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ECS Overview—At A Glance

The endocannabinoid system (ECS) is a complex endogenous signaling system that influences multiple metabolic pathways.1 It is comprised of transmembrane endocannabinoid receptors (the cannabinoid [CB] receptors), their endogenous ligands (the endocannabinoids), the proteins involved in endocannabinoid synthesis and inactivation, as well as the intracellular signaling pathways affected by endocannabinoids.2 The first-discovered and best-studied endocannabinoids are AEA (anandamide) and 2-AG (2-arachidonoyl-glycerol).2-4

The CB receptors are part of the superfamily of G protein-coupled receptors.5 The CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain.6 It is also found in a variety of peripheral tissues such as adipose tissue, liver, muscle, the gastrointestinal tract, and pancreas.1, 6, 7 A second endocannabinoid receptor, the CB2 receptor, is expressed in the spleen and tonsils and on immune cells (B-cells, monocytes, T-cells), indicating a role in immune function.8

Activation of CB1 receptors affects several different major signaling pathways.9 In neurons, CB1 receptor stimulation is directly coupled to inhibition of voltage-activated Ca2+ channels9 and mediates many forms of retrograde signaling.10 In peripheral tissues and neurons, activation of CB1 receptors triggers multiple intracellular signal transduction events, including inhibition of adenylate cyclase and stimulation of mitogen-activated protein kinase.6, 9 The type of signaling pathway modulated by CB1 receptor activation appears to depend on the type of agonist under study as well as the tissue or organ involved.9

The ECS-and the CB1 receptor in particular-is believed to regulate energy balance and behaviors such as food intake, fear, and anxiety, and to modulate lipid and glucose metabolism.5, 11-13 The ECS affects energy balance, glucose homeostasis, and lipogenesis.1, 6, 11, 12, 14 In general, stimulation of the ECS (centrally and peripherally) favors metabolic processes that may lead to weight gain, lipogenesis, and impaired glucose homeostasis.14-20 Although less well studied, other functions of the ECS in normal physiology may be related to immune function, neuroprotection, memory and learning, nociception (pain sense), fertility, and bone mass.21-28

There is strong evidence for functional crosstalk between the ECS and other signaling systems. The ECS interacts with Ca2+ and K+ ion channels, as well as other cellular receptors, neuropeptides, hormones, and their intracellular signal-transduction pathways.29 Understanding these interactions may help expand the view of the physiology and pharmacology of the ECS6 and provide a basis for developing innovative therapeutic strategies for the treatment of various diseases.

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References

  1. Cota D, Woods SC. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351.
  2. De Petrocellis L, Cascio MG, Di Marzo V. The endocannabinoid system: a general view and latest additions. Br J Pharmacol. 2004;141:765-774.
  3. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47:345-358.
  4. Matias I, Bisogno T, Di Marzo V. Endogenous cannabinoids in the brain and peripheral tissues: regulation of their levels and control of food intake. Int J Obesity. 2006;30:S7-S12.
  5. Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112:423-431.
  6. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27:73-100.
  7. Juan-Pico P, Fuentes E, Javier Bermudez-Silva F, et al. Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell. Cell Calcium. 2006;39:155-162.
  8. Demuth DG, Molleman A. Cannabinoid signaling. Life Sci. 2006;78:549-563.
  9. Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nature Rev Drug Discov. 2004;3:771-784.
  10. Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;96:678-682.
  11. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548-2556.
  12. Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nature Neurosci. 2005;8:585-589.
  13. Pagotto U, Vicennati V, Pasquali R. The endocannabinoid system and the treatment of obesity. Ann Med. 2005;37:270-275.
  14. Matias I, Gonthier MP, Orlando P, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and {beta}-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006;91:3171-3180.
  15. Poirier B, Bidouard JP, Cadrouvele C, et al. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab. 2005;7:65-72.
  16. Jbilo O, Ravinet Trillou C, Arnone M et al. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J. 2005;19:1567-1569.
  17. Engeli S, Böhnke J, Feldpausch M et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes. 2005;54:2838-2843.
  18. Bensaid M, Gary-Bobo M, Esclangon A et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Molec Pharmacol. 2003;63:908-914.
  19. Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002;136:550-557.
  20. Hao S, Avraham Y, Mechoulam R, Berry EM. Low dose AEA affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur J Pharmacol. 2000;392:147-156.
  21. Correa F, Mestre L, Molina-Holgado E et al. The role of cannabinoid system on immune modulation: therapeutic implications on CNS inflammation. Mini Rev Med Chem. 2005;5:671-675.
  22. van der Stelt M, Trevisani M, Vellani V et al. Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels. EMBO J. 2005;24:3026-3037.
  23. Wang H, Dey SK, Maccarrone M. Jekyll and Hyde: two faces of cannabinoid signaling in male and female fertility. Endocr Rev. 2006;27:427-448.
  24. Idris AI, van 't Hof RJ, Greig IR, et al. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med. 2005;11:774-779.
  25. de Oliveira Alvares L, Genro BP, Vaz Breda R, Pedroso MF, Da Costa JC, Quillfeldt JA. AM251, a selective antagonist of the CB1 receptor, inhibits the induction of long-term potentiation and induces retrograde amnesia in rats. Brain Res. 2006;1075:60-67.
  26. Arenos JD, Musty RE, Bucci DJ. Blockade of cannabinoid CB1 receptors alters contextual learning and memory. Eur J Pharmacol. 2006;539:177-183.
  27. Mikics E, Dombi T, Barsvari B, et al. The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice. Behav Pharmacol. 2006;17:223-230.
  28. Guindon J, De Lean A, Beaulieu P. Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain. Pain. 2006;121:85-93.
  29. Bisogno T, Ligresti A, Di Marzo V. The endocannabinoid signalling system: biochemical aspects. Pharmacol Biochem Behav. 2005;81:224-238.
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