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J. Biol. Chem., Vol. 280, Issue 33, 29788-29795, August 19, 2005

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The Conformation, Location, and Dynamic Properties of the Endocannabinoid Ligand Anandamide in a Membrane Bilayer^*

Xiaoyu Tian, Jianxin Guo, Fenmei Yao, De-Ping Yang, and Alexandros Makriyannis¶

From the Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115 and the Department of Physics, College of the Holy Cross, Worcester, Massachusetts 01610

The endogenous cannabinoid ligand anandamide is biosynthesized from membrane phospholipid precursors and is believed to reach its sites of action on the CB1 and CB2 receptors through fast lateral diffusion within the cell membrane. To gain a better insight on the stereochemical features of its association with the cell membrane and its interaction with the cannabinoid receptors, we have studied its conformation, location, and dynamic properties in a dipalmitoylphosphatidylcholine multilamellar model membrane bilayer system. By exploiting the bilayer lattice as an internal three-dimensional reference grid, the conformation and location of anandamide were determined by measuring selected inter- and intramolecular distances between strategically introduced isotopic labels using the rotational echo double resonance (REDOR) NMR method. A molecular model was proposed to represent the structural features of our anandamide/lipid system and was subsequently used in calculating the multispin dephasing curves. Our results demonstrate that anandamide adopts an extended conformation within the membrane with its headgroup at the level of the phospholipid polar group and its terminal methyl group near the bilayer center. Parallel static ²H NMR experiments further confirmed these findings and provided evidence that anandamide experiences dynamic properties similar to those of the membrane phospholipids and produces no perturbation to the bilayer. Our results are congruent with a hypothesis that anandamide approaches its binding site by laterally diffusing within one membrane leaflet in an extended conformation and interacts with a hydrophobic groove formed by helices 3 and 6 of CB1, where its terminal carbon is positioned close to a key cysteine residue in helix 6 leading to receptor activation.

Received for publication, March 16, 2005 , and in revised form, June 9, 2005.

^* This research was supported by Grants DA3801 and DA7251 and Training Grant T32-DA7312 from the National Institute on Drug Abuse. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Center for Drug Discovery, Rm. 116, Mugar Hall, Northeastern University, Boston, MA 02115. Tel.: 617-373-4200; Fax: 617-373-7493; E-mail: a.makriyannis{at}neu.edu.

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