(The FASEB Journal. 2007;21:782.9)
© 2007 FASEB
Structure, dynamics, and location of the endocannabinoid 2-AG in lipid bilayers - an NMR and neutron diffraction study
Klaus Gawrisch1,
Nadukkudy V. Eldho2,
Tomohiro Kimura2 and
Mihaela Mihailescu3
1 NIAAA, NIH, 5625 Fishers Ln., Rm. 3N07, Bethesda, MD, 20892,
2 NIAAA, NIH, 5625 Fishers Ln., Bethesda, MD, 20892,
3 Dep. Physiol. Biophys., Univ. California, Med Sci I D346, Irvine, CA, 92697
ABSTRACT
The 2-arachidonoylglycerol (2-AG) is a lipid-derived endocannabinoid that activates cannabinoid receptors in brain and peripheral tissue. It is essentially insoluble in water and readily incorporates into bilayers. This raises the prospect that 2-AG may approach the receptors from the lipid matrix to associate with the ligand binding site located among the seven transmembrane helices. Location of 2-AG in bilayers was determined by solid state NMR experiments and neutron diffraction on lipid bilayers composed of POPC. The 2-AG aligns parallel to the host lipid with its polar end in the lipid-water interface and the arachidonoyl chain in the hydrophobic region. The density distribution of the arachidonyl chain is somewhat higher near the lipid/water interface than in the center of the bilayer. Membrane structure remains mostly unperturbed, even at high concentrations of 2-AG. Molecular order of 2-AG is highest in the polar region, including upper arachidonoyl chain segments, with evidence for a distinct structural motif in the glycerol/carbonyl group. In contrast, the arachidonyl chain is highly flexible, with the C-C bonds from olefin carbons to methylene carbons as the flexible hinges. Correlation times of structural isomerization decrease from a nanosecond near the carbonyl group to 10 ps near the terminal methyl group. The lateral diffusion rate of 2-AG is slightly higher than diffusion of the host lipid. Associations with phospholipids are temporary without evidence for formation of long-lived hydrogen bonds. The lipid-like behavior of the 2-AG and the flexibility of its hydrocarbon chain could be critical for reaching the ligand binding site.
