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Abstract
BackgroundAnandamide is a lipid neurotransmitter which belongs to a class of molecules termed the endocannabinoids involved in multiple physiological functions. Anandamide is readily taken up into cells, but there is considerable controversy as to the nature of this transport process (passive diffusion through the lipid bilayer vs. involvement of putative proteic transporters). This issue is of major importance since anandamide transport through the plasma membrane is crucial for its biological activity and intracellular degradation. The aim of the present study was to evaluate the involvement of cholesterol in membrane uptake and transport of anandamide.Methodology/Principal FindingsMolecular modeling simulations suggested that anandamide can adopt a shape that is remarkably complementary to cholesterol. Physicochemical studies showed that in the nanomolar concentration range, anandamide strongly interacted with cholesterol monolayers at the air-water interface. The specificity of this interaction was assessed by: i) the lack of activity of structurally related unsaturated fatty acids (oleic acid and arachidonic acid at 50 nM) on cholesterol monolayers, and ii) the weak insertion of anandamide into phosphatidylcholine or sphingomyelin monolayers. In agreement with these data, the presence of cholesterol in reconstituted planar lipid bilayers triggered the stable insertion of anandamide detected as an increase in bilayer capacitance. Kinetics transport studies showed that pure phosphatidylcholine bilayers were weakly permeable to anandamide. The incorporation of cholesterol in phosphatidylcholine bilayers dose-dependently stimulated the translocation of anandamide.Conclusions/SignificanceOur results demonstrate that cholesterol stimulates both the insertion of anandamide into synthetic lipid monolayers and bilayers, and its transport across bilayer membranes. In this respect, we suggest that besides putative anandamide protein-transporters, cholesterol could be an important component of the anandamide transport machinery. Finally, this study provides a mechanistic explanation for the key regulatory activity played by membrane cholesterol in the responsiveness of cells to anandamide.
Highlights
Anandamide is a lipid neurotransmitter belonging to the family of endocannabinoids and involved in the regulation of almost all the physiological functions studied including the nervous, the cardiovascular, the respiratory, or the reproductive systems [1]
When cholesterol was positioned in the vicinity of anandamide, Monte Carlo simulations indicated that both lipids progressively changed their conformation to find a remarkable complementary fit
Since we previously showed that cholesterol interacts with sphingosine [13], it was interesting to compare the anandamide-cholesterol complex with the cholesterol-sphingosine one
Summary
Anandamide (arachidonoylethanolamide) is a lipid neurotransmitter belonging to the family of endocannabinoids and involved in the regulation of almost all the physiological functions studied including the nervous, the cardiovascular, the respiratory, or the reproductive systems [1]. Because of its high lipophilicity together with its amphipathic nature anandamide is generally considered to exert its biological effects in membrane bilayers [4]. In this respect, two scenarios could be proposed. Anandamide is readily taken up into cells, but there is considerable controversy as to the nature of this transport process (passive diffusion through the lipid bilayer vs involvement of putative proteic transporters). This issue is of major importance since anandamide transport through the plasma membrane is crucial for its biological activity and intracellular degradation. The aim of the present study was to evaluate the involvement of cholesterol in membrane uptake and transport of anandamide
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