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Part I: The Endocannabinoid System, Mechanisms of Action and Functions

Endocannabinoids: biology, mechanism of action and functions

International Journal of Obesity volume 30, pages S4–S6 (2006)Cite this article

The isolation and identification of endogenous cannabinoid ligands (endocannabinoids) as a family of intercellular signaling molecules that act at the same receptors as the plant-derived cannabinoids has significantly changed our understanding of cellular physiology and metabolism. In the early 1990s, two G-protein coupled receptors termed the cannabinoid CB-1 receptor (CB1) and CB-2 receptor (CB2) were isolated and cloned.1 Their widespread distribution in the central and peripheral nervous system (CB1 receptor) and the immune system (CB2 receptor) led to a search, and subsequent identification, for endogenous ligands of these receptors. In 1992, arachidonoylethanolamide (anandamide) was discovered and shown to be a specific receptor agonist for the CB1 receptor (subsequently it was also found to be a CB2 receptor agonist).2 After 3 years, 2-arachidonoylglycerol (2-AG) was shown to be a second endocannabinoid with efficacy at both CB receptors.3, 4 A number of other putative endocannabinoids have now been proposed. Some 10 years after their isolation, the role of endocannabinoids in regulating food intake and energy balance has been widely recognized, leading to the organization of a symposium, whose proceedings are reported in this issue of International Journal of Obesity. Four speakers, whose presentations are summarized in the reviews following this article, covered the biology, physiology and pharmacology of the endocannabinoids and their receptors; focusing on the role of endocannabinoids in energy homeostasis. In this short overview, a perspective on these topics will be provided.

The endocannabinoid family is expanding and now includes both endogenous agonists and a putative endogenous antagonist, virodhamine.5, 6 Unlike most intercellular signaling systems, the endocannabinoids are made on demand. The biosynthetic pathways for their synthesis and subsequent degradation have now been identified and the distribution of these enzymes suggests, at least in parts of the central nervous system, that they represent a class of key regulators that shape synaptic responses over spatially and temporally restricted areas.7 As pointed out by Matias et al. in their article, many of the biosynthetic enzymes, transporters, intracellular binding proteins (if they exist) and degradative systems have still to be fully described in most of the systems, especially in the periphery, in which endocannabinoids are thought to play key roles. The balance between synthesis, reuptake and degradation represents the limiting factor for the duration of action of endocannabinoids. The conditions for activation of endocannabinoid synthesis are not fully established, particularly concerning the plethora of potential cellular mediators, which may enhance or initiate their synthesis through increasing intracellular calcium. Drugs that increase the apparent extracellular concentrations of the endocannabinoids by inhibiting their uptake into cells have been very valuable tools that have helped establish many physiological or pathophysiological actions of endocannabinoids in vitro and in vivo. However, until the endocannabinoid transporters are finally cloned, doubts will remain as to the specificity of action of these drugs, and more importantly the physiology of endocannabinoid release and reuptake. Along similar lines, it is not clear how most of the components of the endocannabinoid system are altered in pathophysiological states, such as obesity. It is established that endocannabinoid levels are altered in genetically obese animals and that leptin regulates endocannabinoid levels by altering the levels of their biosynthetic precursors.8 However, there are numerous short and long term energy regulating factors whose actions on endocannabinoid synthesis and/or release have yet to be studied.

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Acknowledgements

KAS is an Alberta Heritage Foundation for Medical Research Medical Scientist. Thanks to Adam Chambers, Marnie Duncan and Marja van Sickle for their valuable comments.

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  1. Department of Physiology & Biophysics, Institute of Infection, Inflammation and Immunity and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada

    K A Sharkey

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Sharkey, K. Endocannabinoids: biology, mechanism of action and functions. Int J Obes 30 (Suppl 1), S4–S6 (2006). https://doi.org/10.1038/sj.ijo.0803270

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