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J. Biol. Chem., Vol. 283, Issue 31, 21478-21486, August 1, 2008

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Modulation of Nicotinic Acetylcholine Receptor Conformational State by Free Fatty Acids and Steroids^*

From the Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur-Conicet, and UNESCO Chair of Biophysics and Molecular Neurobiology, C.C. 857, B8000FWB, Argentina

Steroids and free fatty acids (FFA) are noncompetitive antagonists of the nicotinic acetylcholine receptor (AChR). Their site of action is purportedly located at the lipid-AChR interface, but their exact mechanism of action is still unknown. Here we studied the effect of structurally different FFA and steroids on the conformational equilibrium of the AChR in Torpedo californica receptor-rich membranes. We took advantage of the higher affinity of the fluorescent AChR open channel blocker, crystal violet, for the desensitized state than for the resting state. Increasing concentrations of steroids and FFA decreased the K_D of crystal violet in the absence of agonist; however, only cis-unsaturated FFA caused an increase in K_D in the presence of agonist. This latter effect was also observed with treatments that caused the opposite effects on membrane polarity, such as phospholipase A₂ treatment or temperature increase (decreasing or increasing membrane polarity, respectively). Quenching by spin-labeled fatty acids of pyrene-labeled AChR reconstituted into model membranes, with the label located at the M4 transmembrane segment, disclosed the occurrence of conformational changes induced by steroids and cis-unsaturated FFA. The present work is a step forward in understanding the mechanism of action of this type of molecules, suggesting that the direct contact between exogenous lipids and the AChR transmembrane segments removes the AChR from its resting state and that membrane polarity modulates the AChR activation equilibrium by an independent mechanism.

Received for publication, January 14, 2008 , and in revised form, April 23, 2008.

^* This work was supported in part by grants from The Academy of Sciences for the Developing World and the Agencia Nacional de Promoción Científica (to S. S. A.) and from the Universidad Nacional del Sur, the Consejo Nacional de Investigaciones Científicas y Técnicas, and the Agencia Nacional de Promoción Científica (to F. J. B.). 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 a supplemental figure.

¹ To whom correspondence should be addressed. Tel.: 54-291-4861201; Fax: 54-291-4861200; E-mail: silviant{at}criba.edu.ar.

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