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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Identification of a Novel Allosteric Modulator of the Human Dopamine Transporter
ACS chemical neuroscience, v 10(8), pp 3718-3730
24 Jun 2019
PMID: 31184115
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The dopamine transporter (DAT) serves a pivotal role in controlling dopamine (DA)-mediated neurotransmission by clearing DA from synaptic and perisynaptic spaces and controlling its action at postsynaptic DA receptors. Major drugs of abuse such as amphetamine and cocaine interact with DAT to mediate their effects by enhancing extracellular DA concentrations. We previously identified a novel allosteric site in the related human serotonin transporter that lies outside the central substrate and inhibitor binding pocket. We used the hybrid structure based (HSB) method to screen for allosteric modulator molecules that target a similar site in DAT. We identified a compound, KM822, that was found to be a selective, noncompetitive inhibitor of DAT. We confirmed the structural determinants of KM822 allosteric binding within the allosteric site by structure/function and substituted cysteine scanning accessibility biotinylation experiments. In the in vitro cell-based assay and ex vivo in both rat striatal synaptosomal and slice preparations, KM822 was found to decrease the affinity of cocaine for DAT. The in vivo effects of KM822 on cocaine were tested on psychostimulant-associated behaviors in a planarian model where KM822 specifically inhibited the locomotion elicited by DAT-interacting stimulants amphetamine and cocaine. Overall, KM822 provides a unique opportunity as a molecular probe to examine allosteric modulation of DAT function.
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Details
- Title
- Identification of a Novel Allosteric Modulator of the Human Dopamine Transporter
- Creators
- Shaili Aggarwal - Drexel UniversityXiaonan Liu - Drexel UniversityCaitlyn Rice - Drexel UniversityPaul Menell - Drexel UniversityPhilip J. Clark - Drexel UniversityNicholas Paparoidamis - The Wistar InstituteYou-cai Xiao - The Wistar InstituteJoseph M. Salvino - The Wistar InstituteAndréia C. K. Fontana - Drexel UniversityRodrigo A. España - Drexel UniversitySandhya Kortagere - Drexel UniversityOle V. Mortensen - Drexel University
- Publication Details
- ACS chemical neuroscience, v 10(8), pp 3718-3730
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Neurobiology and Anatomy; Pharmacology and Physiology; Chemistry
- Web of Science ID
- WOS:000482546100041
- Scopus ID
- 2-s2.0-85068480902
- Other Identifier
- 991019167780904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal
- Neurosciences