 35:601–608
Oddi S, Fezza F, Pasquariello N et al (2008) Evidence for the intracellular accumulation of anandamide in adiposomes. Cell Mol Life Sci 65:840–850
Kaczocha M, Vivieca S, Sun J et al (2012) Fatty acid-binding proteins transport N-acylethanolamines to nuclear receptors and are targets of endocannabinoid transport inhibitors. J Biol Chem 287:3415–3424
Mechoulam R, Hanuš LO, Pertwee R et al (2014) Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci 15:757–764
Soltesz I, Alger BE, Kano M et al (2015) Weeding out bad waves: towards selective cannabinoid circuit control in epilepsy. Nat Rev Neurosci 16:264–277
Maccarrone M, Bab I, Bíró T et al (2015) Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 36:277–296
Maccarrone M, Rapino C, Francavilla F, Barbonetti A (2021) Cannabinoid signalling and effects of cannabis on the male reproductive system. Nat Rev Urol 18:19–32
Di Marzo V, De Petrocellis L (2010) Endocannabinoids as regulators of transient receptor potential (TRP) channels: A further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem 17:1430–1449
Zygmunt PM, Ermund A, Movahed P et al (2013) Monoacylglycerols activate TRPV1-a link between phospholipase C and TRPV1. PLoS One 8:e81618
Pistis M, Melis M (2010) From surface to nuclear receptors: the endocannabinoid family extends its assets. Curr Med Chem 17:1450–1467
Ross RA (2009) The enigmatic pharmacology of GPR55. Trends Pharmacol Sci 30:156–163
Im DS (2021) GPR119 and GPR55 as receptors for fatty acid ethanolamides, oleoylethanolamide and palmitoylethanolamide. Int J Mol Sci 22:1034
Acknowledgments
I thank Dr. Filomena Fezza and Monica Bari (Tor Vergata University of Rome, Rome, Italy) for kindly preparing the artwork. This investigation was partly supported by funding from the Italian Ministero dell’Università e della Ricerca (MUR) under a competitive PRIN 2017 grant and from Università degli Studi dell’Aquila under intramural competitive grants “RIA 2021” and “Progetti di Ricerca di Ateneo 2021.”
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Maccarrone, M. (2023). Need for Methods to Investigate Endocannabinoid Signaling. In: Maccarrone, M. (eds) Endocannabinoid Signaling. Methods in Molecular Biology, vol 2576. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2728-0_1
Download citation
DOI: https://doi.org/10.1007/978-1-0716-2728-0_1
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-2727-3
Online ISBN: 978-1-0716-2728-0
eBook Packages: Springer Protocols