Gain of function mutants reveal sites important for the interaction of the atypical inhibitors benztropine and bupropion with monoamine transporters.

Article Details

Citation

Copy to clipboard

Mortensen OV, Amara SG

Gain of function mutants reveal sites important for the interaction of the atypical inhibitors benztropine and bupropion with monoamine transporters.

J Neurochem. 2006 Sep;98(5):1531-40. doi: 10.1111/j.1471-4159.2006.04060.x.

PubMed ID

16923164 [ View in PubMed

]

Abstract

Two atypical inhibitors of the dopamine transporter, benztropine, used in the treatment of Parkinson's disease, and bupropion, used as an antidepressant, show very different psychostimulant effects when compared with another inhibitor, cocaine. Taking advantage of the differential sensitivity of the dopamine and the norepinephrine transporters (DAT and NET) to benztropine and bupropion, we have used site-directed mutagenesis to produce gain-of-function mutants in NET which demonstrate that Ala279 in the trans-membrane domain 5 (TM5) and Ser359 in the TM7 of DAT are responsible for the higher sensitivity of DAT to both bupropion and benztropine. Substitution of these two DAT residues into the NET background does not alter the potency of NET-selective inhibitors, such as desipramine. The results from experiments examining the ability of DAT-selective inhibitors to displace [3H]nisoxetine binding in NET gain-of-function mutants suggest that Ser359 contributes to the initial binding of the inhibitor, and that Ala279 may influence subsequent steps involved in the blockade of translocation. Thus, these studies begin to identify residues that are important for the unique molecular interactions of benztropine and bupropion with the DAT, and that ultimately may contribute to the distinct behavioral actions of these drugs.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Bupropion	Sodium-dependent dopamine transporter	Protein	Humans	Yes	Inhibitor	Details
Bupropion	Sodium-dependent noradrenaline transporter	Protein	Humans	Yes	Inhibitor	Details