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The Journal of Neuroscience, July 29, 2009, 29(30):9635-9643; doi:10.1523/JNEUROSCI.0440-09.2009

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Cellular/Molecular
Fluoxetine (Prozac) Binding to Serotonin Transporter Is Modulated by Chloride and Conformational Changes

Sotiria Tavoulari,¹ Lucy R. Forrest,² and Gary Rudnick¹

¹Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, and ²Computational Structural Biology Group, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany

Correspondence on general aspects of this paper should be addressed to Dr. Gary Rudnick, Department of Pharmacology, Yale University, P.O. Box 208066, New Haven, CT 06520-8066. Email: gary.rudnick{at}yale.edu

Correspondence relating to computational modeling and docking should be addressed to Dr. Lucy R. Forrest, Max Planck Institute of Biophysics, Max-von-Laue-Strasse 3, 60438 Frankfurt am Main, Germany. Email: lucy.forrest{at}biophys.mpg.de

Serotonin transporter (SERT) is the main target for widely used antidepressant agents. Several of these drugs, including imipramine, citalopram, sertraline, and fluoxetine (Prozac), bound more avidly to SERT in the presence of Cl^–. In contrast, Cl^– did not enhance cocaine or paroxetine binding. A Cl^– binding site recently identified in SERT, and shown to be important for Cl^– dependent transport, was also critical for the Cl^– dependence of antidepressant affinity. Mutation of the residues contributing to this site eliminated the Cl^–-mediated affinity increase for imipramine and fluoxetine. Analysis of ligand docking to a single state of SERT indicated only small differences in the energy of interaction between bound ligands and Cl^–. These differences in interaction energy cannot account for the affinity differences observed for Cl^– dependence. However, fluoxetine binding led to a conformational change, detected by cysteine accessibility experiments, that was qualitatively different from that induced by cocaine or other ligands. Given the known Cl^– requirement for serotonin-induced conformational changes, we propose that Cl^– binding facilitates conformational changes required for optimal binding of fluoxetine and other antidepressant drugs.

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Received Jan. 27, 2009; revised May 20, 2009; accepted June 26, 2009.

Correspondence on general aspects of this paper should be addressed to Dr. Gary Rudnick, Department of Pharmacology, Yale University, P.O. Box 208066, New Haven, CT 06520-8066. Email: gary.rudnick{at}yale.edu

Correspondence relating to computational modeling and docking should be addressed to Dr. Lucy R. Forrest, Max Planck Institute of Biophysics, Max-von-Laue-Strasse 3, 60438 Frankfurt am Main, Germany. Email: lucy.forrest{at}biophys.mpg.de

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