The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors

Tiziana Bisogno, Mauro Maccarrone, Luciano De Petrocellis, Abbas Jarrahian, Alessandro Finazzi-Agrò, Cecilia Hillard, Vincenzo Di Marzo

Research output: Contribution to journalArticle


It is not yet clear if the endocannabinoid 2-arachidonoyl-glycerol (2-AG) is transported into cells through the same membrane transporter mediating the uptake of the other endogenous cannabinoid, anandamide (N-arachidonoyl-ethanolamine, AEA), and whether this process (a) is regulated by cells and (b) limits 2-AG pharmacological actions. We have studied simultaneously the facilitated transport of [14C]AEA and [3H]2-AG into rat C6 glioma cells and found uptake mechanisms with different efficacies but similar affinities for the two compounds (Km 11.0 ± 2.0 and 15.3 ± 3.1 μ, Bmax 1.70 ± 0.30 and 0.24 ± 0.04 nmol·min-1·mg protein-1, respectively). Despite these similar Km values, 2-AG inhibits [14C]AEA uptake by cells at concentrations (Ki ± 30.1 ± 3.9 μ) significantly higher than those required to either 2-AG or AEA to inhibit [3H]2-AG uptake (Ki ± 18.9 ± 1.8 and 20.5 ± 3.2 μ, respectively). Furthermore: (a) if C6 cells are incubated simultaneously with identical concentrations of [14C]AEA and [3H]2-AG, only the uptake of the latter compound is significantly decreased as compared to that observed with [3H]2-AG alone; (b) the uptake of [14C]AEA and [3H]2-AG by cells is inhibited with the same potency by AM404 (Ki ± 7.5 ± 0.7 and 10.2 ± 1.7 μ, respectively) and linvanil (Ki ± 9.5 ± 0.7 and 6.4 ± 1.2 μ, respectively), two inhibitors of the AEA membrane transporter; (c) nitric oxide (NO) donors enhance the uptake of both [14C]AEA and [3H]2-AG, thus suggesting that 2-AG action can be regulated through NO release; (d) AEA and 2-AG induce a weak release of NO that can be blocked by a CB1 cannabinoid receptor antagonist, and significantly enhanced in the presence of AM404 and linvanil, thus suggesting that transport into C6 cells limits the action of both endocannabinoids.

Original languageEnglish
Pages (from-to)1982-1989
Number of pages8
JournalEuropean Journal of Biochemistry
Issue number7
Publication statusPublished - 2001



  • Anandamide
  • Cannabinoid
  • Endocannabinoid
  • Nitric oxide
  • Transporter

ASJC Scopus subject areas

  • Biochemistry

Cite this

Bisogno, T., Maccarrone, M., De Petrocellis, L., Jarrahian, A., Finazzi-Agrò, A., Hillard, C., & Marzo, V. D. (2001). The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors. European Journal of Biochemistry, 268(7), 1982-1989.