PMID- 26106364
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150624
LR  - 20200930
IS  - 1664-2295 (Print)
IS  - 1664-2295 (Electronic)
IS  - 1664-2295 (Linking)
VI  - 6
DP  - 2015
TI  - Insights into the Modulation of Dopamine Transporter Function by Amphetamine, 
      Orphenadrine, and Cocaine Binding.
PG  - 134
LID - 10.3389/fneur.2015.00134 [doi]
LID - 134
AB  - Human dopamine (DA) transporter (hDAT) regulates dopaminergic signaling in the 
      central nervous system by maintaining the synaptic concentration of DA at 
      physiological levels, upon reuptake of DA into presynaptic terminals. DA 
      translocation involves the co-transport of two sodium ions and the channeling of 
      a chloride ion, and it is achieved via alternating access between outward-facing 
      (OF) and inward-facing states of DAT. hDAT is a target for addictive drugs, such 
      as cocaine, amphetamine (AMPH), and therapeutic antidepressants. Our recent 
      quantitative systems pharmacology study suggested that orphenadrine (ORPH), an 
      anticholinergic agent and anti-Parkinson drug, might be repurposable as a DAT 
      drug. Previous studies have shown that DAT-substrates like AMPH or -blockers like 
      cocaine modulate the function of DAT in different ways. However, the molecular 
      mechanisms of modulation remained elusive due to the lack of structural data on 
      DAT. The newly resolved DAT structure from Drosophila melanogaster opens the way 
      to a deeper understanding of the mechanism and time evolution of DAT-drug/ligand 
      interactions. Using a combination of homology modeling, docking analysis, 
      molecular dynamics simulations, and molecular biology experiments, we performed a 
      comparative study of the binding properties of DA, AMPH, ORPH, and cocaine and 
      their modulation of hDAT function. Simulations demonstrate that binding DA or 
      AMPH drives a structural transition toward a functional form predisposed to 
      translocate the ligand. In contrast, ORPH appears to inhibit DAT function by 
      arresting it in the OF open conformation. The analysis shows that cocaine and 
      ORPH competitively bind DAT, with the binding pose and affinity dependent on the 
      conformational state of DAT. Further assays show that the effect of ORPH on DAT 
      uptake and endocytosis is comparable to that of cocaine.
FAU - Cheng, Mary Hongying
AU  - Cheng MH
AD  - Department of Computational and Systems Biology, School of Medicine, University 
      of Pittsburgh , Pittsburgh, PA , USA.
FAU - Block, Ethan
AU  - Block E
AD  - Department of Cell Biology, School of Medicine, University of Pittsburgh , 
      Pittsburgh, PA , USA.
FAU - Hu, Feizhuo
AU  - Hu F
AD  - Department of Computational and Systems Biology, School of Medicine, University 
      of Pittsburgh , Pittsburgh, PA , USA ; Department of Pharmacology and 
      Pharmaceutical Sciences, School of Medicine, Tsinghua University , Beijing , 
      China.
FAU - Cobanoglu, Murat Can
AU  - Cobanoglu MC
AD  - Department of Computational and Systems Biology, School of Medicine, University 
      of Pittsburgh , Pittsburgh, PA , USA.
FAU - Sorkin, Alexander
AU  - Sorkin A
AD  - Department of Cell Biology, School of Medicine, University of Pittsburgh , 
      Pittsburgh, PA , USA.
FAU - Bahar, Ivet
AU  - Bahar I
AD  - Department of Computational and Systems Biology, School of Medicine, University 
      of Pittsburgh , Pittsburgh, PA , USA.
LA  - eng
GR  - F32 DA034408/DA/NIDA NIH HHS/United States
GR  - P30 DA035778/DA/NIDA NIH HHS/United States
GR  - P41 GM103712/GM/NIGMS NIH HHS/United States
GR  - R01 DA014204/DA/NIDA NIH HHS/United States
PT  - Journal Article
DEP - 20150609
PL  - Switzerland
TA  - Front Neurol
JT  - Frontiers in neurology
JID - 101546899
PMC - PMC4460958
OTO - NOTNLM
OT  - amphetamine
OT  - drug modulation mechanism
OT  - human dopamine transporter
OT  - orphenadrine cocaine
OT  - repurposable drugs
EDAT- 2015/06/25 06:00
MHDA- 2015/06/25 06:01
PMCR- 2015/06/09
CRDT- 2015/06/25 06:00
PHST- 2014/12/20 00:00 [received]
PHST- 2015/05/26 00:00 [accepted]
PHST- 2015/06/25 06:00 [entrez]
PHST- 2015/06/25 06:00 [pubmed]
PHST- 2015/06/25 06:01 [medline]
PHST- 2015/06/09 00:00 [pmc-release]
AID - 10.3389/fneur.2015.00134 [doi]
PST - epublish
SO  - Front Neurol. 2015 Jun 9;6:134. doi: 10.3389/fneur.2015.00134. eCollection 2015.