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Originally published In Press as doi:10.1074/jbc.M011785200 on June 6, 2001

J. Biol. Chem., Vol. 276, Issue 31, 29012-29018, August 3, 2001
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The Uptake Inhibitors Cocaine and Benztropine Differentially Alter the Conformation of the Human Dopamine Transporter*

Maarten E. A. ReithDagger §, Janet L. BerfieldDagger , Lijuan C. WangDagger , Jasmine V. Ferrer, and Jonathan A. Javitch

From the Dagger  Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, Peoria, Illinois 61656 and  Center for Molecular Recognition and Departments of Pharmacology and Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032

The binding affinity of the cocaine analog [3H]2beta -carbomethoxy-3beta -(4-fluorophenyl) tropane (WIN) for the dopamine transporter (DAT) is increased by the reaction of Cys-90, at the extracellular end of the first transmembrane segment, with methanethiosulfonate (MTS) reagents. Cocaine enhances the reaction of Cys-90 with the sulfhydryl reagents, thereby augmenting the increase in binding. In contrast, cocaine decreases the reaction of Cys-135 and Cys-342, endogenous cysteines in cytoplasmic loops, with MTS reagents. Because this reaction inhibits [3H]WIN binding, cocaine protects against the loss of binding caused by reaction of these cysteines. In the present work, we compare the abilities of DAT inhibitors and substrates to affect the reaction of Cys-90, Cys-135, and Cys-342 with MTS ethyltrimethylammonium (MTSET). The results indicate that the different abilities of compounds to protect against the MTSET-induced inhibition of binding are attributable to differences in their abilities to attenuate the inhibitory effects of modification of Cys-135 and Cys-342 as well as to enhance the reaction with Cys-90 and the resulting potentiation of binding. The inhibitor benztropine was unique in its inability to protect Cys-135. Moreover, whereas cocaine, WIN, mazindol, and dopamine enhanced the reaction of Cys-90 with MTSET, benztropine had no effect on this reaction. These two features combine to give benztropine its weak potency in protecting ligand binding to wild-type DAT from MTSET. These results indicate that different inhibitors of DAT, such as cocaine and benztropine, produce different conformational changes in the transporter. There are differences in the psychomotor stimulant-like effects of these compounds, and it is possible that the different behavioral effects of these DAT inhibitors stem from their different molecular actions on DAT.

* This work was supported by National Institute on Drug Abuse Grants DA 08379 (to M. E. A. R.), MH 57324, and DA 11495 (to J. A. J.).The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Dept. of Biomedical and Therapeutic Sciences, College of Medicine University of Illinois, Box 1649, Peoria, IL 61656. Tel.: 309-671-8545; Fax: 309-671-8403; E-mail: MaartenR@uic.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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