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J. Biol. Chem., Vol. 283, Issue 12, 7813-7822, March 21, 2008

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Location and Orientation of Serotonin Receptor 1a Agonists in Model and Complex Lipid Membranes^*

Jakob J. Lopez and Mark Lorch, Supported by a Research Councils UK academic fellowship¹

From the Department of Chemistry, University of Hull, Hull, HU6 7RX, United Kingdom and the Institute for Biophysical Chemistry, J. W. Goethe University Frankfurt, 60438 Frankfurt, Germany

Magic angle spinning (MAS) NMR has been used to investigate the location and orientation of five serotonin receptor 1a agonists (serotonin, buspirone, quipazine, 8-OH-DPAT, and LY-163,165) in single component model lipid and brain lipid membranes. The agonist locations are probed by monitoring changes in the lipid proton chemical shifts and by MAS-assisted nuclear Overhauser enhancement spectroscopy, which indicates the orientation of the agonists with respect to the 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids. In the single component bilayer, the membrane agonists are found predominantly in the top of the hydrophobic chain or in the glycerol region of the membrane. Most of the agonists orient approximately parallel to the membrane plane, with the exception of quipazine, whose piperazine ring is found in the glycerol region, whereas its benzene ring is located within the lipid hydrophobic chain. The location of the agonist in brain lipid membranes is similar to the 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayers; however, many of the agonists appear to locate close to the cholesterol in the membrane in preference to the phospholipids.

Received for publication, September 6, 2007 , and in revised form, January 2, 2008.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed. Tel.: 44-1482-465687; E-mail: M.Lorch{at}hull.ac.uk.

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