Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb as an Allosteric Modulator of the Human Dopamine Transporter

被引:8
|
作者
Aggarwal, Shaili [1 ]
Cheng, Mary Hongying [2 ]
Salvino, Joseph M. [3 ]
Bahar, Ivet [2 ]
Mortensen, Ole Valente [1 ]
机构
[1] Drexel Univ, Coll Med, Dept Physiol & Pharmacol, Philadelphia, PA 19102 USA
[2] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA
[3] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA
关键词
dopamine transporter; allosteric modulation; transport activity; X-RAY STRUCTURES; SEROTONIN TRANSPORTER; BACTERIAL HOMOLOG; NEUROTRANSMITTER; INHIBITOR; MECHANISM; BINDING; ANTIDEPRESSANTS; LEUT; IDENTIFICATION;
D O I
10.3390/biomedicines9060634
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The dopamine transporter (DAT) serves a critical role in controlling dopamine (DA)-mediated neurotransmission by regulating the clearance of DA from the synapse and extrasynaptic regions and thereby modulating DA action at postsynaptic DA receptors. Major drugs of abuse such as amphetamine and cocaine interact with DATs to alter their actions resulting in an enhancement in extracellular DA concentrations. We previously identified a novel allosteric site in the DAT and the related human serotonin transporter that lies outside the central orthosteric substrate- and cocaine-binding pocket. Here, we demonstrate that the dopaminergic psychostimulant sydnocarb is a ligand of this novel allosteric site. We identified the molecular determinants of the interaction between sydnocarb and DAT at the allosteric site using molecular dynamics simulations. Biochemical-substituted cysteine scanning accessibility experiments have supported the computational predictions by demonstrating the occurrence of specific interactions between sydnocarb and amino acids within the allosteric site. Functional dopamine uptake studies have further shown that sydnocarb is a noncompetitive inhibitor of DAT in accord with the involvement of a site different from the orthosteric site in binding this psychostimulant. Finally, DA uptake studies also demonstrate that sydnocarb affects the interaction of DAT with both cocaine and amphetamine. In summary, these studies further strengthen the prospect that allosteric modulation of DAT activity could have therapeutic potential.
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页数:15
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